カテゴリ: 韓国精神疾患

英語でtranscription factors、日本語では転写因子と呼ばれているエピジェネティクスの根幹ともいえる遺伝子の発現を制御する遺伝子リストが、下記英文ウキペディアに掲載されている。出所は2018年2月に出された論文である。転写制御遺伝子リストととでも呼べよう。

List of human transcription factors

このリストとFDA論文が抽出した韓国人ども固有の変異リストが共通する遺伝子名リストを作成し、アップロードしておいた。ただし、ブラウザがクロムではエクセル形式では表示不可となるが、保存用tとする

https://www.hpcreating.com/php/blog/kakikomi/korea/transcription.xlsx

①驚くべきことに、上記の転写因子遺伝子リスト掲載の1639遺伝子について、韓国人ども固有の変異リストとの対比から、1639中の1595について韓国人どもは固有の変異を有している。即ち、韓国人どもは、DNA塩基配列に固有の変異を有しているのは勿論のこと、その遺伝子の発現を制御する遺伝子についてさえも、97.3%もの遺伝子について固有の変異を有していることになる。いつものことながら、韓国人どものDNAの異常性を真に痛感せざるを得ない。彼らはまさしくバケモノである

②しかし、SNV-1が300以上の遺伝子に限ると、CAMTA1、NPAS3の二つの転写因子遺伝子のみである。

CAMTA1についてのNCBIをそのままコピペ。下のグラフでは頭脳との関連を示している

Summary
The protein encoded by this gene contains a CG1 DNA-binding domain, a transcription factor immunoglobulin domain, ankyrin repeats, and calmodulin-binding IQ motifs.

The encoded protein is thought to be a transcription factor and may be a tumor suppressor.

However, a translocation event is sometimes observed between this gene and the WWTR1 gene, with the resulting WWTR1-CAMTA1 oncoprotein leading to epithelioid hemangioendothelioma, a malignant vascular cancer. [provided by RefSeq, Mar 2017]

NPAS3についてのNCBIをそのままコピペ。下のグラフでは頭脳との関連を明確に示している
This gene encodes a member of the basic helix-loop-helix and PAS domain-containing family of transcription factors.

The encoded protein is localized to the nucleus and may regulate genes involved in neurogenesis.
Chromosomal abnormalities that affect the coding potential of this gene are associated with schizophrenia and cognitive disability.

Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

③転写因子遺伝子について、目立つのはZNF遺伝子ファミリーの多さである。韓国人どもはZNF285CP=ZNF806について、SNV-35を大量に共有しており、NCBIでは転写因子関連遺伝子


脳内不安物質
不安・恐怖症を起こす脳内物質を探る
貝谷久宜
講談社ブルーバックス
1997年

セロトニンの受容体は、5-HT1受容体から5-HT7受容体を基本区分として、下位サブタイプに区分される。5-HT1A/Bは、ヒトの攻撃性と関連しているとされる

韓国人という完全な精神面でのDNA異常民族がセロトニンの受容体1Aの多型分布が中国人・日本人・西欧人と異なることは既にメインブログで書いている。

同様にセロトニンの受容体1Bについても同じであろうが、下記ネイチャー掲載論文がある。
Substance Abuse Disorder and Major Depression are Associated with the Human 5-HT1B Receptor Gene (HTR1B) G861C Polymorphism


p22
DSM-Ⅳによれば、不安障害はパニック障害、全般性不安障害、社会恐怖、単一恐怖、強迫性障害、心的外傷後ストレス障害(PTSD)、̚非定形性不安障害に分類されます

p36
パニック障害は現在では100人に約3人の割合で見られる病気で

第二章 不安と恐怖は身体症状に現れる

第三章 不安と恐怖を引き起こす脳内物質
p54 ノルアドレナリン
p56
ノルアドレナリンという興奮性の神経伝達物質

p61 セロトニン
p63
セロトニンの受容体は現在解っているだけで十数種類あって、セロトニンにより神経細胞内の反応をㇷ゚ラス方向にもっていくものとマイナス方向に持っていくものとにわかれます

p65 GABA ギャバ
GABA(ガンマアミノ酪酸)は
抑制性の神経伝達物質です
A/B二種類の受容体があり
不安に関係するのはA受容体で

p72
乳酸がパニック障害を引き起こす原因の一つであることが明らかになっています

p74
カフェイン

p81
コレチストキニン
このホルモンは
神経伝達物質に関係していることが明らかとなっています

伊藤博文と韓国併合
海野福寿
2004年
青木書店

著者は43歳から定年まで明治大学教授であった。この著作から見て、どこをどう見ても、精神疾患レベルの頭のいかれた者である。ちなみに、P135辺りには、伊藤博文暗殺について、別犯人説を唱えている。著者が、通名使用の在日コリアン又は国籍が日本でDNAが朝鮮人であることは100%確実である。青木書店も落ちたもんだ!数えたことはないが本棚には、最低でも100冊以上、青木書店・大月書店が出版した書籍があるが、精神疾患レベルの内容であり、この本の青木書店担当者は中身を読んでないのであろう。


p31
日露戦争下の韓国
この人物は、1年ほど韓国で研究生活をしている。表現の問題の過ぎないが、当時韓国など存在していないからして、まさに精神疾患レベルである。

p45
保護条約は韓国を保護するかーー第二次日韓協約
【章タイトルである。どうも韓国では、この手の漫画的内容が歴史であるようだ。当時韓国など存在していない

The Impact of Personality Traits and Acculturation on the Mental Health of Korean American Adolescents
Minjeong Kim et.al
2016

ABSTRACT

138 Korean American adolescents completed a demographic questionnaire, the revised Stephenson Multigroup Acculturation Scale, the NEO Five-Factor Inventory-3, and Achenbach & Rescorla’s Youth Self Report. 

1. Introduction

2. Methods

The sample included Korean American adolescents who were recruited from Korean churches, Korean language schools, Korean shopping malls and restaurants, mental health centers serving Asian and Pacific Islander communities, and websites for the Korean community in California.


3. Results

The sample included 138 adolescents. 57 participants (41%) were males and 81 were females (59%). The mean age of the participants was 14.43 years (10 - 19 years, SD = 2.09). 

Their length of residence in the US ranged from less than 1 to 18 years, with a mean score of 12.36 years (SD = 4.14).

About 61% of the participants reported that “their family had enough money but no extra”, and 36% reported that “they had more money than they need”.

Means and correlations for study variables with continuous scores are shown in Table 1

Table 1. Means and correlations for age, length of time in the US, acculturation, personality traits, and total mental health problems.

 Length of residence in the US was the only demographic variable that was significantly correlated with mental health problems. 



Table 2. Effects of time in the US, acculturation, and personality traits on mental health problems.
presents findings for Aim 1.
Although length of residence in the US was correlated with mental health in the bivariate analysis, it was not a significant predictor when scores for acculturation and all personality traits were entered in the second step. Consistent with preliminary bivariate correlations, only the 2 personality traits of neuroticism and agreeableness were significant predictors of mental health problems for the adolescents. Neuroticism (β = .63, p < .001) was positively associated with mental health problems, while agreeableness (β = −.18, p < .01) was negatively associated with mental health problems. The total model explained 52.6% of the variance in mental health problems (F (7, 115) = 18.24, p < .001).


DISC1–ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1T Soda et.al
Naturre 16 April 2013

①DISC1(=タンパク質)遺伝子ファミリーについて精神面での完全なDNA異常民族である韓国人どもは、やはり、固有の変異を大量に有している。
DISC1FP1=251
DISC1=144
DISC1-1T1=7
合計402
②DISC1(=タンパク質)遺伝子と統合失調症の関係はスコットランド人で初めて分かったことを知った。韓国人どもの表現型としての統合失調症の生涯発病率は、中国人・日本人と大きさが無いことは確実である。しかし、同時に韓国人どもが精神面で集団として見た場合正常な連中ではないことも、63もの国際的な科学関連賞受賞者が誰一人としていないというデータから見て確実である。
③従って、韓国人どもは精神面で特殊な表現型を有しているはずである。例えば、集団特性としての激怒、一切の反省を行わない、客観データを無視する等々である。メカニズムを知りたくて読んだだが、ハッキリしない
④分析手法はマウス実験である




Abstract

Disrupted-In-Schizophrenia 1 (DISC1), a risk factor for major mental illnesses, has been studied extensively in the context of neurodevelopment. 

However, the role of DISC1 in neuronal signaling, particularly in conjunction with intracellular cascades that occur in response to dopamine, a neurotransmitter implicated in numerous psychiatric disorders, remains elusive.

In this study, we identify a novel DISC1 and ATF4 binding region in the genomic locus of phosphodiesterase 4D (PDE4D), a gene implicated in psychiatric disorders. 

We found that the loss of function of either DISC1 or ATF4 increases PDE4D9 transcription, and that the association of DISC1 with the PDE4D9 locus requires ATF4. We also show that PDE4D9 is increased by D1-type dopamine receptor dopaminergic stimulation

We demonstrate that the mechanism for this increase is due to DISC1 dissociation from the PDE4D locus in mouse brain. 

Our results suggest that the release of DISC1-mediated transcriptional repression of PDE4D9 acts as feedback inhibition to regulate dopaminergic signaling.

Introduction

After the initial report on Disrupted-In-Schizophrenia 1 (DISC1) in a large Scottish pedigree,1 the significance of this gene has been extensively studied in human genetics and neurobiology.23 

 Although the involvement of this gene in any specific psychiatric illness categorized by current diagnostic manuals has been debated,4 DISC1 mediates many aspects of neurodevelopment and cellular signaling relevant to neuropsychiatric disorders.

Studies utilizing various mouse models have implicated DISC1 as an important regulator of brain development with roles in neurogenesis,56 progenitor proliferation57 and changes in dendritic arborization, migration as well as the integration of cortical and hippocampal neurons.8910111213



There are four PDE4 genes that constitute this family of phosphodiesterases. Each of these four genes encodes an isoform, and each isoform has a number of variants, each distinguished by their unique N-terminal regions.

In this study, we investigated the role of ATF4 and DISC1 in transcriptional repression and how this functional interaction impacts dopaminergic signaling. 

We find that ATF4 and DISC1 act together in a transcriptional repressor complex to regulate specifically the transcription of PDE4D9, 1 of 11 known PDE4D variants.40 PDE4D9 is a long variant of PDE4D that is phosphorylated and regulated by protein kinase A (PKA) and MAPKAPK2,4041 for further details refer to Lynex et al.42 

We further demonstrate that this repressor activity is decreased by dopamine via GαsSig, which activates PKA and promotes the phosphorylation of DISC1 at S58. 

Our findings illustrate that the DISC1–ATF4 interaction regulates a transcriptional feedback loop that responds to, and modulates, dopaminergic neurotransmission and provide mechanistic insights into how the perturbation of this complex may lead to aberrant signaling that may manifest as symptomatology associated with various psychiatric illnesses.

Materials and methods

Mice

C57/Bl6J (C57) mice were obtained from The Jackson Laboratory (Bar Harbor, ME, USA).

Results

DISC1 binds to the PDE4D gene locus in an ATF4-dependent manner

Given that DISC1 regulates ATF4 transcriptional activity in vitro36 and lacks a DNA-binding domain, we hypothesized that DISC1 associated with the PDE4D gene locus in an ATF4-dependent manner.

These data indicate that the association of DISC1 to the PDE4D locus requires the presence of ATF4.

Pharmacological rescue in patient iPSC and mouse models with a rare DISC1 mutation
Nam-Shik Kim
Nature 03 March 2021

韓国人どもという精神面では遺伝的に見た場合、「完全なバケモノ連中」に関して、特定の遺伝子ファミリーではあるが、決定的な証拠を示す論文を得た

FDA論文で抽出された「完全なDNAバケモノ連中」に関する固有の遺伝子リストからPDE4遺伝子ファミリーの変異数

①SNV-1=2089 合計2089もある。
PRIM2遺伝子を除けば事実上バケモノどもで固有の変異が最も多くかつ確実にヒトの精神に関連している
②SNV-1/ns=15
③SNV-35=138
④SNV-35ns=15
嗅覚に関連するOR4C遺伝子ファミリーについで多い。精神面での完全なバケモノどもをバケモノにしている遺伝子ファミリーである。以前から気づいてはいたがやっと決定的なnature掲載論文が見つかった。集団としてのバケモノどもは、地理的孤立性が幸いし半島に7000万以上生息し、日本にも100万近く生息している。

集団内での精神面での完全なバケモノ比率を8%程度と見積もった場合(=他の連中は概ね表現型としては正常、ただしヘテロ接合の故、発現していないだけであると推測される。セロトニン受容体で実例がある)、半島で560万、日本で8万人となる。金九が精神面でのバケモノの典型例であり、李承晩・李明博等々無数のバケモノたちの顔が浮かんでくる。特に、李明博は、無関係かもしれないが、韓国人男性どもにしかいない顔つきでであり、日本にもほぼ完全に同じ顔をした有名な人物がいる

PDE4DIP 遺伝子
*SNV-35/ns=3
この遺伝子変異は、SNV-35/ns中で最も多い。バケモノどものサンプル35名全員が有している非同義変異である
*SNV-35=138
*SNV-1=1374
*SNV-1/ns=14

PDE4D遺伝子
*SNV-1=503
*SNV-35=1
*SNV-1/ns=1

PDE4B遺伝子
*SNV-1=180

PDE4A遺伝子
*SNV-1=17

PDE4A遺伝子
*SNV-1=15


Abstract

We previously identified a causal link between a rare patient mutation in DISC1 (disrupted-in-schizophrenia 1) and synaptic deficits in cortical neurons differentiated from isogenic patient-derived induced pluripotent stem cells (iPSCs).

 Here we find that transcripts related to phosphodiesterase 4 (PDE4) signaling are significantly elevated in human cortical neurons differentiated from iPSCs with the DISC1 mutation and that inhibition of PDE4 or activation of the cAMP signaling pathway functionally rescues synaptic deficits.

 Heterozygous Disc1 mutant mice exhibit elevated levels of PDE4s and synaptic abnormalities in the brain,and social and cognitive behavioral deficits. 

Pharmacological inhibition of the PDE4 signaling pathway rescues these synaptic, social and cognitive behavioral abnormalities. 

Results

Elevated expression of PDE4 family genes in DISC1 mutant human cortical neurons

Previous RNA-seq analyses of forebrain cortical neurons differentiated from a schizophrenia patient iPSC line with the 4-bp deletion in DISC1 gene (D2 line, Pedigree H; Supplementary Fig. 1a) revealed significant upregulation of multiple transcripts related to the PDE4 family, including PDE4A, 4C, and PDE4DIP (PDE4D interacting protein)14,16, when compared to neurons from a family control iPSC line without the DISC1 mutation (C3, Pedigree H) (Fig. 1a).

14は下記論文
Synaptic dysregulation in a human iPS cell model of mental disorders.
16は下記論文
A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder.

 Furthermore, the dysregulated expression pattern of PDE4 family members, including many isoforms of PDE4A, PDE4B, PDE4C, and PDE4D, was observed in the isogenic DISC1 mutation line engineered from the C3 line (C3-M), whereas the isogenic correction line from the D3 mutant line (D3-R) exhibited similar expression levels to control lines14 (Fig. 1a and Supplementary Fig. 1b), indicating that the DISC1 mutation is causal for elevated expression of these genes.

The protein expression levels of PDE4A, PDE4B, and PDE4C showed corresponding changes to transcripts in neurons from different iPSC lines (Supplementary Fig. 1c–d).

Fig. 1: Mechanism-guided pharmacological rescue of synaptic defects of human neurons carrying the DISC1 mutation.
figure 1

a Summary of q-PCR validation of RNA-seq results of increased mRNA levels of PDE4A, PDE4C, and PDE4DIP in human forebrain neurons carrying the DISC1 mutation (D2 and D3: neurons derived from patient iPSC lines with DISC1 mutation; C1 and C3: neurons derived from control iPSC lines; C3-M: neurons derived from an isogenic knock-in DISC1 mutant line under the background of the C3 control iPSC line; D3-R: neurons derived from an isogenic DISC1 mutant correction line under the background of the D3 patient iPSC line). Values represent mean ± s.d. (n = 3 independent differentiation cultures for qPCR analysis; comparison to C3 using One-way ANOVA with p values indicated). b Effects on the density of SV2+ synaptic puncta in 6-week old forebrain neurons upon treatment with different small molecules. NCGC00071192: 2 µM; NCGC00067819: 2 µM; NCGC00067541: 2 µM; NCGC00071837: 2 µM; NCGC00015985: 10 µM; NCGC00065586: 10 µM; NCGC00030627: 20 µM; NCGC00024862: 20 µM; NCGC00070528: 10 µM; Rolipram: 100 nM. Values represent mean ± s.e.m. (n = 3 independent differentiation cultures; comparison to C1 using One-way ANOVA with p values indicated). cd Representative confocal images of 4-week old neurons from different iPSC lines immunostained with SV2 and DCX upon vehicle (DMSO) or Rolipram (100 nM) treatment. Scale bar, 20 μm (c). Also shown is the quantification of SV2+ puncta density in neurons derived from different iPSC lines with or without Rolipram treatment (d). Values represent mean ± s.e.m. (n = 4 independent differentiation cultures; One-way ANOVA with p values indicated). ef Representative confocal images of 4-week old neurons co-cultured with astrocytes from different iPSC lines immunostained with SV2, PSD95, and MAP2 upon vehicle (DMSO) or Rolipram (100 nM) treatment. Scale bar, 20 μm (e). Also shown is the quantification of SV2+PSD95+ puncta density in neurons derived from different iPSC lines with or without Rolipram treatment (f). Values represent mean ± s.e.m. (n = 3 independent differentiation cultures; One-way ANOVA with p values indicated). Source data are provided as a Source Data file.

Rescue of synaptic deficits of DISC1 mutant neurons by PDE4 inhibition


These results suggest that dysregulation of the PDE pathway might represent a common pathological molecular signature in human neurons derived from patients with schizophrenia and other major mental disorders and could be a potential target for drug development. 

Increased PDE4 expression and synaptic deficits in the adult brain of humanized Disc1 mutant mice

To complement our in vitro patient iPSC model with an in vivo model for behavioral analyses, we generated a humanized mouse model by knocking in the 4-bp deletion in the Disc1 gene at the same position of exon 12 as identified in mental disorder patients (Supplementary Fig. 4a).


Discussion

Although it is controversial whether DISC1 is a general risk gene for schizophrenia, rare DISC1 mutations with high penetrance in specific pedigrees that are linked to schizophrenia and other major mental disorders nevertheless provide an opportunity to understand the molecular and cellular mechanisms underlying disease pathophysiology that may be shared with other genetic risk profiles.

The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

Daniel E. Vosberg et. al

Nature 28 October 2019



①韓国人どもは、DCC遺伝子について SNV-1を467有している
②DCC遺伝子については、他にも多数ヒトの精神と関連する論文が出ている
③この論文はメインブログに記載済みである


Abstract

Axon guidance molecules direct growing axons toward their targets, assembling the intricate wiring of the nervous system.

One of these molecules, Netrin-1, and its receptor, DCC (deleted in colorectal cancer), has profound effects, in laboratory animals, on the adolescent expansion of mesocorticolimbic pathways, particularly dopamine.

Now, a rapidly growing literature suggests that
(1) these same alterations could occur in humans,
and
(2) genetic variants in 
Netrin-1 and DCC are associated with depression, schizophrenia, and substance use.

Together, these findings provide compelling evidence that Netrin-1 and DCC influence mesocorticolimbic-related psychopathological states that emerge during adolescence.

Fig. 1


figure 1


Human genetic investigations of DCC
Schizophrenia

Several studies have linked DCC polymorphisms with schizophrenia.

In a candidate gene study, comprising 556 schizophrenia patients and 208 healthy controls, a SNP (rs2270954) in DCC was found to be nominally associated with schizophrenia. 

A second candidate gene study of 454 patients with schizophrenia and 486 healthy controls reported a nominal association with a DCC SNP (rs2229080) on exon 3 [56]. 

Depression

Over the past six years, there has been rapidly accumulating evidence that both genetic variants and other factors that alter DCC expression also affect susceptibility to mood dysregulation and suicide.


DCC haploinsufficiency: personality traits and drug-related behaviors

While GWAS studies typically detect relatively subtle effects of DCC polymorphisms [77], loss-of-function haploinsufficient DCC mutation carriers were expected to exhibit larger effects, detectable with smaller sample sizes. 

DCC haploinsufficiency: dopamine mesocorticolimbic connectivity

The associations between DCC and psychiatric disorders might be a consequence of DCC-related alterations to mesocorticolimbic pathways.

Striatal brain volume

We recently reported that both DCC haploinsufficient humans and mice exhibit reduced striatal volumes.

Cortical volume

The DCC haploinsufficient Quebecers also demonstrate modest volumetric increases in two cortical regions: the mPFC/anterior cingulate cortex and the ventral mPFC [79]. In comparison, among human carriers of another DCC mutation, a completely different phenotype is observed, such that there is a complete absence of the cingulate gyrus [98].

Table 1 Summary of human genetic studies of DCC and Netrin-1

From: The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

References

Genetic approach

Gene

Sample size

Ancestry

Phenotype

Mood disorders

Manitt et al. [60]

mRNA expression

DCC mRNA

30 cases, 35 controls

Not available

Depressed suicide completers

Dunn et al. [64]

Genome-wide association study (GWAS)

DCC gene

3138

Hispanic

Depression

Okbay et al. [65]

GWAS

DCC gene

161,460

European

Depression

Smith et al. [75]

Meta-GWAS

Netrin-1

91,370, replication samples: (6659, 8687)

White, United Kingdom

Neuroticism

Torres-Berrío et al. [54]

mRNA expression

DCC mRNA

11 cases, 12 controls

Not available

Depressed suicide completers

Zeng et al. [66]

Pathway analysis, multilevel regional heritability, and polygenic risk score

Netrin-1 signaling pathway

25,214

European

Depression

Aberg et al. [62]

Methylome-wide association study (MWAS)

DCC methylation sites

812 cases, 320 controls

European

Depression

Leday et al. [61]

Genome-wide gene expression

DCC mRNA

207 cases, 157 controls

Caucasion

Depression

Roberson-Nay et al. [74]

Genome-wide methylation study

Netrin-1

150 monozygotic twin pairs

Caucasion

Depression

Wray et al. [69]

GWAS

DCC gene

135,458 cases, 344,901 controls

European

Depression

Arnau-Soler et al. [67]

Gene-based test

DCC gene

99,057

White, United Kingdom

Depression

Barbu et al. [72]

Polygenic risk score

Netrin-1 signaling pathway

~6400

Not available

Depression

Lee et al. [76]

Meta-GWAS

DCC gene

232,964 cases, 494,162 controls

European

Cross-disorder

Strawbridge et al. [69]

Gene-based test

DCC gene

122,935

White, United Kingdom

Suicidality

Ward et al. [73]

Meta-GWAS, polygenic score, genetic correlations

DCC gene

375,275

European

Anhedonia

Personality traits and substance use

Khadka et al. [85]

Parallel independent component analysis

DCC gene

426

Caucasion, African-American, Hispanic, other

Impulsivity

Zanetti et al. [84]

GWAS

DCC gene

5339, replication: 1662

African-American

Cigarette smoking

Ward et al. [71]

GWAS

DCC gene

53,525 cases, 60,443 controls

White, United Kingdom

Mood Instability

Vosberg et al. [79]

Rare mutation cohort

DCC gene

20 cases, 36 controls

Caucasion French Canadian (cases)

Novelty seeking & tobacco use

Kichaev et al. [83]

GWAS

DCC gene

n ~ 458,000

European

Cigarette smoking

Lee et al. [76]

Meta-GWAS

DCC gene

232,964 cases, 494,162 controls

European

Cross-disorder

Linnér et al. [82]

Meta-GWAS

DCC gene

n = 518,633

European

Cigarette smoking

Schizophrenia and psychosis

Grant et al. [53]

Candidate gene

DCC gene

556 cases, 208 controls

African American, Asian, Caucasion

Schizophrenia

Yan et al. [56]

Candidate gene

DCC gene

454 cases, 486 controls

Han Chinese

Schizophrenia

Okayama et al. [59]

Next-generation sequencing

DCC gene

3 cases

Japanese

Atypical psychosis

Smeland et al. [58]

GWAS

DCC gene

82,315

European, East Asian

Schizophrenia

Lee et al. [76]

Meta-GWAS

DCC gene

232,964 cases, 494,162 controls

European

Cross-disorder

Neurobiology

Hibar et al. [89]

GWAS

DCC gene

30,717

European

Putamen Volume

Elliot et al. [90]

GWAS

DCC gene

9707

White, United Kingdom

Putamen Volume

Luo et al. [92]

Polygenic risk score

Schizophrenia-associated genes including DCC

Discovery (n = 905); replication (n = 166)

Han Chinese

Putamen, thalamus, temporal gyrus volumes; mPFC rs-fMRI activity; working-memory

Smeland et al. [58]

GWAS

DCC gene

11,598

European

Putamen volume

Vosberg et al. [79]

Rare mutation cohort

DCC gene

20 cases, 36 controls

Caucasion French Canadian (cases)

Mesocorticolimbic anatomical connectivity & putamen volume

Barbu et al. [72]

Polygenic risk score

Netrin-1 signaling pathway

~6400

Not available

Thalamic raditions, white matter integrity


Genetic association of impulsivity in young adults: a multivariate study

S Khadka et.al

30 September 2014

この論文で抽出された衝動性との関連遺伝子リストは次のとおり。
論文抜粋メモは省略する

Gene

TNXB=0

C2=0

RDBP=0

CHST11=108

HLAB=0

HLAC =0

CFB=0

NOTCH4 =0

HLADRA 0

MICA=0

HLADMB =0

DCC =467

PIGT=9

CTNNA2 =553

HLADQA2 

SULT2B1=0

CTBP2 =70, SNV-35が1

PRKG1 =417, SNV-35が1

CSNK2B =0

RORA =0

 


Gene

CYP19A1 =47

ATP6V0A4 =0

PDE1C=176

PRKG1 =417, SNV-35が1

RYR3 =219, 2

CTNNA3=605 SNV-35が1

PPP2R2A=33

ABCG2=48SNV-35が1

PRKCA =195

CHST11=108

ABCC1=110 SNV-35が4

RYR2=304, 4

MGAM=86

KCNK5=20

RELN =0

CACNB1=18

PRKCH=116

MAPK10=177

ITGA3=15

WBSCR17 =251



Corticolimbic DCC gene co-expression networks as predictors of impulsivity in children

Jose M. Restrepo-Lozano et.al

Nature 07 April 2022


①NCBIではDCC遺伝子は、This gene encodes a netrin 1 receptor.と明記している。

netrin 1 receptor impulsivenessで検索すると下記論文がある
The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

及び
Genetic association of impulsivity in young adults: a multivariate study

②DRD1~2遺伝子がドーパミン受容体である。韓国人どもは、DRD遺伝子について、韓国人固有の変異は少ない。しかし、多型は?

③韓国人どもは、DCC遺伝子についてSNV-1=467, SNV-35=1として大量かつ集団的に固有の変異を有している。連中の民族性に深く関連する遺伝子であることはほぼ確実である


Abstract

Inhibitory control deficits are prevalent in multiple neuropsychiatric conditions. 

Evidence suggests the involvement of the Netrin-1/DCC signaling pathway and its associated gene networks in corticolimbic development. 

Here we investigated whether an expression-based polygenic score (ePRS) based on corticolimbic-specific DCC gene co-expression networks associates with impulsivity-related phenotypes in community samples of children.

We propose that the corticolimbic DCC-ePRS can serve as a novel type of marker for impulsivity-related phenotypes in children.


Introduction

Transient postnatal developmental overexpression of dopamine D2 receptor in the striatum leads to adult mesocortical dopamine PFC dysfunction and cognitive deficits, indicating that striatal dopamine maturational events interact with those controlling mesocortical dopamine axon growth [25].

These disorders are characterized by PFC and NAcc dysfunction and deficits in impulse control [30,31,32,33]. 

We aggregate genotypes weighted by the GTEx across all SNPs within the co-expression network into an expression-based polygenic score (ePRS), according to the individual’s genotype [4243].

Results

Fig. 2: Association between ePRS scores and impulsivity-related phenotypes.

Investigation of blood group genotype prevalence in Korean population using large genomic databases

Cheol O Bae et.al

Nature 15 September 2023




①韓国人どもは、この論文の分析及び韓国赤十字の実際の血液型分析でも、B型が27%と日本人に比べて7%程度B型が多い。

②中国人については、下記のバカでかいサンプル数の論文で28%程度であり、韓国人どもと同じである

Distribution characteristics of ABO blood groups in China
Yang Sun
9, September 2022

. We collected data of 23 million ABO blood group population from 34 provincial-level administrative regions in China.

The ranking of ABO blood groups phenotypic distribution in China is O > A > B > AB. The proportions of A, B, O and AB type in China population are 28.72%, 28.17%, 34.20%, and 8.91%, respectively.


Abstract

In this study, we analyzed data from a large Korean population to provide an updated prevalence of blood group antigen phenotypes, including rare ones.

A robust dataset comprising 72,291 single nucleotide polymorphism arrays, 5318 whole-exome sequences, and 4793 whole-genome sequences was extracted from the Korean Genome and Epidemiology Study, Genome Aggregation Database, and Korean Variant Archive and then analyzed.

Introduction

In the Korean population, limited data are available regarding the distribution of blood group phenotypes and genotypes, including extended phenotypes and rare blood group types. Previous studies have determined the genotypical blood group composition of the Korean population5,6,7,8,9. However, the overall genotypic prevalence of blood group antigens, especially rare ones, is difficult to determine because of limited sample size.

Results

For the ABO blood group, individuals with A, B, AB and O phenotypes were observed to be 25,044 (34.65%), 19,676 (27.22%), 8008 (11.08%) and 19,554 (27.05%) respectively.

These results are consistent with the ABO blood type distribution reported in the 2022 blood services statistics by Korean Red Cross15, as well as with previous study16.

韓国人どもは、この論文の分析及び韓国赤十字の実際の血液型分析でも、B型が27%と日本人に比べて7%程度B型が多い

Table 1 Frequencies of blood group antigen phenotype predicted based on Korean SNP array data (n = 72,291).

From: Investigation of blood group genotype prevalence in Korean population using large genomic databases

Group

Phenotype

Individuals

Frequency (%)

ABO*

A

25,044

34.65

B

19,676

27.22

AB

8008

11.08

O

19,554

27.05

S

ss

65,364

90.42

Ss

6741

9.32

SS

186

0.26

C

cc

8345

11.54

Cc

32,174

44.51

CC

31,772

43.95

E

ee

35,569

49.20

Ee

30,182

41.75

EE

6540

9.05

Duffy

Fy(a+b−)

62,334

86.23

Fy(a+b+)

9588

13.26

Fy(a−b+)

369

0.51

Kidd

Jk(a+b−)

16,721

23.13

Jk(a+b+)

35,901

49.66

Jk(a−b+)

19,669

27.21

Diego

Di(a+b−)

188

0.26

Di(a+b+)

7335

10.15

Di(a−b+)

64,768

89.59

Dombrock

Do(a+b−)

732

1.01

Do(a+b+)

13,040

18.04

Do(a−b+)

58,519

80.95

JR

Jr(a+)

72,275

99.98

Jr(a−)

16

0.02

KANNO

KANNO1+ 

72,109

99.75

KANNO1− 

182

0.25

  1. *72,282 individuals analyzed (9 undetermined results).

What genes are differentially expressed in individuals with schizophrenia? A systematic review

Alison K. Merikangas et.al

Nature 28 January 2022



①PubMed パブメド
生命科学や生物医学に関する参考文献や要約を掲載するMEDLINEなどへの無料検索エンジン

②Embase
出版文献の生物医学および薬理学の書誌データベース

③Web of Science
クラリベイト・アナリティクスにより提供されている世界最大級のオンライン学術データベースである。信頼できる学術誌を厳選して収録し、世界7,300以上の研究機関で利用されているほか、政策決定や大学ランキングにも採用されている。 


Abstract

Though there have been more than 300 studies of gene expression in schizophrenia over the past 15 years, none of the studies have yielded consistent evidence for specific genes that contribute to schizophrenia risk. 
The aim of this work is to conduct a systematic review and synthesis of case–control studies of genome-wide gene expression in schizophrenia. 

健常者と統合失調症患者の対比論文で、かつ、GWAS論文のようなイントロンを含むSNPではなく遺伝子のみを対象とした論文をレビューして絞り込む手法

Comprehensive literature searches were completed in PubMed, EmBase, and Web of Science, and after a systematic review of the studies, data were extracted from those that met the following inclusion criteria: 

大文字が過去論文の検出に使用したサイト。これが知りたかった



human case–control studies comparing the genome-wide transcriptome of individuals diagnosed with schizophrenia to healthy controls published between January 1, 2000 and June 30, 2020 in the English language. 

Genes differentially expressed in cases were extracted from these studies, and overlapping genes were compared to previous research findings from the genome-wide association, structural variation, and tissue-expression studies.

The transcriptome-wide analysis identified different genes than those previously reported in genome-wide association, exome sequencing, and structural variation studies of schizophrenia. Only one gene, GBP2, was replicated in five studies. Previous work has shown that this gene may play a role in immune function in the etiology of schizophrenia, which in turn could have implications for risk profiling, prevention, and treatment. 

Methods

Stages of literature review

To maximize the number of potential studies included in the review, the initial searches were completed in three electronic bibliographic databases:
(1) PubMed (https://pubmed.ncbi.nlm.nih.gov/);
(2) EMBASE (https://www.embase.com/);
and
(3) Web of Science (https://login.webofknowledge.com/). 

After the literature searches were completed, the references were downloaded to the Rayyan systematic review web app [23] where duplicate references were identified and removed. 

.

Results

Fig. 1: PRISMA flow diagram.
figure 1
上の図のように大部分の論文を独自の基準で除外している。残った26の論文が下記

Table 1 Summary of the 26 manuscripts, describing 28 studies, included in this review.

From: What genes are differentially expressed in individuals with schizophrenia? A systematic review

Author

Year

N

Mean age (SD)

Sex (%F)

Method

Tissue

Notes

HC

SZ

HC

SZ

HC

SZ

Blood

  Bousman et al. [47]

2010

25

24

41 (9)

38 (8)

41.7

41.7

Microarray

Blood

Ingenuity*

  Chen et al. [42]

2016

3

3

29.6 (12.3)

30.5 (12.9)

33.3

33.3

Microarray

Blood

lncRNA*

  Gardiner et al. [48]

2012

76

112

37.8 (15.6)

40.7 (12.4)

53.4

39.1

Microarray

Blood

KEGG*

  Kuzman et al. [103]

2009

32

32

28.2 (7.9)

28.2 (7.9)

75

75

Microarray

Blood

 

  Lee et al. [104]

2012

26

26

29.5

29.1

42.3

42.3

Microarray

Blood

 

  Leirer et al. [105]

2019

149

68

29.9 (10.5)

26.6 (7.7)

14

55

Microarray

Blood

 

  Wei et al. [49]

2015

400

564

27.4 (7.4)

26.2 (8.2)

54.4

52.1

Microarray

Blood

microRNA*

  Wu et al. [44]

2016

49

47

28.8 (2)

39.6 (2.2)

51

42.5

Microarray

Blood

 

  Yu et al. [39]

2015

130

105

22.7 (6.8)

25.0 (8.3)

53.9

52.4

Microarray

Blood

microRNA*

  Zhang et al. [50]

2015

2795

2570

36.2 (13.3)

33.5 (10.7)

63.9

48.3

Microarray

Blood

microRNA*

Brain

  Altar et al. [100]

2005

9

8

49.3 (6.7)

43.4 (15.5)

22.2

37.5

Microarray

HIPPO

Cohort 1*

2005

15

14

47.2 (10.9)

43.3 (9.9)

26.7

28.6

Microarray

HIPPO

Cohort 2

  Collado-Torres et al. [41]

2019

200

133

40.9

51.6

28.5

35.3

Imputed

HIPPO

 

2019

226

153

45

50.6

30.1

32

Imputed

DLPFC

 

  Harris et al. [89]

2008

13

14

42 (7.5)

43.8 (8.7)

23

35.7

Microarray

DLPFC

 

  Hauberg et al. [97]

2019

279

258

65.5

69

43

36

RNAseq

DLPFC

 

  Huckins et al. [43]

2019

65,264

40,299

NR

NR

NR

NR

Imputed

DLPFC

 

  Hwang et al. [92]

2013

15

14

48.1 (10.7)

43.6 (13)

40

35.7

RNAseq

HIPPO

 

  Liu et al. [106]

2018

27

22

34.2 (17.5)

43.6 (9.9)

22.2

13.6

RNAseq

Amygdala

 

  Mudge et al. [99]

2008

6

14

43.1 (9.2)

45.2 (11.8)

0

0

Microarray

Cerebellum

 

  Schmitt et al. [45]

2012

10

10

61.2 (14.6)

66.3 (12.0)

20

50

Microarray

STG

NS

  Sellmann et al. [46]

2014

10

10

61.2 (14.6)

66.3 (12.0)

20

50

Microarray

STC

NS

  Tian et al. [54]

2018

24

22

37.5 (15.4)

43.4 (10.1)

20

10

Microarray

Amygdala

NS

  Wu et al. [107]

2012

9

9

44.2 (16.6)

44.3 (16.7)

0

0

RNAseq

STG

 

Other

  Cattane et al. [108]

2015

20

20

48.4 (12.2)

44.6 (12.7)

55

50

Microarray

Skin fibroblast

 

  Lin et al. [109]

2016

7

8

34.4 (12.3)

31.5 (5.7)

28.5

50

RNAseq

IPSC

 

  Sanders et al. [110]

2017

660

529

43.6 (0.9)

46.5 (1)

54

50

RNAseq

LCL

 

  Sanders et al. [111]

2013

446

413

45.7 (1.2)

42.3 (1.5)

55

28.3

Microarray

LCL

 
  1. DLPFC dorsolateral prefrontal cortex, HC healthy control, HIPPO hippocampus, F female, IPSC induced pluripotent stem cell, LCL lymphoblastoid cell line, lncRNA long non-coding RNA, NR not reported, NS no statistically significant findings reported, SZ schizophrenia, SD standard deviation, STC superior temporal cortex, STG superior temporal gyrus.
  2. *Excluded from data extraction.

このレビュー論文でSCZと関連性があるとされた重要な遺伝子リスト
https://www.nature.com/articles/s41380-021-01420-7/tables/2

この他に、付属表1にて、6771のSCZ関連遺伝子リストを作成しているが、どうゆうわけか、ワードファイルになっている。

朝鮮人強制連行をめぐる証言
正論 2003年3月号


坪井幸生氏
1913年生まれ、昭和12年朝鮮総督府入府、警察畑を朝鮮総督府~帰国後も継続して歩んだ人物
朝鮮総督府時代は主に保安畑を歩んだと本人が明言。直接的に関与していた人物である

大師堂経尉氏
1917年生まれ、昭和17年朝鮮総督府入府、農工部所属


大師堂
「強制連行」と言われている問題ですが、最初は募集、昭和17年3月からは官斡旋、19年にはいいってから徴用だったと思います

問いかけ
徴用令違反は日本人でも同じ扱いでしたか

坪井
あったと思いますよ。内地は大部分が徴兵でしたから、男で徴用というのはあまりなかったんじゃないか

坪井
昭和14年頃
当時朝鮮人が日本内地にどんどん来るので、内地としては、労働力の需給問題や治安問題もあって、内務省は「渡航を制限したい」というのです。しかし、朝鮮人も日本人であり、総督府としては渡航を制限されると困るわけです
当時は朝鮮人の渡航を制限しよとする内務省と制限するなと言う朝鮮総督府が対立していました。
やがて日本で労働力を必要とするようになり、「朝鮮人労働者を入れて欲しい」と変わってきた。企業が労働力を補充するため、朝鮮半島へ募集に行ったりした。最後は徴用令をしいて労働力を補充したというのが実態です


坪井【いわゆる創氏改名について】
台湾ではこれを許可制にした。
非常に数が少ない。1割くらいです

坪井
朝鮮語を使っちゃいかんと言う法令は一度も出していない。そんなものを出すはずがない。

大師堂【いわゆる創氏改名について】
台湾のように許可制にしておけばこんなことはなかったんでしょうがね。

Individual risk alleles of susceptibility to schizophrenia are associated with poor clinical and social outcomes

Shinji Sakamoto et.al

Nature 17 December 2015

韓国人どもは、csmd1遺伝子について、FDA論文によれば、サンプル35名で1700を超える韓国人ども固有の変異を有している。
遺伝的に最も近い日本人の大規模サンプルで、関連性が確認されたことは、大きいが、韓国人どもは、おそらく、統合失調症ではなく、韓国人ども固有の精神疾患を有しており、その遺伝的原因かもしれない。火病の疾患感受性遺伝子として、csmd1は今のところ検出されていないが、おバカな韓国人どもが、主に研究しているためかもしれない?

Abstract

We also investigated the polygenic risk scores of 46 SNPs. Allele-wise association analysis detected three SNPs, including rs2623659 in the CUB and Sushi multiple domains-1 (CSMD1) gene, associated with severity of illness at end point.

Materials and methods

Subjects

The subjects of this association study comprised 455 unrelated Japanese patients fulfilling the ICD-10 (International Classification of Disease, Version 10, WHO 1992) diagnostic criteria for schizophrenia (243 males and 212 females, mean age±s.d. at the time of blood sampling 50.4±12.6 years).

SNP selection and SNP genotyping

Candidate SNPs were selected for this study as follows. First, we selected 91 SNPs from the 200 most significant markers in a Japanese GWAS of schizophrenia,22 following the quality control criteria (that is, call rate 95%, autosomal chromosomes, Hardy–Weinberg equilibrium 0.0001, and minor allele frequency 5%) and criteria used in a previous study.22 Second, of these 91 SNPs, we identified 46 SNPs that had the same direction of risk for susceptibility to schizophrenia in both the original GWAS sample and the replication sample of a previous study.22 For the 46 SNPs, we set reference alleles as having an odds ratio (OR) of >1 to define ‘risk alleles’ (that is, patients with schizophrenia had more risk alleles than the controls).

Results

Table 2 Associations between risk alleles of susceptibility to schizophrenia in GWAS and clinical or social outcomes in patients with schizophrenia

A: Allele-wise analyses of severity of illness at end point

SNPs

chr

BP

Closest gene

R a

NR b

RAF_S c

RAF_NS d

P-value

OR (95% CI)

rs8116303

20

37914989

 

A

G

16.26

9.00

0.002

1.96 (1.24–3.12)

rs3129601

13

21460993

 

A

G

21.76

14.24

0.004

1.68 (1.14–2.47)

rs2623659

8

3623779

CSMD1

T

C

52.04

43.71

0.011

1.40 (1.05–1.86)

B: Allele-wise analyses of clinical factors influencing severity of illness at end point

 

Treatment response

Severity of illness at the baseline

SNPs

RAF_NR e

RAF_R f

P-value

OR (95% CI)

RAF_S c

RAF_NS d

P-value

OR (95% CI)

rs8116303

21.52

15.13

0.011

1.56 (1.06–2.30)

13.96

6.52

0.076

2.33 (0.71–7.63)

rs3129601

51.23

44.74

0.037

1.30 (0.97–1.73)

18.99

19.57

0.538

0.96 (0.45–2.04)

rs2623659

15.15

10.93

0.050

1.44 (0.93–2.24)

49.33

39.13

0.090

1.51 (0.82–2.78)

C: Allele-wise analyses of social outcome

SNPs

chr

BP

Closest gene

R a

NR b

RAF_SM g

RAF_SA h

P-value

OR (95% CI)

rs2294424

6

11860537

C6orf105

A

G

66.12

55.36

0.002

1.57 (1.15–2.16)

rs6550146

3

32679747

 

A

G

43.38

34.43

0.012

1.46 (1.05–2.03)

rs8116303

20

37914989

 

A

G

14.93

9.91

0.032

1.6 (0.97–2.63)


Discussion


Rs2623659 is an intron SNP located in the CUB and Sushi multiple domains-1 (CSMD1) gene on chromosome 8p23.2. CSMD1 is a complement control-related protein.26 In situ hybridization and neuron immunolabeling showed that CSMD1 is synthesized in the developing central nervous system.26 

In neuropsychological behavior phenotypes, CSMD1 knockout mice showed behaviors suggestive of blunted emotional responses, anxiety and depression.
27 

CSMD1 is related to neurodevelopmental disorders, including schizophrenia, epilepsy and speech delay.282930 

The other SNPs in 
CSMD1 (rs10503253, rs7017888 and rs7011965) were listed as carrying risks for susceptibility to schizophrenia in a recent GWAS targeting a Caucasian population.303132 

In addition, rs10503253 was reported to be associated with cognitive disability in both patients with schizophrenia and healthy participants.
3334 

Taken together with our findings, we speculate that 
CSMD1 has a role not only in the susceptibility to schizophrenia but also in cognitive disability or clinical outcomes of patients with schizophrenia.

A combined analysis of genetically correlated traits identifies 187 loci and a role for neurogenesis and myelination in intelligence

W. D. Hill et.al

Nature 11 January 2018

①この論文で、SNP単位ではなく、GWASで知能と関すると抽出された遺伝子でP値が小さい知能関連遺伝子538を抽出しているが、FDA論文の韓国人ども固有の変異がある遺伝子リストとの照合結果で538中の499もが、検出された。韓国人どもがいかに精神面で特異な連中であるのかが、明白である
②FDA論文のSNV-1が300以上の遺伝子についてのメインブログ記事へのこの論文抽出リストとのダブリ=韓国人どもの精神面でのの異常性については、paper[169]としてリスト追加は完了している。ほとんどはpaper[168]とダブっているが、二つのGWAS論文で確認しえた点が大きい
③韓国人どもはデータ=知能関連GWAS論文とFDA論文が示す点から、精神面ではまさしくバケモノだ!


Abstract


 Our study had four goals:
first, to facilitate the discovery of new genetic loci associated with intelligence;
second, to add to our understanding of the biology of intelligence differences;
third, to examine whether combining genetically correlated traits in this way produces results consistent with the primary phenotype of intelligence;
and, finally, to test how well this new meta-analytic data sample on intelligence predicts phenotypic intelligence in an independent sample.

By combining datasets using MTAG, our functional sample size increased from 199,242 participants to 248,482.

We found 187 independent loci associated with intelligence, implicating 538 genes, using both SNP-based and gene-based GWAS. 

We found evidence that neurogenesis and myelination—as well as genes expressed in the synapse, and those involved in the regulation of the nervous system—may explain some of the biological differences in intelligence.


Results

These SNPs were found in 187 independent loci, identified using FUMA (Supplementary Table 2); [4936] this represents an increase of 169 loci compared to those reported in the Sniekers et al. GWAS alone [16]. 

Supplementary Table 2では、遺伝子近くの複数のSNPを遺伝子毎に記載

A total of 130 of the 187 loci reported in the current study are novel and not reported previously with intelligence or education (Supplementary Table 3).

Supplementary Table 3は遺伝子名はなく、完全にSNP単位

First, we found 187 independent associations for intelligence in our GWAS, and highlighted the role of 538 genes being involved in intelligence, a substantial advance on the 18 loci previously reported [16].

Within the 187 loci, we found clear evidence of functionality, indicated by our ability to link these SNPs to open chromatin states and regulatory elements of the genome, and by the finding that many of the loci contained regions where genetic variation was deleterious.




付属資料table 1 で、この論文が出た2018年までの知能・MDD等々の精神的形質関連のGWAS論文リストがある

付属資料table 5 で、全ての知能関連遺伝子リストがあり、538が太字で重要。
P値が0.0000027358以下を基準として、538を抽出している。
付属資料table 5の
全遺伝子数は1万8000にも達する

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Gail Davies

Nature 29 May 2018 

①この論文で抽出された709の知能関連遺伝子リストとFDA論文が抽出した韓国人ども固有の変異リストの照合の結果、494の遺伝子が検出された。約70%にも及ぶ。従って、韓国人ども固有の変異が明らかに精神面特に知能に集中していることが、逆パターンで、かつ、超大規模サンプルのGWAS論文で完全に確認しえた

②数が多すぎるため、SNV-1が300以上に限定して抽出した結果が下記である。
韓国人固有の遺伝子変異は大部分がヒトのヒトの精神に関連していることを示した公表用ブログには追記済みである

③韓国人どもは、精神面ではまさにバケモノだ!この作業をするたびに実感するとともに、この連中が我が国に多数生息し、事実上の詐欺師や朝鮮人ヤクザとして跋扈している点に疑問を感ずる。
暴力団よりもむしろ事実上の詐欺がより問題なのだ
RBFOX1
PTPRD
MACROD2
SGCZ
CTNNA2
PDE4D
CADM2
DCC
CDH4
PTPRT
AUTS2
NKAIN2
SNX29


EXOC4
DPYD
LARGE
NEGR1
CALN1

AGAP1

Abstract

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16–102) and find 148 genome-wide significant independent loci (P < 5 × 10−8) associated with general cognitive function. 

Gene-based analyses find 709 genes associated with general cognitive function. 


Supplementary Data 6に709の遺伝子リストがある

Genetic variation, brain, and intelligence differences

Ian J. Deary, Simon R. Cox & W. David Hill

Nature 02 February 2021


このレビュー論文からサンプル数の多い論文

 Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. 
2024/2/9メモ済み
paper[168]として文献リストにも掲げている

A combined analysis of genetically correlated traits identifies 187 loci and a role for neurogenesis and myelination in intelligence.
paper[169]として文献リストにも掲げている

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. 
既にメモ済みであり、paper[159]として文献リストにも掲げている

Intelligence in young adulthood and cause-specific mortality in the Danish Conscription Database—A cohort study of 728,160 men.
デンマーク人対象でSNPのみしか記載ない

Genome-wide analysis identifies molecular systems and 149 genetic loci associated with income.
面白そうな論文ではあるが、知能関連では
paper[169]に依拠しているため、割愛する

Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112 151).
既にメモ済みであり、paper[88]として文献リストにも掲げている

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53,949)
この論文の付属資料tableS4にて、約180の遺伝子リストアップされているものの、SNV-1が300以上の遺伝子名は見当たらなかったのでメモ割愛する

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function
既にメモ済みであり、paper[114]として文献リストにも掲げている

Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence. 
既にメモ済みであり、paper[147]として文献リストにも掲げている

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.
サンプル数は多いものの、付属資料で見てもSNPに近い遺伝子名一覧はないため、私には意味が無い

Biological annotation of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals. 
既にメモ済みであり、paper[135]として文献リストにも掲げている



興味深そうな論文
The nature of nurture: Effects of parental genotypes
要約のみ読んだがメモに値しない

Genetics and intelligence differences: five special findings
拾い読みしたが、メモする価値無し。スウェーデン人対象に37万人の兄弟姉妹を対象に分析もしている

Genomic analysis of family data reveals additional genetic effects on intelligence and
personality
要約のみ読んだがメモに値しない

 Pleiotropic meta-Analysis of cognition, education, and schizophrenia differentiates roles of early neurodevelopmental and adult synaptic pathways.


Abstract

Individual differences in human intelligence, as assessed using cognitive test scores, have a well-replicated, hierarchical phenotypic covariance structure.

Here, we summarise and critique the last 10 years or so of molecular genetic (DNA-based) research on intelligence, including the discovery of genetic loci associated with intelligence, DNA-based heritability, and intelligence’s genetic correlations with other traits.

Intelligence differences and genetic variation

Heritability and genetic architecture of intelligence differences

Twin and family studies report that genetic differences are associated with individual differences in intelligence test scores (Box 2). 

Using genomic structural equation modelling [29] it was found that a genetic general factor explained, on average, 58.4% (SE = 4.8%, ranging from 9 to 95% for individual tests) of the genetic variance across seven cognitive tests in people with European ancestry. 

The first of the three studies had a sample size of 248,428; it found 187 (172 novel when it appeared online) independent regions of the genome that were associated with intelligence [46].

The second of the three studies to appear found 148 loci (53 novel when it appeared online) associated with intelligence, with a sample size of 300,046 participants.

The three studies above used polygenic scores to provide out-of-sample predictions of intelligence based solely on DNA-SNP data [314647].

After GWAS of intelligence: clues to mechanisms?

Finding genetic loci whose variants are associated with intelligence differences only helps to understand these differences if we understand the mechanistic consequences of the genetic variation. GWAS data sets’ results on intelligence have found associations between SNP variation and tissue-specific gene expression across many of the brain’s cortical regions (Fig. 2) [314647]. 


パニック症のゲノムワイド関連解析の HLA アリルによる層別解析
杉本(嶋多)美穂子1)・徳永 勝士1)
1) 東京大学大学院医学系研究科国際保健学専攻人類遺伝学分野
2017

TMEM132D=410
COMT=8

である


我々は,パニック症の新規遺伝要因を探索するために,日本人のパニック症についてのゲノムワイド関連解析(GWAS)の結果を用いたパスウェイ解析を実施した。その結果,免疫系,特に HLA の疾患への関連が見出されたため,特にHLA-B,-DRB1 に着目し解析を実施した。HLA 解析の結果,HLA-DRB1*13:02 が疾患と関連することが明らかとなったため,さらに,当該アリルの有無によって他の関連遺伝要因が異なる可能性について検討した。GWAS のデータを,当該アリルを持つ群と持たない群に分けて関連解析を実施したところ,当該アリルを持たない群の解析において,MCPH1内の SNP が多重検定の補正後も有意な関連を示し,またヨーロッパ系集団の GWAS で疾患への関連が報告されているTMEM132D 内の複数の SNP も関連する傾向を示した(rs1397504; P=3.88×10−6)。


パニック症は,代表的な精神疾患である不安障害の一つである。強い不安の発作であるパニック発作や予期不安といった症状を主とし,一部の患者は,パニック発作を起こす可能性のある場所を避けるようになる広場恐怖という症状を合併する。そのため,一旦発症してしまうと患者は生活圏の縮小を余儀なくされ,社会生活上大きな支障となる。不安障害患者の直接治療費全体は,うつ病のそれとほぼ同額であり,生産性の低下によっても同規模の費用の損失があると試算されていることから 1),その病態の解明,治療法の進展が急務である。パニック症の年間罹患率は約 1%,生涯罹患率は 2–2.5%(パニッ
ク発作は 7–9%)と高率であり

これらの研究からいくつかの関連遺伝要因が報告されているが,これら複数の研究間で一致した関連を示す遺伝要因は非常に少なく, 現 在 の と こ ろ TMEM132D(transmembrane protein
132D) な ら び に COMT(catechol-O-methyltransferase)遺伝子のみである 5)。

また,TMEM132D 遺伝子内の多型 の関連は,ヨーロッパ系集団を対象とした GWAS の結 果では同定されたが,我々が実施した日本人の GWAS においては関連が再現されなかった 5,6)

免疫とパニック症の関係についての結果が一致しておらず,これらの結果から免疫系の異常がパニック症の原因となっているのか,あるいは疾患に罹患したことによって引き起こされる二次的な現象なのかを特定することは困難である。

8.精神疾患と HLA
管見によると我々はパニック症と HLA の関連をはじめて報告したが,統合失調症や自閉症,双極性障害などの他の精神疾患ではこれまでに HLA と疾患の関連が複数報告されている。ヨーロッパ系集団とアフリカ系集団を対象とした複数の統合失調症の GWAS では,いずれの研究においても HLA 領域の複数の SNP がゲノムワイド有意な関連を示した 20–23)。自閉症を対象とした研究では,HLA-DRB1*04 がヨーロッパ系集団において疾患に関連する可能性があることが示唆された 24,25)。さらに,双 極 性 障 害 で も,HLA-G 領 域 の イ ン サ ー シ ョ ン な どHLA 領域の関連が示唆されている 26)。HLA がどのように精神疾患に関わっているのかという機序は明らかになっていないが,中枢神経系では脳内の免疫担当細胞であるマイクログリアが主に HLA クラス I,II 分子を発現していることが知られており,脳内の免疫系の異常が疾患と関連している可能性がある。さらに近年,HLAは発達過程や成人の神経系にも発現しており,神経系の発達や可塑性に関わるとの報告もある 27,28)。


9.おわりに
本研究では GWAS のデータをもとに解析を実施し,パニック症と免疫,HLA-DRB1*13:02 の関連を見出した。HLA-DRB1*13:02 の有無で層別解析を実施することで,ヨーロッパ系集団でパニック症への関連が再現されていた遺伝要因である TMEM132D が日本人においても特にHLA-DRB1*13:02 を持たないパニック症に関連するという知見を得た。

Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

Michael J. Gandal et.al

Science. 2018 Dec 14

この論文の本文で抽出された遺伝子名との照合結果。途中から遺伝子名を省略しているが、本文記載のものは全て調べた。エクセルファイルとの突合は省略した

LINC00996=9
LINC00343=28
LINC00634=8
DTNA=102
AHCYL1=16
RBFOX1=1272, SNV-35=1 ASDとSCZ
MATR3=33
QKI=54
RBM3=40
SRRM2=16
U2AF1=57
SRSF11=20
GRIN1=18
NRXN1=418, SNV-35=1 neurodevelopmental disorders
CADPS=170
FAM86B3P =31
RP11–481A20.10=0
BMPR1B=136
DCLK3=15
HAPLN4=7
HLF=24
LMAN2L=13
MCHR1=7

この論文の略語
weighted correlation network analysis (WGCNA) 
 transcriptome-wide association study (TWAS)
differential gene expression (DGE)

differential transcript expression (DTE)
differential splicing (DS) 
fragile X mental retardation protein (FMRP) 
differential transcript usage (DTU)

Abstract 

Here, we integrate genotype and RNA-sequencing in brain samples from 1695 subjects with autism, schizophrenia, bipolar disorder and controls.

We prioritize disease loci likely mediated by cis-effects on brain expression via transcriptome-wide association analysis. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

Introduction

We present results of the analysis of RNA-sequencing (RNA-Seq) data from the PsychENCODE Consortium (17), integrating genetic and genomic data from over 2000 well-curated, high-quality post-mortem brain samples from individuals with SCZ, BD, ASD, and controls (18).

Data was generated across eight studies (), uniformly processed, and combined through a consolidated genomic data processing pipeline ((); Fig S1), yielding a total of 2188 samples passing quality control (QC) for this analysis, representing frontal and temporal cerebral cortex from 1695 unique subjects across the lifespan, including 279 technical replicates (Fig S2). 

we find that isoform-level changes show the largest effects in disease brain, are most reflective of genetic risk, and provide the greatest disease specificity when assembled into co-expression networks.

Gene and Isoform Expression Alterations in Disease


In addition, isoform-level alterations in disease exhibited substantially larger effect sizes compared with gene-level changes (mean |log2FC| 0.25 vs 0.14, P<2×10−16, K-S test), particularly for protein coding biotypes (Fig 1A), consistent with recent work demonstrating the importance of splicing dysregulation in disease pathogenesis (25).

Differential Expression of the Non-coding Transcriptome

Non-coding RNAs (ncRNAs) represent the largest class of transcripts in the human genome and have increasingly been associated with complex phenotypes (26).

 Notable examples are: LINC00996, which is downregulated in SCZ (log2FC −0.71, FDR<5×10−11) and BD (log2FC −0.45, FDR=0.02) and restricted to microglia in brain (Fig S6); LINC00343, expressed in excitatory neurons, and downregulated in BD (log2FC −0.33, FDR=0.012) with a trend in SCZ (log2FC −0.15, FDR 0.065); and LINC00634, an unstudied brain enriched lincRNA downregulated in SCZ (log2FC −0.06, FDR 0.027) with a genome-wide significant SCZ TWAS association as described below.

Local Splicing Dysregulation in Disease

We used LeafCutter (29) to assess local differential splicing (DS) differences in ASD, SCZ and BD using de novo aligned RNA-seq reads, controlling for the same covariates as DGE/DTE (Fig S7).

Only two genes, DTNA and AHCYL1, were significantly DS in all three disorders (Fig S9).We also find significant enrichment of splicing changes in targets of two RNA binding proteins that regulate synaptic transmission and whose targets are implicated in both ASD and SCZ, the neuronal splicing regulator RBFOX1 (FDR=5.16×10−11) (32) and the fragile X mental retardation protein (FMRP) (FDR=3.10×10−21) (33).

Notably, 48 DS genes (10%; FDR=8.8×10−4) encode RNA binding proteins or splicing factors (), with at least six splicing factors also showing DTE in ASD (MATR3), SCZ (QKIRBM3SRRM2U2AF1) or both (SRSF11).

Notable examples include GRIN1 and NRXN1, which are known risk loci for neurodevelopmental disorders (35).

NRXN1 is a heterotypic, presynaptic cell adhesion molecule that undergoes extensive alternative splicing and plays a key role in the maturation and function of synapses (). 

Another example is CADPS, which is located within an ASD GWAS risk locus 

Identifying Drivers of Transcriptome Dysregulation

We next set to determine whether changes observed across levels of transcriptomic organization in psychiatric disease brain are reflective of the same, or distinct, underlying biological processes. 

Transcriptome-wide Association

We next sought to leverage this transcriptomic dataset to prioritize candidate disease risk genes with predicted genetically-driven effects on expression in brain.

We identified 18 genes or isoforms whose expression was significantly associated with PRS (();

Additional associations for ASD included two poorly annotated pseudogenes, FAM86B3P and RP11–481A20.10. In SCZ, At less stringent thresholds (FDR-corrected P<0.05),

we identify BD PRS associations with isoforms of the neuronal calcium sensor NCALD and SNF8, an endosomal sorting protein, as well as several additional associations in the MHC region in SCZ, which harbors the largest GWAS peak comprised of multiple independent signals (),

Taking an orthogonal approach, we performed a formal transcriptome-wide association study (TWAS; ()) to directly identify those genes whose cis-regulated expression is associated with disease (). 

 Eight genes showed consistent association () across multiple analyses -- BMPR1BDCLK3HAPLN4HLFLMAN2LMCHR1UBE2Q2LSNAP91TTC39ATMEM258, and VPS45 (Table S4). 

Networks Refine Shared Cross-Disorder Signals

To place transcriptomic changes within a systems-level context and more fully interrogate the specific molecular neuropathology of these disorders, we performed weighted correlation network analysis (WGCNA) to create independent gene and isoform-level networks (),


Neuronal Isoform Networks Capture Disease Specificity

A salient example of differential module membership and disease association of transcript isoforms is RBFOX1, a major neuronal splicing regulator implicated across multiple neurodevelopmental and psychiatric disorders (). Previous work has identified downregulated neuronal modules in ASD and SCZ containing RBFOX1 as a hub (). 

Here, we identify two neuronal modules with distinct RBFOX1 isoforms as hub genes (Fig 6A).

The second most abundant RBFOX1 isoform is in another module, isoM17, which is downregulated in both ASD and SCZ (Fig 6B). Experiments in mouse indicate that RBFOX1 has distinct nuclear and cytoplasmic isoforms with differing functions, the nuclear isoform primarily regulating pre-mRNA alternative splicing, and the cytoplasmic isoform binding to the 3’ UTR to stabilize target transcripts involved in regulation of neuronal excitability ().

Distinct Trajectories of Neural-Immune Dysregulation

Previous work has identified differential activation of glial and neural-immune processes in brain from patients with psychiatric disorders (), including upregulation of astrocytes in SCZ and BD () and both microglia and astrocytes in ASD ().

Non-coding Modules and lncRNA Regulatory Relationships

Given that many lncRNAs are predicted to have transcriptional regulatory roles, we next assessed whether mRNA-based co-expression networks could provide additional functional annotation for ncRNAs. 

Isoform Network Specificity and Switching

To more comprehensively assess whether aspects of disease specificity are conferred by alternative transcript usage or splicing, versus DE, we surveyed genes exhibiting DTU across disorders (). 

We identified 134 such ‘switch isoforms’, corresponding to 64 genes displaying different DTU between ASD and SCZ (Table S7). 

Shared genetic architectures of educational attainment in East Asian and European populations

Tzu-Ting Chen

Nature 05 January 2024

①GABBR1はこの論文で唯一抽出されたSNPが意味のある位置にある
②韓国には既にNBKバイオバンクコリアがあるにもかかわらず、下記データを使用している。

the Korean genome and epidemiology study (KoGES) consortium

論文検索すると、Genome-wide study on 72,298 individuals in Korean biobank data for 76 traits
という論文で作成されたデータベースであり、大元のデータはNBKである。


Abstract

Educational attainment (EduYears), a heritable trait often used as a proxy for cognitive ability, is associated with various health and social outcomes. 

Here we present the first large-scale GWAS of EduYears in people of East Asian (EAS) ancestry (n = 176,400) and conduct a cross-ancestry meta-analysis with EduYears GWAS in people of EUR ancestry (n = 766,345).

Main

Educational attainment (EduYears: years of education as a continuous phenotype) is a behavioural trait that has been studied extensively and linked to various social, economic and health-related outcomes1,2,3.

Results

EduYears genome-wide associations in EAS population

Self-reported educational attainment (EduYears) and genome-wide genotype data for 107,493 and 72,294 samples were obtained from the Taiwan Biobank (TWB)16 and Korean Genome and Epidemiology Study (KoGES)17, respectively.

After stringent quality control (QC) and genotype imputation, we performed a GWAS for EduYears with 7,470,871 variants in 104,722 TWB samples and 8,064,004 variants in 71,678 KoGES samples (Supplementary Figs. 1a,b and 2a,b and Supplementary Table 1). 

We then performed an EAS genome-wide fixed-effect meta-analysis for EduYears between TWB and KoGES, which retained the association results for 6,951,085 autosomal variants with an imputation quality score (INFO) >0.6 and minor allele frequency (MAF) >0.5% in both cohorts (Fig. 1a, Supplementary Fig. 1c and Supplementary Table 1).

The results of the EAS GWAS meta-analysis were similar to those of the TWB and KoGES separately, except for one locus on chromosome 12 near ALDH2 that showed significant heterogeneity (Supplementary Fig. 3).


Chr

Start

End

Credible set ID

Credible set size

Total PIP

N of significant variantsa

SNP with maximum PIP

Maximum PIP

A1

Effect size

A1 Freq

Marginal P value

Gene

Annotation

2

161,721,597

162,351,261

1

6

0.96

6

rs10930013

0.26

A

−0.021

0.42

7.80 × 10−10

TANK

Intron

4

180,613,679

181,136,169

1

4

0.95

4

rs2871133

0.36

C

−0.020

0.53

3.54 × 10−9

NA

NA

5

93,838,858

94,392,030

1

20

0.95

19

rs255347

0.11

T

0.022

0.73

5.70 × 10−9

MCTP1

Intron

5

106,947,725

107,455,182

1

2

0.96

2

rs7708343

0.62

A

−0.021

0.32

4.46 × 10−9

FBXL17

Intron

6

27,515,505

29,611,229

1

13

0.95

3

rs9461540

0.47

G

−0.027

0.17

6.19 × 10−10

GABBR1

Upstream gene

6

27,515,505

29,611,229

2

6

0.96

6

rs16893804

0.40

G

−0.028

0.22

5.62 × 10−12

NA

NA

10

103,385,878

104,057,295

1

27

0.96

18

rs11191157

0.60

A

−0.023

0.22

2.34 × 10−8

C10orf76

Intron

17

42,899,988

43,438,117

1

10

0.95

10

rs12936234

0.20

C

0.020

0.47

4.28 × 10−9

NMT1

Intron


Heterogeneity of genetic effects within EAS population

Given that the ALDH2 region on chromosome 12 showed a significant association with EduYears exclusively in KoGES but not in TWB, we conducted further investigation to explore potential underlying factors driving this observed heterogeneity. 

 We identified a significant negative global genetic correlation between alcohol drinking and EduYears (rg = −0.193; s.e. 0.063; P = 0.002). Moreover, specifically within the ALDH2 region, we observed a substantial local genetic correlation (ρ = −0.82, P = 7.4 × 10-6).
Remarkably, in the drinker group, the ALDH2 region displayed a significant association with EduYears (P = 2.4 × 1022), while in the non-drinker group, the association was not significant (P = 0.032) (Supplementary Fig. 7). These findings suggest that the observed heterogeneity in the ALDH2 region is probably attributed to potential shared genetic component and gene–environment interactions between alcohol drinking and EduYears, particularly in KoGES.

Biological Insights From 108 Schizophrenia-Associated Genetic Loci

Schizophrenia Working Group of the Psychiatric Genomics Consortium

Nature. 2014 Jul 24

①この論文と下記論文の抽出リストの差に驚愕せざるを得ない
Large-scale interaction effects reveal missing heritability in schizophrenia, bipolar disorder and posttraumatic stress disorder
H J Woo et.al Nature 11 April 2017

上記論文で抽出された統合失調症と双極性障害の疾患感受性遺伝子候補について、韓国人どもは大量に固有の変異を有している

②この論文のデノボ変異を除く統合失調症の疾患感受性遺伝子候補は次のとおり。いずれも韓国人ども固有の変異は少ない。ただし、PCDHA遺伝子座について、1~15までの全てを含む意味であれば、非常に多い。

統合失調症のサンプル数の多い大規模GWAS論文であり、リスト追加せざるを得ない

*本文中に記載
DRD2=20
GRM3=99
GRIN2A=167
SRR=10
GRIA1=128
CACNA1C=302
CACNB2=157
CACNA1I=45

*付属表4から

論文付属表ではPCDHAと表示されているが、遺伝子名としては完全な誤りであるが、あくまで遺伝子座。
PCDHA1=71
PCDHA2=67
PCDHA3=65
PCDHA4=64
PCDHA5=59
PCDHA6=57
PCDHA7=55
PCDHA8=52
PCDHA9=51
PCDHA10=46
PCDHA11=43
PCDHA12=42
PCDHA13=37
PCDHA14=1
PCDHA15=0

PCDHA1~15の合計 710

WBP2NL=23
EP300=40
LRRC48=13
MYO15A=24
ITIH3=13
ADAMTSL3=140
SLC39A8=54
ATXN7=101

Summary

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies.

Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls.

We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported.

Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. 

Schizophrenia has a life time risk of around 1%, and is associated with substantial morbidity and mortality as well as personal and societal costs.- 

All available antipsychotic drugs are thought to exert their main therapeutic effects through blockade of the type 2 dopaminergic receptor, but,since the discovery of this mechanism over 60 years ago, no new antipsychotic drug of proven efficacy has been developed based on other target molecules. 

To date, around 30 schizophrenia-associated loci- have been identified through GWAS. 

Here, we report the results of that analysis, including at least 108 independent genomic loci that exceed genome-wide significance. 

128 Independent Associated Loci

We obtained genome-wide genotype data from which we constructed 49 ancestry matched, non-overlapping case-control samples (46 of European and three of East Asian ancestry, 34,241 cases and 45,604 controls) and 3 family-based samples of European ancestry (1,235 parent affected-offspring trios) (Supplementary Table 1 and Supplementary text). 

we considered around 9.5 million variants.The results are summarized in Figure 1

An external file that holds a picture, illustration, etc.
Object name is emss-59304-f0001.jpg
Manhattan plot
Manhattan plot of the discovery genome-wide association meta-analysis of 49 case control samples (34,241 cases and 45,604 controls) and 3 family based association studies (1,235 parent affected-offspring trios).
The x-axis is chromosomal position and the y-axis is the significance of association (−log10(P)).
The red line shows the genome-wide significance level (5×10−8). SNPs in green are in LD with the index SNPs (diamonds) which represent independent genome-wide significant associations.

Characterization of Associated Loci

Of the 108 loci, 75% include protein-coding genes (40% a single gene) and a further 8% are within 20 kb of a gene (Supplementary Table 3).

Notable associations relevant to major hypotheses of the aetiology and treatment of schizophrenia include DRD2 (the target of all effective antipsychotic drugs) and multiple genes (e.g. GRM3GRIN2ASRRGRIA1) involved in glutamatergic neurotransmission and synaptic plasticity.

In addition, associations at CACNA1CCACNB2, and CACNA1I, which encode voltage-gated calcium channel subunits, extend previous findings implicating members of this family of proteins in schizophrenia and other psychiatric disorders.

Brain and Immunity

To further explore the regulatory nature of the schizophrenia associations, we mapped the credible sets (N=108) of causal variants onto sequences with epigenetic markers characteristic of active enhancers in 56 different tissues and cell lines (Supplementary Text). 

Schizophrenia associations were significantly enriched at enhancers active in brain (Figure 2) but not in tissues unlikely to be relevant to schizophrenia (e.g., bone, cartilage, kidney, and fibroblasts).

Extended Data Table 2

de novo overlapのため省略する



付属table4

PRRG2
FAM5B
PCDHA
WBP2NL
EP300
LRRC48
MYO15A
ITIH3
ADAMTSL3
SLC39A8
ATXN7

心の病の脳科学
なぜ生じるのか、どうすれば治るのか?

林(高木)郎子
加藤 忠史  編
講談社ブルーバックス
2023年

多数の遺伝学論文から見て、韓国人固有の変異のほぼ全てが何らかの精神疾患に関連することは確実である。問題であるのは、精神疾患のキングとも言うべき統合失調症についてである。

①統合失調症発症率について、韓国人どもは中国人日本人と異ならない
②にも係わらず、韓国人どもは統合失調症の疾患感受性遺伝子候補とされる遺伝子について、大量の韓国人固有の変異を有している

従来、私はこの点に関しては、実際には②の抽出誤りがその原因と推察してきたが、ここ数年の健常者10万、患者数千を超えるGWAS論文で抽出されたリストなどから、正しい?ようである。

従って、
①統合失調症の疾患感受性遺伝子は、複数の遺伝子変異による完全な多因子疾患であり、かつ、非累計で作用するため、大量に固有の統合失調症の疾患感受性遺伝子を有する完全なDNA異常集団即ち韓国人でも、実際の発症率は、他の民族集団と異ならないことはありうる。個々の統合失調症の疾患感受性遺伝子について固有の変異を有していても実際の影響はごく少ない
②東洋人に比べ西欧人は、統合失調症のの発症率が少なくとも5倍程度以上高いが、その原因は、統合失調症発症の疾患感受性遺伝子ではなく、発症を抑制する機能を有する遺伝子変異の頻度分布の差にある可能性が高い。(このいい加減な著作からである)
③従って、韓国人どもは、統合失調症の発症に関しては、中国人・日本人よりも遥かに高いリスクを潜在的に有しているものの、発症を抑制する遺伝子変異の分布は、中国人・日本人と異ならない。
④故に、韓国人どもの実際の統合失調症の発症率に統計上の有意差が生じていない

この本からは上記となるが実際には疑問である。

これが正解かもしれない???


p28
統合失調症に関連する遺伝子がシナプスに集中していた
統合失調症の患者さんの脳では、アルツハイマー型認知症のような細胞死による脳の大きさの委縮はありません。恐らくシナプスのほんの少しの不具合が原因であると多くの研究者が考えており、その根拠は遺伝学研究です。一卵性双生児では、二人の遺伝情報(ゲノム)はほぼ100%同一です。一方が統合失調症を発症した場合、もう一方は50%~60%の確率で統合失調症を発症すると言われています

【統合失調症について双子では上記であることは知ってはいたが、50%程度の確率は余りにも低い。
その原因は?】


p29
統合失調症の発症に関連する遺伝子
DISC1やSETD1Aという遺伝子は発症に対する影響度が大きいと言われており、これらの遺伝子が働ききくなる変異があると、そのような変異がない場合に比べて、統合失調症の発症の確率はけた違いに高くなります


FDA論文が抽出したキチガイども固有の変異数リストとの突合結果は次のとおり
DISC1→SNV-1=144
②SETD1A→SNV-1=21, SNA-1/ns=1

この部分で著者が根拠とした論文は巻末の参考文献リストには見当たらない。Nature掲載論文だけで見ると、
DISC1は関連性を完全否定する論文が出た後に肯定する論文が出ている
https://scholar.google.com/scholar?start=0&q=DISC1+gene+schizophrenia&hl=en&as_sdt=0,5

SETD1Aについては、サイエンス掲載論文があり、多分、著者らの言う通りかもしれない?
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=SETD1A+gene+schizophrenia&btnG=
上記検索で表示される
サイエンス掲載論文2022年は、何とヘテロ接合であることが原因としているかのようなタイトルをつけている。読むこと。んなアホなことありうるのか?

いずれにしても、この部分の記述はいい加減なものである


p34
【統合失調症に関する仮説として】
もっとも有名な仮説はドーパミン仮説といいます
これはドーパミンが
過剰に分泌されているという仮説で、広く指示されています

統合失調症の薬はドーパミンの受容体に働く拮抗薬です。受容体の穴をふさいで、ドーパミンを受け取れないようにし、症状が緩和すると考えられています

p57
脳の疾患には、神経変性疾患と精神疾患があります。
顕著な委縮、神経細胞壊死が見られないのが精神疾患だとされています

p119
ASDの発症に強く影響するCNVは、
新生突然変異(デノボ変異)の割合が高いことが解ってきました

p193
2019年、脳内で最もセロトニン濃度の高い場所の一つが視床室傍核であることが報告されました



Large-scale interaction effects reveal missing heritability in schizophrenia, bipolar disorder and posttraumatic stress disorder

H J Woo et.al

Nature 11 April 2017

①大規模サンプルで抽出された精神疾患の疾患感受性遺伝子リストとFDA論文で抽出された韓国人固有の変異の対比表は、下記であり、韓国人は、まさに精神面ではモンスターであることが、完全に明白である
②この論文の表1は、この論文の分析に加え、過去の論文も参照して25の精神疾患疾患感受性遺伝子を抽出しているが、韓国人どもは、その全てにおいて大量の固有の変異を有している。まさしく、精神的には、完全なバケモノである。今後の研究の進展を待つしかない。恐らくは、遅くとも50年以内には、朝鮮人が完全な精神的モンスターであるこことが世界中に知れ渡るであろう。新年早々の恐怖を感じざるを得ない論文であるが、私の作ったリストに追加するしかない

CSMD1=SZ、BP=1786, SNV-35=1
CDH13=SZ、ASD、ADHD=600
PTPRD=BP,ADHD、OCD=1084
RBFOX1=ASD=1272
WWOX=ARCA=797
CSGALNACT1=SZ=196
FHIT=SZ=642, SNV-35=1
MAGI2=SZ=506
LSAMP=BP=800, SNV-35=2
CNTN4=SZ=485, SNV-35=2
DAB1=SZ、BP=528
NPAS3=SZ=309
LRP1B=SZ=677
TMEM132D=Anxiety=410
MACROD2=ASD=693, SNV-35=1
ASIC2=Fear in mice=471
PLCB1=SZ=260
CTNNA3=SZ=605, SNV-35=1
CNTNAP2=SZ、BP=840
FRMD4A=AD=336
ASTN2=SZ、ASD,ADHD=348, SNV-35=1
PCSK5=BP=155
OPCML=SZ=390
SORCS2=BP=373
PTPRT=ASD=434

ADHD, attention-deficit hyperactivity disorder;
AD, Alzheimer’s disease;
ARCA, autosomal recessive cerebellar ataxia;
ASD, autism spectrum disorder;
AUC, area under the curve;
BP, bipolar disorder;
CI, confidence interval;
OCD, obsessive-compulsive disorder;
SZ, schizophrenia.

*Hyung Jun Wooは、Senior Computational Biologistであり、所属はアメリカのBiotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD, USAである。共同執筆者は、全員が同じ所属である


Abstract

Genetic susceptibility factors behind psychiatric disorders typically contribute small effects individually. 

A possible explanation for the missing heritability is that the effects of common variants are not only polygenic but also non-additive, appearing only when interactions within large groups are taken into account.

Here, we tested this hypothesis for schizophrenia (SZ) and bipolar disorder (BP) disease risks, and identified genetic factors shared with posttraumatic stress disorder (PTSD). 

The gene with highest association was CSMD1, which encodes a negative regulator of complement activation. 

ntroduction

Schizophrenia (SZ) and bipolar disorder (BP) are severe psychiatric disorders with overlapping symptoms affecting ~1% of the population.

Materials and methods

Genotype data

For SZ, we used Molecular Genetics of Schizophrenia Genetic Association Information Network (GAIN) (dbGaP accession number phs000021.v3.p2) and non-GAIN studies (phs000167.v1.p1) data

Results

Disease association without interaction effects

Our SZ analysis was based on Molecular Genetics of Schizophrenia data set23 comprising EA and AA subpopulations with 3971 cases and 3666 controls in total.

For BP, we combined the GAIN samples (EA and AA)24 with WT data25 (3216 cases and 4643 controls in total; Supplementary Table 1). 


Table 1 Top 25 genes in high association with SZ+BP under collective inference.

From: Large-scale interaction effects reveal missing heritability in schizophrenia, bipolar disorder and posttraumatic stress disorder

Rank

Gene

AUC (95% CI)

P-value

Known association a

1

CSMD1

0.600 (0.009)

5 × 10−19

SZ,32333435 BP36373839

2

CDH13

0.580 (0.009)

3 × 10−15

SZ,83 ASD,84 ADHD84

3

PTPRD

0.575 (0.009)

3 × 10−14

BP,37 ADHD,85 OCD86

4

RBFOX1

0.574 (0.009)

5 × 10−14

ASD87

5

WWOX

0.570 (0.009)

2 × 10−13

ARCA88

6

CSGALNACT1

0.565 (0.009)

3 × 10−12

SZ40

7

FHIT

0.564 (0.009)

3 × 10−12

SZ89

8

MAGI2

0.561 (0.009)

1 × 10−11

SZ90

9

LSAMP

0.559 (0.009)

3 × 10−11

BP8

10

CNTN4

0.558 (0.009)

5 × 10−11

SZ91

11

DAB1

0.556 (0.009)

1 × 10−10

SZ,92 BP92

12

NPAS3

0.555 (0.009)

1 × 10−10

SZ93

13

LRP1B

0.554 (0.009)

3 × 10−10

SZ94

14

TMEM132D

0.553 (0.009)

4 × 10-10

Anxiety95

15

MACROD2

0.551 (0.009)

8 × 10−10

ASD96

16

ASIC2

0.550 (0.009)

1 × 10−9

Fear in mice97

17

PLCB1

0.548 (0.009)

3 × 10−9

SZ98

18

CTNNA3

0.547 (0.009)

5 × 10−9

SZ83

19

CNTNAP2

0.547 (0.009)

5 × 10−9

SZ99, BP37

20

FRMD4A

0.547 (0.009)

6 × 10−9

AD100

21

ASTN2

0.545 (0.009)

2 × 10−8

SZ,101 ASD,102 ADHD102

22

PCSK5

0.544 (0.009)

2 × 10−8

BP37

23

OPCML

0.544 (0.009)

2 × 10−8

SZ103

24

SORCS2

0.543 (0.009)

3 × 10−8

BP36

25

PTPRT

0.543 (0.009)

3 × 10−8

ASD104

  1. Abbreviations: ADHD, attention-deficit hyperactivity disorder; AD, Alzheimer’s disease; ARCA, autosomal recessive cerebellar ataxia; ASD, autism spectrum disorder; AUC, area under the curve; BP, bipolar disorder; CI, confidence interval; OCD, obsessive-compulsive disorder; SZ, schizophrenia.
  2. aSee Supplementary References.


non random matingに関する理論上の枠組みは存在しないはずである。
確かに、random matingに対する偏差と捉えるしかない。

Effective size of nonrandom mating populations.
A Caballero, W G Hill
01 April 1992

Abstract

Nonrandom mating whereby parents are related is expected to cause a reduction in effective population size because their gene frequencies are correlated and this will increase the genetic drift. The published equation for the variance effective size, Ne, which includes the possibility of nonrandom mating, does not take into account such a correlation, however. Further, previous equations to predict effective sizes in populations with partial sib mating are shown to be different, but also incorrect. In this paper, a corrected form of these equations is derived and checked by stochastic simulation. For the case of stable census number, N, and equal progeny distributions for each sex, the equation is [formula: see text], where Sk2 is the variance of family size and alpha is the departure from Hardy-Weinberg proportions. For a Poisson distribution of family size (Sk2 = 2), it reduces to Ne = N/(1 + alpha), as when inbreeding is due to selfing. When nonrandom mating occurs because there is a specified system of partial inbreeding every generation, alpha can be substituted by Wright's FIS statistic, to give the effective size as a function of the proportion of inbred mates.


【赤字の部分は当たり前としか言いようがない】

Non-random mating and information theory

A. Carvajal-Rodríguez

At the same time, this framework provides the connection between mate choice and the exact mathematical partition of the choice effects, namely sexual isolation, sexual selection and a mixed effect. The sexual selection component is the sum of the intra-sexual male and female selection.

Introduction

Mate choice is arguably one of the most active areas of evolutionary research.

 Alternatively, from a population genetics point of view, mate choice is defined as the observed mating frequency deviation with respect to random mating, considering population gene or phenotype frequencies.

So defined, mate choice can be partitioned into (intra)sexual selection, defined as the observed change in gene or phenotype frequencies in mated individuals with respect to population frequencies, and sexual isolation (behavioral isolation or intersexual selection), defined as the deviation from random mating in mated individuals (Rolán-Alvarez and Caballero, 2000).

For an alternative description of these concepts and a discussion about some of the most widely used descriptions of evolutionary change within the context of sexual selection, I refer the reader to Kuijper et al. (2012) and Rosenthal (2017).

Global tree-ring response and inferred climate variation following the mid-thirteenth century Samalas eruption

Ulf Büntgen et.al

16 January 2022


13世紀における朝鮮半島での人口の大幅な減少について既に減少率は算出していたが、その原因の一つが明確に判明した



Abstract

The largest explosive volcanic eruption of the Common Era in terms of estimated sulphur yield to the stratosphere was identified in glaciochemical records 40 years ago, and dates to the mid-thirteenth century.

Despite eventual attribution to the Samalas (Rinjani) volcano in Indonesia, the eruption date remains uncertain, and the climate response only partially understood. 

Seeking a more global perspective on summer surface temperature and hydroclimate change following the eruption, we present an analysis of 249 tree-ring chronologies spanning the thirteenth century and representing all continents except Antarctica.

Of the 170 predominantly temperature sensitive high-frequency chronologies, the earliest hints of boreal summer cooling are the growth depressions found at sites in the western US and Canada in 1257 CE. 
If this response is a result of Samalas, it would be consistent with an eruption window of circa May–July 1257 CE.

More widespread summer cooling across the mid-latitudes of North America and Eurasia is pronounced in 1258, while records from Scandinavia and Siberia reveal peak cooling in 1259.

Introduction

As recorded in polar ice cores, the largest volcanic sulphur release to the atmosphere in at least the past 2500 years occurred between 1257 and 1259 CE (hereinafter all calendar dates refer to the Common Era; CE) (Palais et al. 1992; Oppenheimer 2003a; Sigl et al. 2015). 


Fig. 4

From: Global tree-ring response and inferred climate variation following the mid-thirteenth century Samalas eruption

Fig. 4

Growth response of 26 temperature-sensitive tree-ring width (TRW) chronologies in the western US (#24) and Canada (#2) that reveal negative anomalies already in 1257. All 26 sites are located between 50 and 3660 m asl (with a mean and median of 2247 and 2364 m asl, respectively), and within 34°–52° N and 104°–126° E


In summary, of the 170 chronologies that contain a predominant temperature signal, the first indication of a cold spell in 1257 originates from distinct growth depressions at 26 high-elevation sites in the western US and Canada (Figs. 34). Widespread summer cooling across the mid-latitudes in North America and Eurasia is, however, most pronounced in 1258, and many boreal records in Scandinavia and Siberia show negative growth anomalies in 1259. In contrast to the marked post-Samalas temperature response in the NH, there is no dramatic hydroclimatic fingerprint exhibited by the 79 precipitation-sensitive chronologies.

Genome-wide association analysis of 19,629 individuals identifies variants influencing regional brain volumes and refines their genetic co-architecture with cognitive and mental health traits

Bingxin Zhao et.al

Nature genetics 2019 Nov 1

FOXO3=42
brain volume GATAD2B=38
lentiform nucleus volume, GNA12=54
white matter integrity, MCC=209
brain cytoarchitecture, HMGA2= 73
brain cytoarchitecture, HRK =15
brain structure, KANSL1=58
brain structure, MAPT=33
brain structure, STH =1
brain structure, CENPW=5
intracranial volume, GMNC=25
intracranial volume, WNT3 =21
intracranial volume, PDCD11=23
intracranial volume, SLC44A5 =148
whole brain volume, MSRB3=61
whole brain volume, BCL2L1=70
whole brain volume,  DCC=467
whole brain volume, CRHR1=40
subcortical brain region volumes, LEMD3=25
whole brain volume,  WIF1 =36
whole brain volume, ASTN2=348 SNV-35が1
hippocampal volume, MAST4=190
hippocampal volume, FAM53B=52
hippocampal volume, METTL10=22
hippocampal volume, FAF1=168
hippocampal subfield volumes, DSCAML1=181
hippocampal subfield volumes, KTN1=43
putamen volume, ZIC4=12
putamen volume, VCAN=36
putamen volume, PAPPA=87
putamen volume, DRAM1=43
putamen volume, DAAM1=67
putamen volume, ALDH1A2 =208

cognitive functions, intelligence, education, neuroticism, neuropsychiatric and neurodegenerative disorders
IGF2BP1=25
WNT3=21PLEKHM=61
AGBL2=13

cognitive functions and intelligence, education and math ability, Alzheimer’s disease
C5orf64=39

Abstract

Volumetric variations of human brain are heritable and are associated with many brain-related complex traits. Here we performed genome-wide association studies (GWAS) of 101 brain volumetric phenotypes using the UK Biobank (UKB) sample including 19,629 participants.

 Gene-based association study found 157 associated genes (124 new), and functional gene mapping analysis linked 146 additional genes. 

Both twin and population-based studies have shown that these volumetric phenotypes can be highly or moderately heritable.

The heritability of brain regions estimated from twin studies can be larger than 80%-12

Recently, the UK Biobank (UKB) study team has collected and released MRI data for more than 20,000 participants. 


In addition, publicly available imaging genetic datasets also emerge from several other independent studies, including Philadelphia Neurodevelopmental Cohort (PNC), Alzheimer’s Disease Neuroimaging Initiative (ADNI), Pediatric Imaging, Neurocognition, and Genetics (PING), and the Human Connectome Project (HCP), among others. These datasets provide a new opportunity to perform better-powered GWAS of all ROI brain volumes.

We used 19,629 UKB individuals of British ancestry in the main discovery GWAS. 

 Four other datasets with relatively small sample sizes (total sample size 2,192 after quality controls) were used to validate the UKB findings, and finally, a meta-analysis was performed to combine all the data.


RESULTS

SNP heritability estimates of the two UKB phases.

In Supplementary Figure 1, we compare the SNP heritability (h2) estimated separately from UKB phase 1 and 2 data.

The sample correlation coefficient of these estimates was 0.85 (correlation = 0.85), indicating moderate to high level of agreement in terms of the degree of genetic contributions to ROI between the two phases.

 In summary, SNP heritability and genetic correlation analyses indicate that most ROI volumes are heritable and have largely consistent genetic basis in the two phases data.

Significant GWAS associations of 101 ROI volumes.

We carried out GWAS of the 101 ROI volumes using
8,944,375 genetic variants after genotyping quality controls. Manhattan and QQ plots of all 101 phenotypes are displayed in Supplementary Datasets 1 and 2, respectively. 

Concordance with previous GWAS results.

We performed association lookups for the 365 independent significant variants and their correlated variants in the NHGRI-EBI GWAS catalog.

We found that 166 independent significant variants (associated with 47 ROI volumes) have previously reported GWAS associations with other traits (Supplementary Table 8).

For the other traits, we highlighted previous associations of 46 variants with mental health disorders (such as schizophrenia, autism spectrum disorder (ASD), and depression), 98 with cognitive functions, 25 with educational attainment, 24 with neuroticism, 14 with Parkinson’s disease, 4 with reaction time, and 3 with Alzheimer’s disease. 

Gene-based association analysis and functional mapping.

We performed gene-based association analysis with GWAS summary statistics for 18,796 candidate genes (Methods). We found 281 significant gene-level associations (P < 2 × 10−8, adjusted for multiple traits) between 157 genes and 55 ROIs (Supplementary Table 12).

Our results replicated 33 genes discovered in previous studies, including FOXO3 in Baranzini et al. for normalized brain volume, GATAD2B in Hibar et al. for lentiform nucleus volume, GNA12 in Sprooten et al. for white matter integrity, MCC in Kim and Webster for brain cytoarchitecture, HMGA2 and HRK in Stein et al. for brain structure, KANSL1MAPTSTH and CENPW in Ikram et al. for intracranial volume, GMNCWNT3 and PDCD11 in Klein et al. for intracranial volume, SLC44A5 in Furney et al. for whole brain volume, MSRB3BCL2L1DCC and CRHR1 in Hibar et al. for subcortical brain region volumes, LEMD3WIF1 and ASTN2 in Bis et al. for hippocampal volume, MAST4FAM53BMETTL10 and FAF1 in van der Meer et al. for hippocampal subfield volumes, DSCAML1 and KTN1 in Chen et al. for putamen volume, and ZIC4VCANPAPPADRAM1DAAM1 and ALDH1A2 in Elliott et al.for brain imaging measurements.

Of the 157 detected genes, 70 have previously been implicated with cognitive functions, intelligence, education, neuroticism, neuropsychiatric and neurodegenerative diseases/disorders, such as IGF2BP1,WNT3,,,PLEKHM-, and AGBL2,,,. Particularly, 47 of the 70 pleiotropic genes were novel genes of ROI volumes, and thus these findings substantially uncovered the gene-level pleiotropy between ROI volumes and these traits (Fig. 2).

 Of the 279 genes, 163 were not discovered in the above gene-based association analysis, which replicated more previous findings on ROI volumes, such as FBXW8 in Stein et al. for brain structure, WNT16 in Zheng et al. for cortical thickness, TBPL2 in Chen et al. for putamen volume, FAT3 in Hibar et al. for subcortical brain region volumes, FAM175BLHPPSLC4A10RNFT2TESCFOXD2DMRTA2CDKN2C and DPP4 in van der Meer et al. for hippocampal subfield volumes, and EPHA3SLC39A8BANK1CHPT1ACADMFAM3CL3HYPDHJKAMP, and AQP9 in Elliott et al. for brain imaging measurements.

We found that 53 (41 new) of the 163 genes were associated with cognitive functions, intelligence, education, neuroticism, neuropsychiatric and neurodegenerative disorders, such as NT5C2,,,ADAM10,, and GOSR1, (Supplementary Fig. 10). Particularly, 182 significant Hi-C interactions were observed in the Hi-C functional mapping analysis (Supplementary Table 16), which yielded 33 significant associations between 13 genes and 16 ROIs (Supplementary Table 17). Of the 13 genes, 5 were not mapped by physical position or eQTL association, such as C5orf64 for left pericalcarine. C5orf64 has been reported to be associated with cognitive functions and intelligence, education and math ability, as well as risk behaviors and Alzheimer’s disease.

The genetic architecture of the human cerebral cortex 
Katrina L. Grasby et.al
Science. 2020 Mar 20

ヒトの精神=大脳皮質に正面から取り組んだ重要論文であり、不眠症が重大な精神疾患と同じく疾病名として挙げられている。しかし、その理由は多分、うつ病その他との不眠症の関連によるものであろう

付属資料のtable S11を利用して韓国人ども固有の変異との関係を調べ重複する遺伝子名は下記の通り

SNTG1=376
C10orf11=351
FIP1L1=320
BANK1=228
DCDC1=208

S1-S20.
GUID: D72024FF-EA92-496D-872A-25702E00F2B1
S2.
GUID: C8F9590A-9A47-4EB6-AC3A-17AAF3B276C9
S3.
GUID: B595BB7E-081F-44C0-BCE7-293FA0B28FE4
S4.
GUID: A2593810-A851-4BF2-8934-80B839A32B7F
S5.
GUID: C201DBE6-C0E3-413A-BE30-2D3581F28D4A
S11.
GUID: E531886D-C38F-43D4-B043-7E2120339251
付属資料のグラフ


Abstract

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. 

To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals.

We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis.

Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

INTRODUCTION:

The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). 

RATIONALE:

To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts.

RESULTS:

We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. 

Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). 

 When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness.

 After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity.

We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment.

Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism

CONCLUSION:

This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function.▪


Graphical abstract

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Identifying genetic influences on human cortical structure.
(A) Measurement of cortical surface area and thickness from MRI.
(B) Genomic locations of common genetic variants that influence global and regional cortical structure.
(C) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells.
(D) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE.

To identify genetic loci associated with variation in the human cortex, we conducted genome-wide association meta-analyses of cortical SA and THmeasures in 51,665 individuals, primarily (~94%) of European descent, from60 cohorts fromaround the world (tables S2 to S4). 

.

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Object name is nihms-1586184-f0001.jpg
Regions of the human cortex and associated genetic loci.
(A) The 34 cortical regions defined by the Desikan-Killiany atlas.
(B) Ideogram of loci that influence cortical SA and TH.


Within each cohort, we used an additive model to conduct a genome-wide association study (GWAS) for each of the 70 phenotypes. 

The principal meta-analysis comprised results from 33,992 participants of European ancestry (23,909 from49 cohorts participating in the ENIGMA consortium and 10,083 from the UK Biobank). 

We sought replication for loci reaching genome-wide significance (P ≤ 5×10−8) in an additional ENIGMA cohort (777 participants) and the CHARGE consortium () (13,952 participants). In addition, wemeta-analyzed eight cohorts of non-European ancestry (2944 participants) to examine the generalization of these effects across ancestries. 

Across the 70 cortical phenotypes, we identified 306 loci that were genome-wide significant in the principal meta-analysis (P ≤ 5 × 10−8) (Fig. 1B and table S5). Of these, 118 have not been previously associated with either intracranial volume (ICV) or cortical SA, TH, or volume ().

We examined gene-based effects (allowing for a 50-kb window around genes) and found significant associations for 253 genes across the 70 cortical phenotypes (table S6). The meta-analytic results are summarized as Manhattan, QQ, Forest, and LocusZoom plots (figs. S2 to S5).

Loci influencing regional SA and TH

A total of 224 loci were nominally associated with regional SA and 12 with regional TH; of these, 175 SA and 10 TH loci survived multiple testing correction (table S5).

The strongest regional association was observed on chromosome 15q14 with the precentral SA (rs1080066, z-score PMA = 1.8 × 10−137Prep = 4.6 × 10−189; variance explained = 1.03%) (Fig. 4A). 

【このSNPは遺伝子名としては LOC105370777 である】

As we observed strong association with the SA of both pre-and post-central gyri (Fig. 4C), we localized the association within the central sulcus in 5993 unrelated individuals from the UK Biobank. The most significant association between rs1080066 and sulcal depth was observed around the pli de passage fronto-pariétal moyen (linear regression coefficient t test P = 7.9 × 10−21), a region associated with hand fine-motor function in humans (), which shows distinctive depth patterns across different species of primates () (Fig. 4D).


 rs1080066 is a fetal cortex eQTL for a downstream gene, EIF2AK4 (t test FDRFETAL = 4.8 × 10−2), that encodes the GCN2 protein, which is a negative regulator of synaptic plasticity, memory, and neuritogenesis (). 


The functional data also highlight THBS1 via chromatin interaction between the rs1080066 region and the promoter in neural progenitor cells and an eQTL effect in whole blood (z-score FDRBIOSgenelevel = 6.1 × 10−6). THBS1 has roles in synaptogenesis and the maintenance of synaptic integrity ().

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Object name is nihms-1586184-f0004.jpg
Fig. 4. Genetics of regional measures.
(A) Regional plot for rs1080066, including additional lead SNPs within the LD block and surrounding genes, chromatin interactions in neural progenitor cells, chromatin state in RoadMap brain tissues, and BRAINSPAN candidate gene expression in brain tissue.
(B) Ideogram of 15q14, detailing the significant independent loci and cortical regions.
(C) rs1080066 (G allele) association with SA of regions.
(D) rs1080066 association with central sulcus depth and depth of several primate species. RoadMap chromatin states: TssA, active transcription start site (TSS); TssAFlnk, flanking active TSS; TxFlnk, transcription at gene 5′ and 3′; Tx, strong transcription; TxWk, weak transcription; EnhG, genic enhancers; Enh, enhancers; Het, heterochromatin; TssBiv, bivalent/poised TSS; BivFlnk, flanking bivalent TSS/enhancer; EnhBiv, bivalent enhancer; ReprPC, repressed Polycomb; ReprPCWk, weak repressed Polycomb; Quies, quiescent/low. BRAINSPAN cortical tissue types: DFC, dorsolateral prefrontal cortex; VFC, ventrolateral prefrontal cortex; MFC, anterior cingulate cortex; OFC, orbital frontal cortex; M1C, primary motor cortex; M1C-S1C, primary motor-sensory cortex; PCx, parietal neocortex; S1C, primary somatosensory cortex; IPC, posteroventral parietal cortex; A1C, primary auditory cortex;TCx, temporal neocortex; STC, posterior superior temporal cortex; ITC, inferolateral temporal cortex; Ocx, occipital neocortex; V1C, primary visual cortex.

Consistent with enrichment in the pathway analyses, many other loci were located in regions with functional links to genes involved in Wnt signaling (fig. S7B), including 1p13.2, where rs2999158 

【このSNPは遺伝子名として
MOV10 

On 14q23.1, we observed 20 significant loci (table S5) from four LD blocks. The strongest association here was for the precuneus SA (rs73313052: z-score PMA = 1.1 × 10−24Prep = 2.2 × 10−35).

【このSNPは遺伝子名としてLOC107984642 

These loci are located near DACT1 and DAAM1, both of which are involved in synapse formation and are key members of the Wnt signaling cascade (). rs73313052 and high-LD proxies are eQTLs for DAAM1 (t test FDRCMC < 1.0 × 10−2) in the adult cortex (tables S11 and S12). 

Several of our regional associations occur near genes with known roles in brain development. For example, on chromosome 1p22.2, rs1413536 (associated with the inferior parietal SA: z-score PMA = 1.6 × 10−10Prep = 3.1 × 10−14) is an eQTL in the adult cortex for LMO4 (t test FDRCMC < 1.0 × 10−2), with chromatin interactions between the region housing both this SNP and rs59373415 (associated with the precuneus SA: z-score PMA = 1.6 × 10−10Prep = 5.3 × 10−12) and the LMO4 promoter in neural progenitor cells (tables S11 and S12). Lmo4 is one of the few genes already known to be involved in areal identity specification in the mammalian brain ().

Genetic relationships with other traits

To examine shared genetic effects between cortical structure and other traits, we performed genetic correlation analyses with GWAS summary statistics from 23 selected traits.

We observed significant positive genetic correlations between total SA and general cognitive function (), educational attainment (), and Parkinson’s disease (), indicating that allelic influences resulting in larger total SA are, in part, shared with those influencing greater cognitive capabilities as well as increased risk for Parkinson’s disease. 

F
or total SA, significant negative genetic correlations were detected with insomnia (), attention deficit hyperactivity disorder (ADHD) (), depressive symptoms (), major depressive disorder (), and neuroticism () (Fig. 5A and table S16), again indicating that allelic influences resulting in smaller total SA are partly shared with those influencing an increased risk for these disorders and traits. 

在日の涙
間違いだらけの日韓関係
辺 真一
飛島新社
2017年

赤字の部分が重要である。潰されたとあるが、韓国政府によるものかどうかを明記していない

p6
父は1931年
済州道から来日した
進駐軍の余剰物資を
闇市に流す利権を手に入れたようだ
一時は辺3兄弟といえば上野界隈では闇市を仕切るちょっとした「顔」だったようだ

【その後は札幌で焼き肉店経営】

p7
自分がこの国では異邦人だと目覚めさせてくれたのは父の名刺であった。名字(姓)が実に頻繁に変わるのである。
渡辺
田辺
和田部
基本的には我が家の通名は渡辺で私もそれを踏襲した

p11
私を最初は日本人と勘違いして、朝鮮高校卒と分かっても入学を認めてくれたのは明治学院大学である

p14
当時在日コリアンの進む道は3つしかないと言われていた
一つは親の仕事を継ぐこと
屑鉄屋とか焼肉屋など飲食店、パチンコ、街金融

二つ目は腕っぷしに自信のある人間が暴力団、やくざ稼業に入る。
柳川組組長【それぞれの暴力団名の後に、そのトップの通名と朝鮮人名が明記】
東声会
会津小鉄会
極東会
稲川会

3つ目は、才能が有ったり顔が良い場合、スポーツ界や芸能界に入ること

p15
在日は
90%はまだ通名を使っている

p17
民族意識の強かった私が大卒後に就職を決めたのは、朝鮮総連の機関紙や雑誌を発行する出版報道機関の新聞記者であった

p22
朝鮮総連のような北朝鮮系の外国組織は日本以外には存在しない。一時アメリカに「第二の朝鮮労連」を作る動きがあった。最終的には潰されたものの在米韓国人の多くは北朝鮮に属する地域の出身者である

p33
私は何十回と韓国訪れているが、3世、4世の在日韓国人が「パンチョッツパリ(半分日本人)」との差別を受け

p159
北朝鮮は名前にも漢字を使わなくなっているから、基本的には当て字をしている、

p160
漢字を追放したことで、韓国人自身が過去の資料や書籍を読めなくなり



Multi-trait analysis for genome-wide association study of five psychiatric disorders

Yulu Wu et.al

Nature 19 July 2020


公表済みデータ利用のサンプル数計は、100万以上にもにも達する。本当にGWAS分析したのであれば、正しい結果が出るはずである。中国人が書いた遺伝学論文を信用しないわけではないが、知る限りでの最大数のGWAS分析論文。

公表済みデータ利用のサンプル数計は、100万以上にもにも達する。本当にGWAS分析したのであれば、正しい結果が出るはずである。中国人が書いた遺伝学論文を信用しないわけではないが、知る限りでの最大数のGWAS分析論文。分析が正しければ、DCCと他は多分異なり、そして、韓国人どもという完全なる精神面でのDNA異常民民族どもは、DCC遺伝子に大量の韓国人固有の変異が生じており、かつ、DCC遺伝子がヒトの精神と関連するものであることを示す多くの論文がある

GABBR1=0
GLT8D1=8
HIST1H1B=6
HIST1H2BN=8
HIST1H4L=4
KCNB1=41
DCC=467


Abstract

We conducted a cross-trait meta-analysis of genome-wide association study on schizophrenia (SCZ) (n = 65,967), bipolar disorder (BD) (n = 41,653), autism spectrum disorder (ASD) (n = 46,350), attention deficit hyperactivity disorder (ADHD) (n = 55,374), and depression (DEP) (n = 688,809). After the meta-analysis, the number of genomic loci increased from 14 to 19 in ADHD, from 3 to 10 in ASD, from 45 to 57 in DEP, from 8 to 54 in BD, and from 64 to 87 in SCZ.

We observed significant enrichment of overlapping genes among different disorders and identified a panel of cross-disorder genes. A total of seven genes were found being commonly associated with four out of five psychiatric conditions, namely GABBR1GLT8D1HIST1H1BHIST1H2BNHIST1H4LKCNB1, and DCC.

Methods

Samples

The summary statistics were obtained from GWAS of SCZ8, BD8, ASD6, ADHD7, and DEP21. Samples in the Psychiatric Genomics Consortium Major Depression (PGCMD) dataset included both MDD and DEP participants who were assessed by questionnaire (see Supplementary Figures and notes)21.

Results

MTAG results

Our single-trait input files are the results of previously published GWAS or GWAS meta-analyses. The schematic overview of the five cohorts is shown in the Supplementary figures and notes. Summary statistics of GWAS for ADHD, ASD, BD, DEP, and SCZ were analyzed (Fig. 1). The effective sample size in the MTAG results was estimated to be 61,421, 60,817, 65,682, 955,012, and 67,764 for ADHD, ASD, BD, DEP, and SCZ, respectively.

【統合失調症と双極性障害の強い関係が印象的である】

Fig. 3: Genetic correlations and path diagram of genomic structural equation modeling (SEM) of the five disorders.
figure 3

【タンパク質、そのレセプター、そのトランスポーター、発現形質=疾病名の関係図で印象的である】

Fig. 4: Sub-network enrichment analysis (SNEA) results of the eight genes.
figure 4

Discussion

The present meta-analysis confirmd that there were varied degrees of genetic associations among the five major psychiatric disorders, particularly between SCZ and BD. 

Among 146 genes, there were seven genes common to four disorders, including GLT8D1KCNB1GABBR1HIST1H1BHIST1H2BN, and HIST1H4L in SCZ, DEP, BD, and ASD, and DCC in ADHD, ASD, DEP, and SCZ.

Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways

Kyoko Watanabe et.al

Nature 14 July 2022

やはり、不眠症は韓国人どもの固有の民族病であることが、このバカでかいサンプル数の正確な分析で完全に明らかとなった

DAB1=528

NEGR1=312
FOXP1=244, SNV-35=1
LSAMP=800, SNV-35=2
BTBD9=158
SDK1=431
FAM120A=37
RC3H2=31
EXD3=163
PTPRD=1064, SNV-35=1
ZBTB26=9
STRBP=43
NTM=385
OLFM4=8
NPAS3=309
RBFOX1=1272, SNV-35=1
SNX29=390, SNV-35=1
DCC=467
TCF4=147
C20orf112=63

Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists.

.Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches.

It is moderately heritable (twin-based heritability 38–59% (ref. 4 ),  and single-nucleotide polymorphism (SNP)-based heritability 7% (ref. 5 )) and genome-wide association studies (GWAS) have improved understanding of the complex polygenic etiology of insomnia5–7 . A recent GWAS in over 1.3million individuals reported >200 genomic loci linked to insomnia, in which the polygenic risk score (PRS) explained a quarter of the estimated heritability5 , implicated several neurobiological processes, cell types, brain areas and circuitries and showed considerable overlap with genetic risk for psychiatric disorders5,7 .


Here we performed a meta-analysis of insomnia GWAS in the UK Biobank and 23andMe, Inc. cohorts, including 593,724 cases and 1,771,286 controls.

We found 554 loci, implicating 3,898 genes using standard functional annotation and gene-based methods.

Results

無題


The latter indicates that, at most, 92.1% of the observed inflation is due to the high polygenicity of insomnia


Insomnia is currently estimated to be the third most polygenic trait, following major depressive disorder (MDD) and educational attainment8 (Supplementary Note).

In addition, we performed sex-specific meta-analyses to evaluate whether results may differ between males and females.
Using LDSC13, we estimated the genetic correlation (rg) between GWAS results for males and females to be 0.92 (P<1×10–323), 0.85 (P=3.2×10–64) and 0.91 (P<1×10–323) in the meta-analysis

SNP and gene-based findings from the meta-analysis.
Next, we performed a gene-based association test using MAGMA. Of 19,751protein-coding genes analyzed, 1,429 reached genome-wide significance (0.05/19,751=2.53×10–6; Fig. 1a and Supplementary Table 8).

The most significant gene was PTPRD (P=7.2×10–37), which has been associated with insomnia5 , restless leg syndrome (RLS)15, type 2 diabetes16 and coronary artery disease17.  restless leg syndrome (RLS)15, type 2 diabetes16 and coronary artery disease17. Results show that the association of PTPRD is unlikely to be driven by a misclassification or comorbidity of RLS within insomnia cases (Supplementary Note and Supplementary Table 9).
【PTPRD遺伝子については、restless leg syndrome (RLS)等にによるものであり、直接、不眠症の原因ではないという分析結果】


The second-most significant gene was LSAMP (P=2.8×10–36), which was not significant in the previous insomnia GWAS but has been associated with MDD18 and suicidal behavior19, which are highly genetically correlated to insomnia.

【まさに韓国人どもにぴったり当てはまる。うつ病、自殺傾向と不眠症。やはり、遺伝的に見た場合には、韓国人どもはバケモノである】

The most significantly associated genes from the previous insomnia GWAS, MEIS1 (ref. 11) and BTBD9 (ref. 5 ), were also supported in the current study (P=1.2×10–14 and 4.8×10–24, respectively). 

Genome-wide study of immune biomarkers in cerebrospinal fluid and serum from patients with bipolar disorder and controls

Ruyue Zhang et.al

Nature 05 February 2020

①この論文の先行研究紹介冒頭では、双極性障害の遺伝率を58%~93%にも及ぶと明記している。
しかし、日本では、MSDマニュアルで、下記のとおり。司馬遼太郎さんが、韓国人どもの感情の変化の激しさに言及されていたことを思い出す

「双極性障害の発症には、おそらく遺伝も一部関与しています。」
「双極性障害の正確な原因は分かっていません。双極性障害の発症には遺伝が関与していると考えられています。また、体内で作られる特定の物質(ノルアドレナリンやセロトニンなどの神経伝達物質)が正常に調節されていない可能性があります。(神経伝達物質は神経細胞が情報を伝達する際に必要な物質です。)」

②Table 1 Top GWS regions for each biomarker in CSF.

CNTNAP5=340
EYS=759
FER1L3=0
ACAA2=16
LINC01288=0
FAM129A=65
EDEM3=22
C8orf37-AS1=14
TUT1=5
ZNF876P=15
LINC01192=0
SEPT2=3
FARP2=52
SATB2=65

Table 2 Top GWS SNPs for each immune biomarker in blood serum.
一部の遺伝子については省略した

FANCI=24
SLC39A12=40
USP3=142
FBXL22=4
UNKL=22
VDR=47
CNTN4=485
ST6GAL2=33
METTL9=19
DDAH1=281 ただし、SNV-35が75もある
TFPI=34
CALCRL=45
SPTLC1=35
ROR2=134
ST6GAL2=33
CENPF=22
PITPNC1=122
NDE1=49
MYH11=80
ZFYVE28=82
ZNF45=19
ZNF221=6
TRAPPC12=51
SLC8A1=241  SNV-35が1
ZMAT2=12
WDR55=3
TMCO6=9
NPAS3=309
LOC101927410=0
FSTL5=260
UBASH3B=62


Abstract

Bipolar disorder is a common, chronic psychiatric disorder. Despite high heritability, there is a paucity of identified genetic risk factors. 

To explore the genetic associations with immune biomarker levels in cerebrospinal fluid (CSF) and blood serum which previously showed differences in bipolar disorder, 
we performed a study involving 291 individuals (184 bipolar disorder patients and 107
controls.

CSFは脳脊髄液

The strongest association in CSF was found for markers within the CNTNAP5 gene with YKL-40 (rs150248456, P = 2.84 × 10−10). 

The strongest association in serum was also for YKL-40 but localized to the FANCI gene (rs188263039, P = 5.80 × 10−26). 

Introduction

Bipolar disorder is a chronic psychiatric disorder characterized by recurrent episodes of mania or hypomania and depression that afflicts about 60 million people worldwide1,2,3

Despite heritability estimates ranging between 58–93%4,5,6, only a few dozen single nucleotide polymorphisms (SNPs) with small effect sizes have been associated with bipolar disorder in large-scale genome-wide association studies (GWAS)7,8,9,10,11.

Results

Demographics and clinical characteristics

We included 184 bipolar disorder patients (67 men and 117 women) and 107 controls (46 men and 61 women) for the serum measurements.

Genetic variants associated with immune biomarkers in CSF

A total of >5.6 million SNPs from 114 bipolar patients and 83 controls were included in our final meta-analysis for biomarkers in CSF. 

The genome-wide association analysis results for the six biomarkers in CSF are shown in Fig. 1. The number of genome-wide significant regions (Index SNPs’ P-values < 5 × 10−8) for each GWAS meta-analysis on YKL-40, MCP-1, sCD14, and IL-8 in CSF was 4, 3, 2, and 6, respectively. No SNPs of genome-wide significance were associated with TIMP-1 and TIMP-2.

Table 1 illustrates the genome-wide significant (GWS) regions for each biomarker in CSF. The top GWS SNPs associated with YKL-40 were located in the genes CNTNAP5, EYS, and FER1L3. For MCP-1, the SNP with the strongest association was located within ACAA2 gene (rs10438979, PA/G = 1.64 × 10−9). The other two top GWS SNPs were located near or within LINCO1288FAM129A, and EDEM3. Two GWS SNPs were related to sCD14 levels in CSF, which are located in the gene area of C8orf37-AS1 and TUT1.

 The GWS SNPs associated with IL-8 were located in the genes ZNF876P, LINC01192, SEPT2, FARP2, and SATB2.

Table 1 Top GWS regions for each biomarker in CSF.

From: Genome-wide study of immune biomarkers in cerebrospinal fluid and serum from patients with bipolar disorder and controls

Chr

Index SNP

A1/A2

Freq

ß

p-value

N

Position

KB

Genes

Waves

YKL-40

2

rs150248456

A/G

0.989

−88.276

2.84e-10

2

chr2:125287495..125383005

95.51

CNTNAP5

1,3

6

rs11753319a

C/G

0.951

−39.387

2.89e-08

2

chr6:64902720..65013122

110.40

EYS

1,2,3

10

rs182911102a

T/C

0.985

−64.832

3.15e-08

4

chr10:94991992..95075604

83.61

FER1L3

1,2,3

1

rs16856846

A/T

0.020

62.660

4.11e-08

3

chr1:232470911..232485096

14.19

 

1,2

MCP-1

18

rs10438979a

A/G

0.960

−230.358

1.64e-09

1

47267946

0

ACAA2

1,2,3

8

rs193114076a

A/G

0.011

370.998

9.68e-09

3

chr8:34726827..34789467

62.64

LINC01288

1,2,3

1

rs114271760

A/G

0.014

362.410

1.45e-08

5

chr1:184697347..184966318

268.97

FAM129A,EDEM3

1,3

sCD14

8

rs182557857

T/C

0.012

94.392

2.05e-08

4

chr8:96576432..96626315

49.88

C8orf37-AS1

1,3

11

rs117456286

A/G

0.013

89.513

4.76e-08

1

62345761

0

TUT1

1,3

IL-8

4

rs142700748a

T/C

0.975

−20.461

2.82e-09

1

234362

0

ZNF876P

2,3

3

rs184700722

T/C

0.011

−16.515

4.41e-09

1

162966687

0

LINC01192

1,3

2

rs182193570a

A/G

0.017

26.143

5.79e-09

1

242292698

0

SEPT2

2,3

2

rs187443429a

T/C

0.024

23.725

1.45e-08

1

242392862

0

FARP2

2,3

2

rs9646754a

T/C

0.034

20.001

1.74e-08

1

200300101

0

SATB2

1,2,3

2

rs115307848a

A/G

0.021

22.536

2.79e-08

3

chr2:199894134..200004958

110.82

 

1,2,3


First, this is the first combined GWAS of peripheral and central immune biomarkers focusing on bipolar disorder to date, which shed light on the genetic regulation of the immune system in bipolar disorder.

Second, we studied biomarkers measured in CSF that closely reflect the chemistry of the brain.

Third, there is no evidence of heterogeneity for markers with the strongest association in our study, using Q-tests (P > 0.50) and I2 index (I2 = 0.00), while other SNPs showed high heterogeneity with Q-tests (P < 0.10) and I2 index (I2 > 10).

We used the random-effects model for meta-analysis, which conservatively accounts for heterogeneity. We detected a number of SNPs associated with immune biomarker levels with large effect sizes. Compared to results from previous GWAS on bipolar disorder,
the strength of the associations (i.e., effect sizes) between genetic variations and immune mediators is stronger than that with bipolar disorder itself8,11,39.

Whole-genome sequencing analysis of suicide deaths integrating brain-regulatory eQTLs data to identify risk loci and genes

Seonggyun Han et.al

Nature 04 October 2023

ラトビア等バルト3国以外のOECD加盟国では、即ち人口1000万以上のOECD加盟国では、ダントツの自殺率1位を長年突っ走っている韓国人どもを、出生率の異常を極めた低下とともに、考察すれば、この世には、人類が神と呼ぶ超自然的なパワーが存在するのかもしれないと強く感ずる。

単なる集団遺伝学マニアの私の目には、人類が神と呼ぶ超自然的なパワーは、集団として見た場合に、異様なほど非同義変異が多い韓国人という極めて特異な集団への、自然淘汰の圧力である。
連中に固有の変異は、異様なほど、ヒトの精神に関連している。

CNN3=15

NBL1=14

KIAA1143=14

MPRIPP1=4

PDCD6IP=32

ZNF501=7

ZNF502=6

TBCA=78

LEMD2=9

BCAP29=23

SLC18A2=19

GDI2=30

SNX19=18

CBLN3=3

IGF1R=134

KLHL36=14

KRT23=4

PCP4=34

ARSA=15

RFPL3S=8



Abstract

Recent large-scale genome-wide association studies (GWAS) have started to identify potential genetic risk loci associated with risk of suicide; however, a large portion of suicide-associated genetic factors affecting gene expression remain elusive.

Subsequent genomic analyses were conducted in whole-genome sequencing (WGS) data from 986 suicide deaths of non-Finnish European (NFE) ancestry and 415 ancestrally matched controls. Additional independent USGRS suicide deaths with genotyping array data (n = 4657) and controls from the Genome Aggregation Database were explored for WGS result replication. One significant eQTL locus, rs926308 (p = 3.24e−06), was identified.

The rs926308-T is associated with lower expression of RFPL3S, a gene important for neocortex development and implicated in arousal. 

Gene-based analyses performed using Sherlock Bayesian statistical integrative analysis also detected 20 genes with expression changes that may contribute to suicide risk.

From analyzing publicly available transcriptomic data, ten of these genes have previous evidence of differential expression in suicide death or in psychiatric disorders that may be associated with suicide, including schizophrenia and autism (ZNF501, ZNF502CNN3IGF1RKLHL36NBL1PDCD6IPSNX19BCAP29, and ARSA). 


Introduction

Suicide death is a major public health problem and leading cause of death [1]. 
We then performed an association test of the eQTLs with suicide risk by analyzing genomic data generated from unrelated suicide deaths and ancestry-matched controls. In addition, we conducted a gene-based analysis to identify genes whose expression changes contribute to suicide risk [30]. 

Materials and methods

An overview of the research design is illustrated in Fig. 1.

.

Fig. 1: The study design for genomic analyses in comprehensive regulatory brain eQTLs.
figure 1

Results

A detailed summary of the suicide death cohorts analyzed in this study is provided in Table 1. The controls with jointly called WGS (N = 415) were unrelated adults of European ancestry, and were 51.1% female. Controls were ascertained for absence of major psychiatric disease.

Supplementary Table S4. Sherlock integrative analysis result

CNN3
NBL1
KIAA1143
MPRIPP1
PDCD6IP
ZNF501
ZNF502
TBCA
LEMD2
BCAP29
SLC18A2
GDI2
SNX19
CBLN3
IGF1R
KLHL36
KRT23
PCP4
ARSA
RFPL3S

Supplementary Table S5. Expression analysis of psychiatric diseases for genes identified by Sherlock integrative analysis 

ZNF501  Autism Spectrum Disorder
ARSA  Bipolar Disorder
BCAP29 Schizophrenia
CNN3 Schizophrenia
IGF1R  Schizophrenia
PDCD6IP Schizophrenia
SNX19 Schizophrenia
ARSA Schizophrenia
NBL1  Schizophrenia
IGF1R Suicide Attempter
KLHL36  Suicide Attempter
PDCD6IP Suicide Attempter
SNX19 Suicide Attempter

Whole genome sequencing of 45 Japanese patients with intellectual disability
Chihiro Abe-Hatano et.al
6 February 2021

①SNV-1の数は下記数値
②有無はイギリスの成人対象の26万人規模のGWAS知能関連遺伝子抽出リストにあるかどうか?

②の突合から、分析に失敗した論文であると断定してよい。
その原因は、サンプル中の19名が、0-2歳児であることが原因である可能性が極めて高い。
0-2歳児であれば、知能はチンパンジーと同じである。

ADNP=18=無し
SATB2=65=無し
ANKRD11=144=無し
PTEN=30=無し
TCF4=147=無し
SPAST=46=有
KCNA2=8=無し
SMS=9=無し
SLC6A8=2=無し
IQSEC2=11=無し
AGTPBP1=68=無し
DYRK1A=72=無し

Here,we report 12 pathogenic and likely pathogenic variants:
seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2,
three hemizygous variants of SMS, SLC6A8,and IQSEC2,and
one homozygous variant in AGTPBP1.

Furthermore, a novel 76kb deletion containing exons1and 2 in DYRK1A was identified.


This is the first report of WGS analysis in Japanese patients with ID.


無題





Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Jeanne E Savage et.al

Nature genetics 2018 Jun 25



この論文の引用数は、2023年時点で1000を超えており、GWAS論文としては多い

①この論文では、特にSLC39A8を遺伝子を知能関連とGWAS分析結果として本文中で記載

②この約27万人というバカでかいGWAS論文で知能関連として抽出された遺伝子と韓国人ども固有の遺伝子SNV-1、SNV-35との共通数値は下記。韓国人どもの知能に関する決定的な論文を得た。韓国人どもは、ノーベル賞はおろか全63もの国際的な科学関連賞の受賞者数がゼロであるという確率上絶対にありえない奇妙な結果を示している。その遺伝的な根本原因を明確に示す決定的な論文データを得た

KMT2C=1091, 96
PTPRD=1084, 1
RP11-420N3.2=978, 2
LRP1B=677, 0
TPTE=664, 29
PARK2=568, 0
GPC5=527, 0
RP11-69H14.6=486, 4
ZDHHC11=468, 3
GALNTL6=459, 0
LRRC4C=448, 1
PARD3B=430, 0
NRXN1=418, 1
CAMTA1=416, 0
TMEM132D=410, 0
RPTOR=395, 0
ERBB4=387, 
CTNND2=354, 1
DPYD=319, 0
LARGE=317, 0
CALN1=311, 
NPAS3=309, 
THSD7B=306, 0
AGAP1=303, 1
THOC3=285, 35
以降省略


Intelligence is highly heritable and a major determinant of human health and well-being. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence

Here, we present the largest genetic association study of intelligence to date (N=269,867), identifying 205 associated genomic loci (190 novel) and 1,016 genes (939 novel) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis.

We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. 

SupplementaryTable S11
Supplementary Table 11. Exonic non-synonymous (ExNS) variants in the genomic loci associated with intelligence in a GWAS meta-analysis of 269,867 independent individuals. 
【11に146の非同義変異リスト。】

Supplementary Table 12.
Genes implicated by positional, eQTL, or chromatin interaction mapping of SNPs associated with intelligence in a GWAS meta-analysis of 269,867 independent individuals.
【12に800を超えるメタ分析結果】

Supplementary Table 15.
Genes significantly associated with intelligence in gene-based association tests (GWGAS) for 269,867 independent individuals.
【15に506の遺伝子リスト
この遺伝子リストと韓国人ども固有の変異リストSNV-1と共通遺伝子リスト

KMT2C
PTPRD
RP11-420N3.2
LRP1B
TPTE
PARK2
GPC5
RP11-69H14.6
ZDHHC11
GALNTL6
LRRC4C
PARD3B
NRXN1
CAMTA1
TMEM132D
RPTOR
ERBB4
CTNND2
DPYD
LARGE
CALN1
NPAS3
THSD7B
AGAP1
THOC3
WDPCP
GOLGA8A
LPP
SOX2-OT
CDK14
C7orf10
AC144838.3
TENM4
THSD4
CDKAL1
ZBTB20
RPS6KA2
SUPT3H
UTRN
ANK3
SORCS1
EIF2B5
MSRA
CACNA1A
CSGALNACT1
SNX29P2
PHACTR1
CDH8
以降省略




Supplementary Table 16.
Details of 105 genes implicated by four strategies: positional, eQTL, and chromatin interaction mapping of significant GWAS SNPs, and gene-based association testing.


Supplementary Table 23.
Tests for overrepresentation of genes mapped by significant GWAS SNPs in sets of genes with previously identified associations with human traits and diseases.

下記で一部抽出
【知能】
SCMH1, FOXO6, NEGR1, NPIPB9, ATXN2L, TUFM, SH2B1, ATP2A1, ZNF638, AFF3, ARHGAP15, CSE1L, SEPT3, WBP2NL, NAGA, FAM109B, NDUFA6, 

【認知機能】
CYB561D1, PTPRO, PCDH17, AKAP6, GFAP, ARHGAP27, KANSL1, LRRC37A, WNT3, RNF43, HSF5, MTMR4, SEPT4, TEX14, RAD51C, PPM1E, TRIM37, SKA2, BRWD1, TCF20, IP6K2, RHOA, TCTA, AMT, NICN1, BSN, STAB1, NT5DC2, CADM2, CDKAL1, GLCCI1


Supplementary Table 25. Genes implicated in intelligence using various association methods in the present and previous studies.


Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology

Niamh Mullins et.al

Nature genetics 2021 May 17


LINC01748=0
NUF2=32 CDG
LMAN2L=13 CDG
SCN2A =50
CERS6 =125
PCGEM1 = CDG
TRANK1=48 SCZ, CDG
ITIH1=11 SCZ, CDG
MDFIC2=0
CD47=21
KIAA1109=59 MD
ADCY2=138
HOMER1=52
SSBP2=115
KDM3B=33 CDG
DOCK2=162
MHC=0 MD, SCZ, CDG, MOOD
POU3F2=0 CDG
SYNE1=170
RPS6KA2=243
MAD1L1=287 MD, SCZ, CDG
THSD7A=163
SP4=38
MPP6=47 SCZ, CDG, MOOD
SRPK2=126 SCZ, ASD, CDG
PLXNA4=253
MRPS33=6 CDG
miR124–1=0 SCZ, ALC, ASD
MSRA=207 SCZ, ALC, ASD
RP1–84O15.2=0 SCZ, ADHD, CDG
PLEC=33
ZCCHC7=74 MD, CDG, MOOD
TUBBP5=75 snv-35=4
CACNB2=157 SCZ, CDG
ANK3=229
ADO=94
ADD3=41
FADS2=28 MD, CDG, MOOD
FKBP2=12
PACS1=78

SHANK2=322 MD
ODZ4=0
CACNA1C=302 SCZ, CDG, MOOD
CUL4A=53
BCL11B= 49 SCZ, CDG
C15orf53=3 CDG
STARD9=52
HOMER2 =48  SCZ
ZNF592=26 SCZ, CDG
FURIN=4 SCZ, CDG
C16orf72=11
GRIN2A=167  SCZ, CDG
RPL13=16
RTN4RL1=44
ERBB2=57
HDAC5=17
STK4=46
WFDC12=3
KCNB1=41 CDG
OSBPL2=34
SLC25A17=12 MD, SCZ, CDG, MOOD

Abstract

Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci.

Results

GWAS results.

We conducted a GWAS meta-analysis of 57 BD cohorts collected in Europe, North America and Australia (Supplementary Table 1), totaling 41,917 BD cases and 371,549 controls of European descent (effective n = 101,962, see Online Methods).

Table 1 |

Genome-wide significant loci for bipolar disorder from meta-analysis of 41,917 cases and 371,549 controls

CHR SNP Previous report^ for BD (citation) Name for novel locus+ Previous report^ for psychiatric disorders
1 rs2126180 LINC01748
1 rs10737496 NUF2 CDG
2 rs4619651 LMAN2L (PGC2) CDG
2 rs17183814 SCN2A (PGC2)
2 rs13417268 CERS6
2 rs2011302 PCGEM1 CDG
2 rs2719164 intergenic (PGC2) CDG
3 rs9834970 TRANK1 (PGC2) SCZ, CDG
3 rs2336147 ITIH1 (PGC2) SCZ, CDG
3 rs115694474 MDFIC2
3 rs696366 CD47 (PGC2)
4 rs112481526 KIAA1109 MD
5 rs28565152 ADCY2 (PGC2)
5 rs6865469 HOMER1
5 rs6887473 SSBP2 (PGC2)
5 rs10043984 KDM3B CDG
5 rs10866641 DOCK2
6 rs13195402 MHC MD, SCZ, CDG, MOOD
6 rs1487445 POU3F2 (PGC2) CDG
6 rs4331993 SYNE1 (Green 2013)
6 rs10455979 RPS6KA2 (PGC2)
7 rs12668848 MAD1L1 (Hou 2016, Ikeda 2017) MD, SCZ, CDG
7 rs113779084 THSD7A (PGC2)
7 rs6954854 SP4
7 rs12672003 MPP6 SCZ, CDG, MOOD
7 rs11764361 SRPK2 (PGC2) SCZ, ASD, CDG
7 rs6946056 PLXNA4
7 rs10255167 MRPS33 (PGC2) CDG
8 rs62489493 miR124–1 SCZ, ALC, ASD
8 rs3088186 MSRA SCZ, ALC, ASD
8 rs2953928 RP1–84O15.2 (lincRNA) SCZ, ADHD, CDG
8 rs6992333 PLEC
9 rs10973201 ZCCHC7 MD, CDG, MOOD
9 rs62581014 TUBBP5
10 rs1998820 CACNB2 SCZ, CDG
10 rs10994415 ANK3 (PGC2)
10 rs10761661 ADO
10 rs2273738 ADD3 (Charney 2017, PGC2)
11 rs174592 FADS2 (PGC2) MD, CDG, MOOD
11 rs4672 FKBP2
11 rs475805 PACS1 (PGC2)
11 rs678397 PC (PGC1, PGC2)
11 rs12575685 SHANK2 (PGC2) MD
11 rs12289486 ODZ4 (PGC1)
12 rs11062170 CACNA1C (PGC2) SCZ, CDG, MOOD
13 rs35306827 CUL4A
14 rs2693698 BCL11B SCZ, CDG
15 rs35958438 C15orf53 CDG
15 rs4447398 STARD9 (PGC2)
15 rs62011709 HOMER2 SCZ
15 rs748455 ZNF592 (PGC2) SCZ, CDG
15 rs4702 FURIN SCZ, CDG
16 rs28455634 C16orf72
16 rs7199910 GRIN2A (PGC2) SCZ, CDG
16 rs12932628 RPL13
17 rs4790841 RTN4RL1
17 rs11870683 ERBB2 (Hou 2016)
17 rs61554907 ERBB2 (Hou 2016)
17 rs228768 HDAC5 (PGC2)
20 rs67712855 STK4 (PGC2)
20 rs6032110 WFDC12 (PGC2)
20 rs237460 KCNB1 CDG
20 rs13044225 OSBPL2
22 rs5758064 SLC25A17 MD, SCZ, CDG, MOOD

CHR, chromosome; BP, GRCh37 base pair position; SNP, single nucleotide polymorphism; OR, odds ratio; s.e., standard error, A1, tested allele; A2, other allele; freq, frequency; BD, bipolar disorder; CDG, Cross-disorder GWAS of the Psychiatric Genomics Consortium; MD, major depression; SCZ, schizophrenia; MOOD, mood disorders; ASD, autism spectrum disorder; ALC, alcohol use disorder or problematic alcohol use; ADHD, attention deficit/hyperactivity disorder.

*Locus overlaps with genome-wide significant locus for bipolar I disorder.
^Previous report refers to previous association of a SNP in the locus with the psychiatric disorder at genome-wide significance. PGC1 = PMID 21926972; PGC2 = PMID 31043756; Hou 2016 = PMID 27329760; Ikeda 2017 = PMID 28115744; Green 2013 = PMID 22565781; Charney 2017 = PMID 28072414.
+Novel loci are named using the nearest gene to the index SNP. P values are two-sided and based on an inverse variance weighted fixed effects meta-analysis.

Discovery of the first genome-wide significant risk loci for attention-deficit/hyperactivity disorder

Ditte Demontis et.al

Nature Genetics 2018 Nov 26

ST3GAL3 *79
KDM4A *15
KDM4A-AS1 *3
PTPRF *44
SLC6A9 *15
ARTN *2
DPH2 *3
ATP6V0B*3
B4GALT2*2
CCDC24*1
IPO13*7
SPAG16*414  SNV-1/ns=3
PCDH7*157
LINC02497*0
LINC00461*67
MIR9–2*0
LINC02060*0
TMEM161B-AS1*49
FOXP2*166
MIR3666*4
LINC01288*0
SORCS3*230
DUSP6*2
POC1B*30
SEMA6D*187
LINC01572*0

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. 

We report a genome-wide association meta-analysis of 20,183 diagnosed ADHD cases and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, revealing new and important information on the underlying biology of ADHD.

Results

Genome-wide significantly associated ADHD risk loci

Genotype array data for 20,183 ADHD cases and 35,191 controls were collected from 12 cohorts (Supplementary Table 1).

Table 1.

Results for the genome-wide significant index variants in the 12 loci associated with ADHD identified in the GWAS meta-analysis of 20,183 cases and 35,191 controls. Index variants are LD independent (r2 < 0.1), and are merged into one locus when located with a distance less than 400kb. The location (chromosome [Chr] and base position [BP]), alleles (A1 and A2), allele frequency (A1 Freq), odds ratio (OR) of the effect with respect to A1, and association P-values from inverse-variance weighted fixed effects model, of the index variant are given, along with genes within 50kb of the credible set for the locus.

LocusChrBPIndex VariantGenesA1A2A1 FreqORP-value
1144184192rs11420276ST3GAL3, KDM4A,
KDM4A-AS1, PTPRF,
SLC6A9, ARTN, DPH2,
ATP6V0B, B4GALT2,
CCDC24, IPO13
GGT0.6961.1132.14 × 10−13
2196602440rs1222063IntergenicAG0.3281.1013.07 × 10−8
32215181889rs9677504SPAG16AG0.1091.1241.39 × 10−8
4320669071rs4858241IntergenicTG0.6221.0821.74 × 10−8
5431151456rs28411770PCDH7, LINC02497TC0.6511.0901.15 × 10−8
6587854395rs4916723LINC00461, MIR9–2,
LINC02060,
TMEM161B-AS1
AC0.5730.9261.58 × 10−8
77114086133rs5886709FOXP2, MIR3666GGTC0.4631.0791.66 × 10−8
8834352610rs74760947LINC01288AG0.9570.8351.35 × 10−8
910106747354rs11591402SORCS3AT0.2240.9111.34 × 10−8
101289760744rs1427829DUSP6, POC1BAG0.4341.0831.82 × 10−9
111547754018rs281324SEMA6DTC0.5310.9282.68 × 10−8
121672578131rs212178LINC01572AG0.8830.8917.68 × 10−9

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

Eli A Stahl et.al

Nature genetics 2019 May 1

SHANK2 遺伝子は、ASD、精神薄弱等々関連論文が極めて多数あり、ヒトの精神に関連する遺伝子であることがほぼ確実な遺伝子。NCBIでの検索でも頭脳との関連が明確に示されており、一々論文を探す必要のないレベルでヒトの精神と関連していることが確実である。

PLEKHO1 13, snv-35=1
LMAN2L 13
SCN2A 50
TRANK1 48, snv-1=2
ITIH1 11
CD47 21
FSTL5 260 snv-1=1
ADCY2 138
SSBP2 115 snv-1=2
RIMS1 168 snv-1=1
POU3F2 2
RPS6KA2 243 snv-1=1
THSD7A 163 snv-1=1
SRPK2 126
MRPS33 6
ANK3 229 snv-1=2
ADD3 41
FADS2 28 snv-1=2
PACS1 78 snv-1=1
SHANK2 322 snv-1=1
CACNA1C 302 snv-1=1
STARD9 52 snv-1=1
ZNF592 26 snv-1=1
GRIN2A 167 snv-1=1
HDAC5 17
ZCCHC2 40

NCAN 17
STK4 44 snv-1=2

TFAP2B 11
DFNA5 23
SLC25A17 12
HLF 24
PHF15 18 snv-1=1 ODZ4 なし

Abstract

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1×10−4 in an additional 9,412 cases and 137,760 controls. 

Here, we report the second GWAS of the PGC Bipolar Disorder Working Group, comprising 20,352 cases and 31,358 controls of European descent in a single, systematic analysis, with follow up of top findings in an independent sample of 9,412 cases and 137,760 controls.

RESULTS

GWAS of bipolar disorder (BD)

We performed a GWAS meta-analysis of 32 cohorts from 14 countries in Europe, North America and Australia (Supplementary Table 1A), totaling 20,352 cases and 31,358 controls of European descent (effective sample size 46,582).


Table 1.

Genome-wide significant bipolar disorder risk loci

Locus Name*1Lead SNPCHRBPA1/A2GWAS Meta-analysisFollow-up samplesCombined
Freq. A1ORP-value*2ORP-value*3ORP-value*2
A. Thirty loci with lead SNP P < 5×10−8 in combined GWAS+followup analysis

1,PLEKHO1rs75441451150,138,699T/C0.811.0954.8E-071.0640.0101.0854.8E-08
2,LMAN2L**rs57195239297,376,407I/D0.340.925.8E-090.960.0300.933.8E-09
3,SCN2Ars171838142166,152,389A/G0.0750.871.5E-070.890.00170.882.0E-09
4,[Intergenic]***rs613329832194,465,711I/D0.410.932.3E-080.950.00310.937.9E-10
5,TRANK1**rs9834970336,856,030T/C0.510.905.5E-140.980.150.935.7E-12
6,ITIH1**rs2302417352,814,256A/T0.490.924.9E-090.940.00120.936.6E-11
7,CD47rs38046403107,793,709A/G0.531.0759.3E-081.0440.0161.0652.0E-08
8,FSTL5rs117241164162,294,038T/C0.160.903.3E-080.950.0310.922.4E-08
9,ADCY2**rs20055069557,587,236I/D0.820.911.2E-070.940.0110.921.5E-08
10,SSBP2rs10035291580,796,368T/C0.681.0811.1E-071.0470.0181.0702.7E-08
11,RIMS1rs57970360672,519,394D/I0.441.0663.1E-061.0620.00161.0643.5E-08
12,POU3F2**rs2388334698,591,622A/G0.520.938.6E-080.950.00510.944.0E-09
13,RPS6KA2rs104559796166,995,260C/G0.530.934.6E-080.970.0460.944.3E-08
14,THSD7Ars113779084711,871,787A/G0.301.0687.3E-061.0952.9E-051.0762.5E-09
15,SRPK2rs731883217105,048,158T/C0.330.927.0E-080.940.00150.921.1E-09
16,MRPS33rs2012318747140,700,006D/I0.250.929.4E-080.930.00080.926.2E-10
17,ANK3**rs109943181062,125,856C/G0.0571.1514.5E-071.1300.00211.1456.8E-09
18,ADD3**rs5913444910111,745,562I/D0.161.1055.0E-081.0590.0171.0901.2E-08
19,FADS2**rs122268771161,591,907A/G0.291.0951.2E-081.0620.00731.0859.9E-10
20,PACS1rs108960901165,945,186A/G0.811.0942.1E-071.0620.00891.0841.9E-08
21,PCrs71225391166,662,731A/G0.350.932.2E-070.960.0150.943.8E-08
22,SHANK2rs125756851170,517,927A/G0.311.0661.2E-051.0885.7E-051.0737.7E-09
23,CACNA1C**rs10744560122,387,099T/C0.341.0872.9E-091.0520.00861.0763.6E-10
24,STARD9rs44473981542,904,904A/C0.121.1121.1E-071.0720.00791.0999.4E-09
25,ZNF592rs1392212561585,357,857I/D0.280.928.5E-090.970.0820.932.7E-08
26,GRIN2Ars11647445169,926,966T/G0.650.931.2E-070.939.8E-050.931.1E-10
27,HDAC5rs1121147641742,201,041T/G0.690.931.7E-060.940.00210.932.5E-08
28,ZCCHC2rs115577131860,243,876A/G0.291.0741.2E-061.0590.00381.0693.6E-08
29,NCAN**rs1114444071919,358,207T/C0.151.1242.4E-101.0400.0751.0971.3E-09
30,STK4rs2020128572043,682,549I/D0.280.9233.0E-070.9420.00430.9291.1E-08

B. Additional loci with lead SNP P < 5×10−8 in GWAS analysis

TFAP2Brs55648125650,816,718A/G0.900.894.9E-080.950.0680.918.5E-08
DFNA5rs17150022724,771,777T/C0.880.892.7E-080.960.0870.918.6E-08
SLC25A17rs1383212241,209,304A/G0.501.0834.7E-091.0120.281.0601.9E-07
HLFrs8843011753,367,464T/C0.371.0845.8E-091.0130.261.0612.1E-07
PHF15rs3293195133,906,609A/G0.431.0821.5E-081.0190.181.0612.1E-07
ODZ4**rs734966881179,156,748A/T0.141.111.0E-081.0160.291.0834.2E-07
[Intergenic]***rs57681866257,975,714A/G0.060.855.0E-080.970.230.891.2E-06
[Intergenic]***rs132313987110,197,412C/G0.110.893.4E-080.9980.470.924.6E-06
*1Loci are numbered 1 to 30, ordered by genomic position, with previously reported gene name for published loci
*2P-values for GWAS and combined analyses are two-tailed, bold and underlined if p < 5×10−8.
*3P-values for follow-up are one-tailed based on the direction of effect in the discovery GWAS, bold and underlined if p < 0.05.
**Previously published and named loci. (Locus 12 would be named as Intergenic, nearest gene is POU3F2 691Kb.)
***Intergenic loci nearest genes: Locus 4 PCGEM1 824kb, Table 1B chr2 locus VRK2 298Kb, Table 1B chr7 IMMP2L 106Kb.

Integrative functional genomic analysis of human brain development and neuropsychiatric risks

Mingfeng Li et.al

Science. 2018 Dec 14

MEF2C=71

SATB2=65

TCF4=147

TSHZ3=30

Abstract

Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.

Graphical Abstract

INTRODUCTION:
Disruption of this regulation can lead to neuropsychiatric disorders.

RATIONALE:

The regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types.

RESULTS:

Here we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood.

Moreover, genes including MEF2CSATB2, and TCF4, with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity.

CONCLUSION:

We generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease.


Cellular and temporal convergence of neuropsychiatric disease risks



At the gene level, multiple genes in ME37 identified using our less stringent criteria for interaction were associated with up to four or more different traits and disorders, including MEF2CZNF184TCF4, and SATB2, all genes critical for neurodevelopment and/or implicated in neurodevelopmental disorders () (Fig. 7, B and C). 

Genetic Relationships Between Schizophrenia, Bipolar Disorder, and Schizoaffective Disorder

Alastair G. Cardno Michael J. Owen
3, May 2014



Nearest Gene 韓国人固有の変異数、非同義変異数
MIR137            27,0
VRK2               191,2
ZNF804A          129,1
PCGEM1           10,0
MHC                   0
MMP16                90,0
CSMD1                1786, 1、SNV-35が1、
LSM1                   24,0
CNNM2                51
NT5C2                   26,1
AMBRA1               73,1
NRGN                     2,0
CCDC68                18,1
TCF4                       147,0
ODZ4                       0
CACNA1C                302,1
NCAN                        17,0
ZNF804A                  129,1
ITIH3-ITIH4              13,0
ANK3                        229,2


ほとんどがダブっており、下記2つのみ
Nearest Gene
STT3A  13,0
SYNE1  170、6











Abstract

There is substantial evidence for partial overlap of genetic influences on schizophrenia and bipolar disorder, with family, twin, and adoption studies showing a genetic correlation between the disorders of around 0.6.

Schizoaffective disorder has been less investigated but shows substantial familial overlap with both schizophrenia and bipolar disorder. 

A twin analysis is consistent with genetic influences on schizoaffective episodes being entirely shared with genetic influences on schizophrenic and manic episodes, while association studies suggest the possibility of some relatively specific genetic influences on broadly defined schizoaffective disorder, bipolar subtype.

Table 2.

Genome-Wide Association Study Findings for Schizophrenia and Bipolar Disorder From the Review by Sullivan et al 70



PhenotypeChromosome Where Marker Is LocatedNearest GeneOR
Schizophrenia1MIR1371.12
2VRK21.09
2ZNF804A1.10
2PCGEM11.20
6MHC1.22
8MMP161.10
8CSMD11.11
8LSM11.19
10CNNM21.10
10NT5C21.15
11AMBRA11.25
11NRGN1.12
18CCDC681.09
18TCF41.20
Bipolar disorder11ODZ41.14
12CACNA1C1.14
19NCAN1.17
Schizophrenia and bipolar disorder combined2ZNF804A1.11
3ITIH3-ITIH41.12
10ANK31.22
12CACNA1C1.11

Table 3.

Disorder Specificity of Genome-Wide Association Study Findings for Schizophrenia and Bipolar Disorder in the Psychiatric Genomics Consortium Cross-Disorder Group Study of 5 Psychiatric Disorders (2013) 73



Phenotype in Original GWASChromosome Where Marker Is LocatedNearest GeneDisorders Showing Association
Schizophrenia1MIR137SZ, ASD
2PCGEM1SZ, ASD
6MHCSZ
8MMP16SZ
8CSMD1SZ
10CNNM2SZ, MDD
10NT5C2SZ, BPD, MDD, ASD, ADHD
11STT3ASZ
18CCDC68SZ, BPD, MDD
18TCF4SZ, ASD
Bipolar disorder6SYNE1BPD
10ANK3BPD
11ODZ4BPD
12CACNA1CBPD, SZ, MDD

Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

Suzanne Sniekers et.al

Nature genetics 2017 May 22

①韓国人固有の変異は大部分が何らかのパーソナリティー障害・精神疾患に関連しているが、同時にやはり知能にも関連している。以下二つの遺伝子に関して、追記すること

EXOC4  320,1

NEGR1  312,1

②GWAS論文で知能をターゲットにしている論文は必ずこの論文を参照文献にあげているはず。
この論文の引用数は500を超えるので、この論文から2017年6月以降の論文は思ずる式に出てくる
以下はその例である

Tutorial: a guide to performing polygenic risk score analyses


Analysis of shared heritability in common disorders of the brain


Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals


Despite substantial heritability
 (0.54)
and confirmed polygenic nature, initial genetic studies were mostly underpowered

Here we report a meta-analysis for intelligence of 78,308 individuals.

We identify 336 single nucleotide polymorphisms (SNPs) (METAL P<5×10−8) in 18 genomic loci, of which 15 are novel. 

Roughly half are located inside a gene, implicating 22 genes, of which 11 are novel findings.

Gene-based analyses identified an additional 30 genes (MAGMA P<2.73×10−6), of which all but one have not been implicated previously. 

Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg=0.89, LD Score regression P=5.4×10−29). These findings provide novel insight into the genetic architecture of intelligence.

All association studies were performed on individuals of European descent

The estimated rg was 0.89 (SE=0.08, P=5.4×10−29), indicating substantial overlap between the genetic variants influencing intelligence in childhood and adulthood, and warranting a combined meta-analysis.

The full meta-analysis of all 13 cohorts (maximum N=78,308) included 12,104,294 SNPs.

SNP-based heritability was estimated at 0.20 (SE=0.01) in the total sample, and this was comparable in adults (0.21, SE=0.01) and children (0.20; SE=0.03). These estimates were obtained using LD Score regression and are likely to be biased downwards.

The meta-analysis identified 18 independent genome-wide significant loci (Fig. 1Fig. 2aTable 1), including 336 top SNPs (i.e. below the genome-wide threshold of significance; Supplementary Table 4)

Functional annotation of the 336 genome-wide significant SNPs showed that a large proportion was intronic (162/336) (Fig. 2b). 

Lead SNPs rs12928404 (located in the intronic region of ATXN2L) had the highest probability of being a regulatory SNP based on the Regulome database score and of the eight lead SNPs that were eQTLs, this SNP was associated with differential expression of the largest number of genes (i.e.14). Focusing on brain tissue, the T allele of this SNP, which was associated with higher intelligence scores, was associated with lower expression of TUFM (Supplementary Table 6).

【右の数値が、韓国人ども固有の変異数,SNV-1】

ATXN2L  11,0

TUFM  3,0


Table 1

FOXO3  42,0
PDE1C  176,0
CYP2D7  8, 1
EXOC4  320,1
ARHGAP15  231,0
NEGR1  312,1
CSE1L  17,0
ATXN2L  11,0
MEF2C  71,0
LINC01104  0
SKAP1  86
APBA1  87
ZNF638  70,1






Contribution of rare and common variants tointellectual disability in a high-risk population subisolate of Northern Finland 

Mitja I Kurki et.al

May 28, 2018

①この論文の著者らは、1年後ほぼ同じ内容の論文を再度発表し、ネイチャー掲載されている。
この論文の記述はダラダラしているが、ネイチャー掲載論文はずっと短い。こんなこともあるのか?と驚いた

Contribution of rare and common variants to intellectual disability in a sub-isolate of Northern Finland

Abstract
The contribution of de novo variants in severe intellectual disability (ID) has been extensively studied whereas the genetics of mild ID has been less characterized. To elucidate the genetics of milder ID we studied 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. Using exome sequencing, we show that rare damaging variants in known ID genes are observed significantly more often in severe (27%) than in mild ID (13%) patients. We further observe a significant enrichment of functional variants in genes not yet associated with ID (OR: 2.1). We show that a common variant polygenic risk significantly contributes to ID. The heritability explained by polygenic risk score is the highest for educational attainment (EDU) in mild ID (2.2%) but lower for more severe ID (0.6%). Finally, we identify a Finland enriched homozygote variant in the CRADD ID associated gene.

②驚いたことに、韓国人どもは、RORA遺伝子について、SNV-35を1つ共有している。SNV-1は257に過ぎないものの充分に多い。

Overlapping microdeletions involving 15q22.2 narrow the critical region for intellectual disability to NARG2 and RORA

等、RORA遺伝子もヒトの精神に関連する遺伝子であることはほぼ確実である

Abstruct

To elucidate the genetic background of milder ID we studied a regional cohort of 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland.
We analyzed rare variants using exome sequencing and CNV genotyping and common variants using common variant polygenic risk scores. As controls we used a Finnish collection of exome sequenced (n=11311) and GWAS chip genotyped (n=11699) individuals.

 
Finally, we identified a homozygote variant in the CRADD gene to be a cause of a specific syndrome with ID and pachygyria.

The frequency of this variant is 50x higher in the Finnish population than in non-Finnish Europeans, demonstrating the benefits of utilizing population isolates in rare variant analysis of diseases under negative selection. 


Introduction 


Intriguingly siblings of mild ID individuals have low IQ compared to the general population whereas the IQ of siblings of severe ID individuals do not differ from the general population5 .

This suggests that mild ID represents a low extreme in a normal distribution of IQ, while severe ID is a distinct condition with different etiology5 .

 Finland is a wellcharacterized genetic isolate where the small size of the founder population, subsequent bottleneck effects, and genetic drift have caused an enrichment of some rare and low frequency variants as compared to other European populations7,8.

In a population with a recent bottleneck, such as Finland, variants conferring a high risk for a disease with reduced fecundity can exist at markedly higher frequencies than in older populations because negative selection has not had time to drive down the allele frequencies, and therefore these variants are easier to associate to a disease 9 .

【この記述は韓国人どもにまさに当てはまる】

Interestingly, ID (Figure 1) and other neurodevelopmental and neuropsychiatric diseases (NDD) like schizophrenia (Supplementary Figure 1) have a higher prevalence in North-Eastern Finland as compared to South-Western Finland10,11. It has been hypothesized that such a pattern is related to the recent bottlenecks of these regions.

Here we describe a comprehensive genetic characterization of 442 independent NFID patients with unknown disease etiology, enriched for mild (51.4%) forms of ID (Table 1).

We then examined the genetic architecture of this ID cohort that has undergone a population bottleneck and has a high proportion of mild ID cases

we compared the identified variants to 640 exome-sequenced individuals with cognitive impairment, schizophrenia (SCZ) or autism spectrum disorder (ASD).無題
 
Figure 1. ID prevalence estimates in different municipalities in Finland. The primary NFID collection municipalities of Northern Ostrobothnia, Kainuu and Lapland are outlined in solid black. The approximate boundary between early and late settlements is shown with a dashed line.

無題2

 Materials and Methods

Samples

Starting in January 2013 subjects for the NFID (Northern Finland Intellectual Disability) project have been recruited from the Northern Ostrobothnia Hospital District Center for Intellectual Disability Care and from the Department of Clinical Genetics of Oulu University Hospital.

Identification of sequenced neurodevelopmental disorder cases from population registries and disease collections 

We identified individuals with neurodevelopmental disorder (NDD) phenotypes (intellectual disability, schizophrenia, autism and epilepsy) among 5904 individuals with exome sequence data in the FINRISK study. 

Regional prevalence estimation of intellectual disability and schizophrenia in Finland

The Social Insurance Institution of Finland provides social security coverage for Finnish residents. The Social Insurance Institution of Finland centrally provides all disability pensions in Finland and maintains a database of all residents on a disability pension and the reason for the pension.

Results 

We first estimated the regional prevalence of ID in Finland using the social security disability benefits register.

We observed a higher prevalence of individuals receiving disability benefits for ID in the Eastern and Northern parts of Finland as compared to Southern and Western Finland (Figure 1).

After joint genotype calling and quality control we analyzed the exomes of 442 independent ID patients (Table 2) and 2,206 genetically matched population controls.

Mutations in known genes causing cognitive impairment 

 To identify those individuals who had a potential causative variant in the exome analysis, we first searched for damaging missense or protein truncating variants (PTV) in 818 known, curated genes selected from the DDD-study (see Materials and Methods and full gene list in Supplementary Table 1).

. Within these 818 genes we identified a likely pathogenic mutation in 64 patients (Supplementary Table 2).


FINRISK population cohort, we observed the strongest enrichment in the PTV class of variants (OR: 12.04, 95% CI: 5.46–28.56, p: 1.4e-11) followed by dominant acting (OR: 6.03, 95% CI: 3.57–10.24, p: 7.5e-12) and recessive (OR: 1.83, 95% CI: 0.7–4.30, p: 1.4e-1) constrained/damaging missense variant classes (Figure 2).

 Burden of variants in genes not previously implicated in cognitive impairment

Table 3 Homozygous Finnish enriched variants observed >= 2 times across NFID and the Southern and Northern Finnish NDD cases and not observed in any controls as homozygous. Variants in highlighted rows are significant after multiple testing correction. 

【下が抽出された遺伝子リスト。数字は、韓国人固有の変異とSNV-1,
RORA遺伝子が注目される

table 3

CRADD missense 71, 1

HGF missense 19, 0

EPS8 missense 87, 1

BPNT1 missense 12,1

INTS1 missense 20,1

MRPS5 missense 28,1

TACC2 missense 118,2

ADAM15 missense 6,1

POTEC missense 55,2 ただし、snv-35=2

TMPRSS15 missense 70,0

RORA missense 257,0 ただし、snv-35=1

OR56A4 missense 3,1

ART1 missense 32,0
 
NLRP13 frameshift 20,1

MTUS1 missense 103,2

SMG7 missense 38,0

PTCHD1 missense 10,1


Discussion 
Here we have described a comprehensive genetic analysis of an ID cohort from a population with a relatively high prevalence of ID.

We observed educational attainment, IQ and schizophrenia polygenic risk scores to be associated with ID explaining an estimated 0.94%, 0.48% and 0.55% of the heritability on the liability scale, respectively

Finally, we studied if some variants enriched in Finland in the relatively recent bottleneck would be associated with ID in our cohort.

We conclusively identified a recessive variant in the CRADD gene enriched in Finland in three NFID patients and one NDD patient from the population NDD cohorts (Table 3).

The allele frequency of this variant is 50x higher in the Finnish population than in nonFinnish Europeans.

We also observed three cases that were homozygous missense variant carriers in the INTS1 gene (Table 3). Recently a loss-of-function variants in INTS1 have been identified in three unrelated moderate to severe ID patients 44. One of our patients had mild ID and the two others had moderate/severe ID

However one variant among the top 10 variants, a missense variant in the  DENR gene, was totally absent in non-Finnish GnomAD individuals, is very rare in the Finnish population but enriched in Northern Finland (6.3x10-4 in GnomAD Finns; 9.7x10-4 in our Northern Controls and 3.1x10-4 in Southern controls).

The variant replicated in the Northern NDD cohort and was extremely rare in Southern Finnish NDD cases and controls (1/322 in cases and 1/1,594 in controls) but had a high OR estimate consistent with associations in NFID and Northern NDD samples.

South Korean scientists’ outcry over planned R&D budget cuts
Nature
05 October 2023
Sara Reardon

メモすべき点は下記。

South Korea’s scientists have been left reeling after the government proposed substantial cuts to the 2024 federal research budget. 


Government spending on research and development in the country has been among the highest in the world, as a proportion of gross domestic product (GDP), and the announcement has sparked a rare outcry from researchers.

The cuts, announced by South Korea’s Ministry of Science and ICT (MSIT) on 22 August, are the first to target science funding in more than three decades.

Since 1991, the country’s R&D budget has increased steadily, accounting for more than 4.5% of GDP in 2023, according to the Organisation for Economic Co-operation and Development, or OECD (see ‘Growing budget’).

Even when South Korea experienced a financial crisis in 1998, the research budget remained steady.


無題

South Korean scientists, the person says, have not collaborated as much as those in Europe and the United States, either domestically or internationally, so the government plans to expand the budget for international research exchange.

Sinking morale

異常とは何か
小俣 和一郎
講談社現代新書
2010年

メモすべき点は下記

フロイトの精神分析
教壇精神医学からは白眼視され、長い間にわたって疑問視されることとなる

p30
近代精神医学の成立以降、「異常=精神病(精神障害)」という認識の基礎が出来上がり、それは次第に一般社会の中へ浸透していく

p98
私は精神病じゃない
【4つの統合失調症らしき患者の症例が出ている】


朝鮮世祖の字小主義とその挫折
河内 良弘(京大教授~天理大学教授)
天理大学学報

記述内容の水準の高さから、本物の研究者と感じたので、著者略歴を調べた。

李氏朝鮮の事大主義は良く知られているが、この字小主義には驚いた。しかし、「野人皆慕悦威徳、争来朝見」とは恐らくは当時の対馬の人々が李成桂に謁見したことを示すと思われる。
対馬は山地ばかりであり、宿命的に交易(又はいわゆる倭寇)によってしか、生存できない。

この貴重な一次資料に基づく内容から、朝鮮半島の人々の屈折した精神異常性を真に痛感する。

同じ頃、安南=ベトナムでも、中国をまねて、自らに朝貢する国を有する形式をとっている。つまり、安南は、字小主義ではなく、直接に中国をまねている。李氏朝鮮創始者は、安南の真似=中国の猿真似すらできず、この字小主義をとらざるを得なかったのだ。

貴重な論文である

朝鮮の世祖は、女真人や倭人を臣下となし、女真人の土 地をわが藩簸とよび、夷狭をわが子として招撫する立場を「字小之義」と呼んだ。字小の義とは、中国の古語で、者が小者をいたわり、はぐくむ意で、事大の礼を逆の立場から言いかえたものである。

魯山君日記

時世祖、以務農輿学、養兵為事。期於控弦百万、威制夷秋、習陣訓兵。倭野人皆慕悦威徳、争来朝見。

世祖の威徳を慕い、倭人および野人が、争い来りて朝見すとは、世祖を儒教的徳治思想にいう理想的君主に擬し記述であって、世祖の直接の発言ではないが、実録記者が世祖の理想とするところに即して記るした一文である

諭威士口道都節制使郭連域目、野人倭人、倶為我藩態。
倶為我臣民。王者等視無異。或用為力、或用為声、不
可以小弊拒却来附之心。予即位以後、南蛮北秋、来附
者甚衆。皆願為我子、此天所誘也。非予智力。但来往
駅路、有弊国家、支待難継。以時宜授卿方略、如左。

 世祖は、こうした政治的立場、すなわち野人倭人をわが臣民となし、その土地をわが藩簸とよび、夷秋をわが子として撫値する立場を、「字小の義」と呼んだ。


少数者の権利主張と「 共同性」形成
-日本における定住外国人と国家への参画をめぐって-
 鄭暎恵(ちょん・よんへ 広島修道大学助教授
シ ンポ ジ ウ ム ・構 造 変 容 と法 社 会 学(2)

著者の主張は、下記に尽きる

一 九五二年四月二八日午後一〇時三〇分一方的に日本国籍を剥奪されるまでは、これら在日朝鮮人は全て日本国籍保有者だったことを忘れてはならない。

しかし、ノーベル賞は言うまでもなく全63もの国際的な科学関連賞の受賞者が皆無であるにもかかわらず、「嘘と騙し」にのみ長じている故に「我々は優秀な民族というバカげた幻想」に浸りきっているため、長年、父祖3代にわたり、日本に住みながら日本国籍を取得せずにいる精神面での完全なDNA異常民族ども。貴様らの精神面での異常性に関する遺伝学論文に基づく明確な証拠が存在する。FDA論文だ!

それなら、長年日本に住んでいるのだからして国籍取得すればよく、バカでもチョンでもそれくらい解るだろう。

一九九八年四月一 〇日、指紋押捺を拒否したことを理由に再入国不許可の処分を受けていた在日韓国人二世の チェ・ソンエさんに対して、最高裁は逆転敗訴の判決を出した。

( 1) 地方参政権を要求する運動とアイデンティティ
韓国籍を有する在日朝鮮人の二世・三世を中心に、地方参政権を要求する運動が八〇年代末より台頭してきた。

在日朝鮮人の二大民族組織である民団と総連では組織としての主張が大きく異なっている。

民団は地方参政権を要求し、総連は「 内政干渉になるから」と参政権一切の要求を否定している ( 後述)

差別をなくすためには、まず参政権の要求から始めるべきだという。

在日党を結成した李英和は、在日外国人が参政権を求める理由は「 単純明快」だとして、
(1)民 主主義と基本的人権の保障、
(2)日 本社会の国際化の必要、
(3)既 得権の返還および植民地支配の戦後「 補償」( 旧植民地出身者への人権保障) の三点をあげている。

(2) 日本での参政権一 切を「 拒否」する運動とアイデンティティ

朝鮮総連といった民族組織を中心に、日本における定住「 外国人」が何であれ参政権を要求することは大きな間違いだと否定する主張がある。数としては、参政権を要求する人々より少数かもしれないが、その主張は前者とは違う意味とレベルにおいて、近代国家への批判が含まれていて興味深い

内政干渉となるから参政権を要求しない代わり、アウトサイダーである自分たちにも干渉してくれるなと、日本社会からの支配を拒否している。

3) 地方参政権獲得を要求しないが否定もしない定住外国人とアイデンティティ

 定住外国人が参政権をもつことに対して、要求も拒否もしない人々が多くいる

日本への定住性は高いが、本人は帰化申請をすることもなく外国籍のまま、日本に住む外国人で、韓国籍朝鮮籍以外の人の多くがここに入るのではないだろうか。

日本選挙学会による「 選挙制度改革に関する有識者調査」(一 九九〇) だ が、定住外国人の参政権につい あった ( 複数回答)。 て、国政選挙に関して「 認めた方がいい」は四九・一 %、都道府県選挙は五五・七 %、市町村選挙は六九・八 %であった

次に、毎日新聞 ( 一 九九二年七月一 六日) によれば、九二年参議院議員立候補者のうち、「 永住資格のある在日外国人への選挙権付与」に関して、自民党が賛成二一 %と反対三七%、共産党が賛成二一 %と反対七〇%。その他社会党が七八%、公明党が八〇%、連合の会が七九%、民社党が六七%と、それぞれ賛成が多数派だった。

第三に、民団によると、全国三三〇二ある地方議会のうち、一 三五〇の議会が定住外国人の地方参政権を支持す、 る意見書/趣旨採択をしているという。

一九四七年外国人登録令が出され日本国籍を有しながらも外国人と見なされたことに始まり、一 九五二年四月二八日午後一〇時三〇分一方的に日本国籍を剥奪されるまでは、これら在日朝鮮人は全て日本国籍保有者だったことを忘れてはならない。


フィリピン戦線の日本兵
草の根の証言集
アルフォンソ・P・サントス
瓜谷みよ子 訳
パンリサーチ出版局
1987年

歴史は、50年程すると歪曲され、創出される。特に、完全な精神異常民族である韓国人どもが典型例である。

下記にメモした内容とほぼ同じことが、ヘリコプターで連れ去られた等々朝鮮人従軍慰安婦の最初期の証言に多数見られる。従って、第二区分を韓国精神疾患とする。

p43
その時処刑部隊の隊長が
突然、携帯電話のベルが鳴った
【1987年であれば、フィリピンでも携帯電話は珍しかったはずである。日本ですら、50%位の人しか持ってはいなかった。ベルがなったという翻訳から、無線通信ではない】

p50
ハイウェイで日本軍を待ち伏せしたり
【1942年頃のフィリピンにハイウェイなどないが、主要幹線道路という意味か?】

p190
大佐は以前この老人に雇われていたのだ
【当時の陸軍大佐は、連隊長・軍の参謀長クラスである】

Multi-ancestry eQTL meta-analysis of human brain identifies candidate causal variants for brain-related traits

Biao Zeng et.al

Nature Genetics 2022 Aug 1

FDA論文付属エクセルファイルと図3bの照合結果
ZNF823=10
THOC7=13
FURIN=7
CACNA1C=302, ns1=1
ABCB6=9
ZFAND2B=6
CNPPD1=3, ns1=1
FAM134A=7
EEF1A2=22
CNTN4=485,ns1=1, ns35=2
CLCN3=39
INO80E=5
PCCB=25
PBX424,ns1=1
GATAD2A=55
KCTD13=11,ns1=1
RERE=168,ns1=1
B3GAT1=16
XPNPEP3=33

Abstract

 We developed the multivariate multiple QTL (mmQTL) approach and performed a large-scale multi-ancestry eQTL meta-analysis to increase power and fine-mapping resolution. Analyzing 3,983 RNA-seq samples from 2,119 donors, including 474 non-European individuals, yields an effective sample size of 3,154.

Joint statistical fine-mapping of eQTL and GWAS identified 329 variant-trait pairs for 24 brain-related traits driven by 204 unique candidate causal variants for 189 unique genes.

Introduction

 we developed the multivariate multiple QTL (mmQTL) pipeline and applied it to a combined analysis of brain tissues from PsychENCODE, Religious Orders Study and Memory and Aging Project (ROSMAP) and GTEx.

Results

Analysis overview

We performed a multi-ancestry eQTL meta-analysis on RNA-seq gene expression data from non-overlapping samples from the dorsolateral prefrontal cortex (DLPFC) from PsychENCODE and ROSMAP, and 13 brain regions from GTEx (Figure 1A). 


Identifying candidate causal risk variants for brain-related traits

Integrating our eQTL fine-mapping results with candidate causal variants from large-scale GWAS45 using a joint fine-mapping approach9 identifies 7,564 variant-trait pairs (CLPP > 0.01) including 2,102 unique candidate causal variants and 1,666 unique genes among 668 complex traits (Extended Data Figure 7).

These results include 329 variant-trait pairs for 24 brain-related traits for 204 and 189 unique candidate causal variants and genes, respectively (Figure 6A).

Analysis of SZ and BD, two neuropsychiatric diseases with high genetic co-heritability identified candidate causal variants for 20 genes predicted to confer risk for one or both diseases (Figure 6B).

The top genes with CLPP > 0.5 for either of these diseases include ZNF823THOC7 and FURIN.

Candidate causal variants elucidate potential molecular mechanisms

rs117618017 is the top causal variant for AD and drives the expression of APH1B, a subunit of the gamma-secretase complex, which includes multiple AD risk genes as components (Figure 7A). 

戦争の歴史 日本と中国
こんなに違う日中の戦争観
黄文雄
2007年
ワック株式会社

(1)中国正史検索サイトでの結果
人相食
中国正史サイトにて、膨大な量がヒットする。これだけで、研究者なら論文書くことができる
意外であるのは、清史稿が25カ所と最も多く、確かに、黄氏の長年の研究どおりの記述がある

*清史稿(籠城に伴う記述)
頃大凌河之役,城中人相食,明人猶死守,及援盡城降,而錦州、松、杏猶不下,豈非其人讀書明理盡忠其主乎?自今凡子弟年十五歲以下、八歲以上,皆令讀書

*明史(大干ばつに伴う記述)
是秋,陝西、山西大旱饑,人相食。停歲辦物料,免稅糧,發帑轉粟,

(2)明実録、清実録、朝鮮人どもの猿真似記録 検索サイトでの検索結果
人相食での検索結果
*朝鮮人どもの猿真似記録=朝鮮王朝実録では18カ所と意外に少ない。
*清史稿に人相食の記述が多いにもかかわらず、清実録が5カ所であるのは、清史稿の作成における意図的操作がなされたと考えるしかないように感ずるが、よくわからん???。
*中国清朝の公式記録である清実録では、検索で一つのページに清時代における災害・飢饉等の異常事態がまとめられている。

乾隆帝統治下で山東省全域で人肉食があったことが解り、イメージが覆る。省レベルでは、この1回きりであり、道光帝十三年は記述が曖昧過ぎる。(全国的なものであった可能性もある)

順治元年春,荊門大饑。冬,鄖縣大饑。二年,棗陽、襄陽、光化、宜城大饑,人相食 。三年,太平、瑞安、崇陽大饑。四年,蘇州、震澤、嘉定、太湖、潛山、石埭、建德、宿松、江山、常山大饑。五年春,廣州、鶴慶、嵩明大饑, 人相食 
康熙
三十七年春,平定、樂平大饑, 人相食 
四十二年夏,永年、東明饑。秋,沛縣、亳州、東阿、曲阜、蒲縣、滕縣大饑。冬,汶上、沂州、莒州、兗州、東昌、鄆城大饑, 人相食 。四十三年春,泰安大饑, 人相食 ,死者枕藉;肥城、東平大饑, 人相食 ;武定、濱州、商河、陽信、利津、霑化饑;兗州、登州大饑,民死大半,至食屋草;昌邑、即墨、掖縣、高密、膠州大饑, 人相食 

乾隆
五十一年春,山東各府、州、縣大饑, 人相食 
道光
十二年春,昌平饑。夏,紫陽大饑, 人相食 
十三年春,諸城、日照大饑,民流亡。夏,保康、鄖縣、房縣饑, 人相食 
十四年春,歸州、興山大饑, 人相食 
二十七年,南樂饑, 人相食 

咸豐二年春,日照大饑。夏,全縣大饑。六年,黃縣、臨朐饑。七年春,肥城、東平大饑,死者枕藉;魚台、日照、臨朐亦饑, 人相食 

同治
五年,蘭州饑, 人相食 
七年春,即墨、孝義廳、藍田、沔縣饑。夏,涇州大饑, 人相食



(3)検索語句の検討
一般的な表現として 相食 が最も適切であり、相食=人肉食である。これ以外に無い。
人相食、民相食、人至相食 等々があり、人を削除して、相食での検索がベストである

朝鮮人どもの猿真似記録 62ヶ所とヒット数多いが、調べて見ると、実際に人肉食が、あったと思われるのは3回から4回であるが、中国とは条件が全く異なるので、やはりというしかない

1


2



3

4



5

p36
【元寇に関する記述として】
中国史上、海を渡っての遠征はモンゴル人の元のみであった

p73
三千年の防衛思想を大転換した中国

p74
国家戦略を「守勢」から「攻勢」に転じたのである
この「戦略的国境」とは「戦略的国境は、国家民族の運命を左右するもので、大陸棚、公海、南・北極、宇宙3次元を含むものでなければならない」としている

p75
中国人民解放軍は1987年
「地理的国境」の考え方から「戦略的国境」の考え方への転換を主張し、鄧小平の支持を得て国防戦略が守勢から攻勢へと転換した
中国の国家戦略が「陸」から「海」に変わったのは中国三千年史のなかで、初めての戦略大転換であった

p193
「三光作戦」
この「光」とは「からっぽ」という意味の中国語であり、日本語などではないことから、これも中国人の創作であることが分かる

p233
中国は唐以降から食人の風習が定着しているので、人間が多元的な食物として発展していった。それは私が数十年かけて中国の古典を渉猟し、百以上の食人籠城戦を研究したことから得られた、中国兵糧の特質である

p237
軍隊が民衆を捕食するのは、唐末が最盛期である

p247
専ら弱者を捕食する「食人集団」も現れた。史書はそれを「餓族」あるいは「噉人族」「飢寇」と称する

p256
軍中で食用人間を飼育する「宰殺務」
五代の時代(907~960)軍中に「宰殺務」(屠殺係)の役職が設けられ、専門に「高等哺乳動物」である霊長類・万物の長を飼育し、食用に供したことが伝えられている







A Functional Genetic Variation of the Serotonin (5-HT)Transporter Affects 5-HT1A Receptor Binding in Humans

Sean P. David et.al

The Journal of Neuroscience, March 9, 2005

多型データを得る目的のみである


In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [ 11C]WAY 100635. 


Materials and Methods

Two separate groups of healthy volunteers were included in this study. The first cohort consisted of 140 healthy British Caucasian subjects (64 males, mean  SD age of 51.5  8.8 years; 76 females, mean  SD age of 52.4  8.8 years; whole group, mean  SD age of 52.0  8.8 years) who were randomly selected from the OXCHECK study (Imperial Cancer Research Fund, 1995), this cohort was genotyped to study the population frequencies of known SNPs in the 5-HT1A receptor gene.

Table 1. Group characteristics and genotype frequencies for 5-HT1A SNPs in population of healthy Caucasian volunteers

crazyKorean4
Genotype frequencies and percentages for 140 healthy Caucasian controls from the greater Oxfordshire, United Kingdom,region are listed.Genetic variationwithinthis populationwas observed in onlyfour of nine SNPs,forwhich Hardy-Weinberg equation values are indicated. Characteristics of the subjects are as follows: age, median of 51.7 years, range of 36.4 – 68 years; mean  SD of 52.0  8.8.

Serotonin-1A receptor C-1019G polymorphism affects brain functional networks 
Haixia Zheng et.al
02 October 2017 nature scientific reports

韓国人という完全な精神異常民族、即ち、一切が感情で決定される奇妙な連中に関する決定的な、かつ、誰にでも分かり易い完全な証拠を見つけた。

セロトニン受容体遺伝子5-HT1Aの多型だ。感情だけの特殊な連中よ!貴様らの異常性の明白を極めた証拠だ!反論できるものならしてみろ!データ偽造・捏造しかないであろう

民族集団名 サンプル数 論文 C/C C/G G/G
韓国人 149 1 4.7% 34.9% 60.4%
韓国人 111 2 6.3% 41.4% 52.3%
中国人 400 3 59.7% 34.3% 6%
日本人 120 4 56.7% 33.3% 10%
白人・黒人・ヒスパニック 107 5 32% 47% 23%

論文 1  
Culture, serotonin receptor polymorphism and locus of attention

論文 2
Association Study between 5-HT1A Receptor Gene C(-1019)G Polymorphism and Panic Disorder in a Korean Population

論文 3 
Association between the serotonin 1A receptor C (-1019) G polymorphism and major depressive disorder in the northern Han ethnic group in China

論文 4
Serotonin-1A receptor C-1019G polymorphism affects brain functional networks

論文 5
Human 5-HT1A receptor C(x1019)G polymorphism and psychopathology

Abstract

The serotonin-1A (5-HT1A) receptor is strongly implicated in major depression and other affective disorders due to its negative regulation of serotonin neurone firing rates.

Behavioural and clinical studies have repeatedly reported that the −1019G allele carries a high susceptibility for affective disorders.

Here, we employed a genetic neuroimaging strategy in 99 healthy human subjects to explore the effect of serotonin-1A receptor polymorphism on brain resting-state functional connectivity (FC). 

We used functional magnetic resonance imaging, along with a seed-based approach, to identify three main brain networks: the default mode network (DMN), the salience network (SN) and the central executive network. We observed a significant decrease in the FC of the DMN within the dorsolateral and ventromedial prefrontal cortices in G-carriers.

Furthermore, compared with the C-homozygote group, we observed decreased FC of the SN within the ventromedial prefrontal cortex and subgenual anterior cingulate cortex in the G-carrier group.

Our results indicate that 5-HT1A receptor genetic polymorphism modulates the activity of resting-state FC within brain networks including the DMN and SN. 

Introduction

5-Hydroxytryptamine (5-HT), more commonly known as serotonin, is the most widely distributed neurotransmitter in the brain, and dysfunctions of the serotonergic system are thought to be important factors for major depressive disorder and other forms of affective disorders1,2,3.

In vivo, human positron emission tomography (PET) studies have demonstrated that the expression of autoreceptors is modulated by a 5-HT1A receptor gene C(−1019)G polymorphism, and, specifically, that the binding potential is increased with increasing frequency of the G allele5,6

This is associated with increased negative feedback and, consequently, decreased serotonin signalling. 

In accordance with these findings, clinical studies have also reported that the −1019G allele is associated with fear expression7, trait anxiety8, schizophrenia9, major depression and suicide10
【まさしく、韓国人という完全な精神異常民族にぴったり当てはまる】

Genetic studies have confirmed that the −1019G allele abolishes the transcription factor human nuclear deformed epidermal autoregulatory factor-1 (DEAF-1) and partially impairs Hairy/Enhancer-of-split-5 (Hes5), resulting in an increase in 5-HT1A receptor expression at the presynapse of serotonin-containing neurons of the raphe nuclei,

whereas it decreases postsynaptic 5-HT1A receptor expression in non-serotonin-containing neurons of the forebrain (hippocampus, cortex)
5,10,20,21








Furthermore, during emotional processing tasks, the 5-HT1A C(−1019)G polymorphism has been shown to impact the activity of forebrain targets, such as the amygdala8, insula and anterior cingulate7.

Interestingly, as in affective function, the G allele in healthy participants is also associated with a decrease in cognitive ability such as in error detection and attentional processing22,23
【まさしく、韓国人どもがあてはまる】

Taken together, we therefore hypothesised that the C(−1019)G 5-HT1A receptor polymorphism is a potential neurochemical modulator for FC in human brain networks that associate with emotional and/or cognitive processing.

To summarise, in the current study, we aim to fill this gap in the known effects of 5-HT1A C(−1019)G variant on resting-state brain networks. We used resting-state fMRI to investigate how the polymorphism of the 5-HT1A receptor affects brain functional networks and whether it is correlated with emotional and cognitive function in healthy adults.

Materials and Methods

current study included a total number of 120 Japanese participants (77 males, 43 females) who were voluntarily participating in the brain check-up system at the Shimane University Institute of Health Science.

he mean age of the participants was 56.3 ± 14 (SD) years.

All participants reported free of neurological and psychiatric disorders and brain injury.

We excluded 21 participants who showed abnormalities in structural MRI: 8 participants who exhibited apparent cerebral microbleeds, 7 with silent brain infarction and 6 with pathological subcortical white matter lesions. 
【韓国人という精神異常民族に同様の手段を用いれば、半数近くがはじかれるかもしれない】

 Finally, 99 healthy participants (65 males, 34 females, mean age 53.9 ± 13.1 (SD) years, ranging from 34 to 87 years old) were included in the statistical analysis.

Genotyping for the 5-HT1A Receptor

Genotypic analysis for 5-HT1A receptor (1019C/G) polymorphisms was carried out using the TaqMan SNP Genotyping Assay system (Assay ID: C_11904666_10; Applied Biosystems, Foster, CA, USA) as previously described in other studies by our group31.

Results

Genotyping

Genotyping was performed in all 120 samples. In order to control genotyping error, control samples with known genotypes were added to each 384-well plate.

Genotype distribution of the C(−1019)G polymorphism was checked by the Chi-square test and was consistent with Hardy-Weinberg Equilibrium (X 2 = 2.62, p = 0.11).

The minor allele frequency (G allele) was 0.267 (CC:68, CG:40, GG:12) which was consistent with the general Japanese population (0.247)9.

Since 21 participants showed abnormalities in structural MRI, they were excluded from the following analyses. 

As a result, 99 samples without abnormal structural MRI findings (CC:59, CG:28, GG:12) were used in the analyses of the effect of 5-HT1A receptor polymorphism on brain FC.

9
Serotonin 1A receptor gene, schizophrenia and bipolar disorder: An association study and meta-analysis.

【ここ以降は必要ないため読まず】


Culture, serotonin receptor polymorphism and locus of attention

Heejung S. Kim et.al

07 September 2009

Social Cognitive and Affective Neuroscience, Volume 5

韓国人という精神面での完全なDNA異常集団において、精神面での形質として顕著にみられるのが、抑制のきかない怒りという奇妙な現象である。19世紀において、李氏朝鮮においてカソリック布教にたずさわっていたフランス人の著作でも、その点を明記している上に、多くの識者が共通して指摘している。

通常、セロトニン受容体遺伝子5-HTR1Aについては、健常者とうつ病患者等々を比較して分析される場合が大部分である。この論文は韓国人の心理学者が筆頭著者であり、心理学の側面から私にはくだらんと思える分析をしているが、データだけ頂戴したところ、韓国人に関して、5-HTR1A多型の明確な相違が出てきた

①この論文による韓国人とヨーロッパ系アメリカ人との5-HTR1A多型の大きな相違

韓国人ども
C/C 4.69%
C/G 34.89%
G/G 60.4%

ヨーロッパ系アメリカ人
C/C 24.28%
C/G 46.43%
G/G 29.29%

②中国人に関して、同様に5-HTR1A多型を分析した結果

Association between the serotonin 1A receptor C (-1019) G polymorphism and major depressive disorder in the northern Han ethnic group in China

crazyKorean

上の通りであり、健常者に限れば、G/Gは、驚くべきことに、10%以下であり、ヨーロッパ系アメリカ人よりも少ない

 ③serotonin 1A receptor C (-1019) G polymorphismで論文検索すると論文がわんさかある。

A.韓国人どもで健常者、サンプル数111
C/C 6.30%
C/G 41.44%
G/G 52.25%

Association Study between 5-HT1A Receptor Gene C(-1019)G Polymorphism and Panic Disorder in a Korean Population より
crazyKorean2

B.サンプルは次の構成であり、アジア人以外の場合
白人479 (69%)
アフリカ系113 (16%)
ヒスパニック86 (12%)
アジア人10 (1.4%)
その他8 (1%)
サンプル数合計 696

C/C 32%
C/G 47%
G/G 23%
Human 5-HT1A receptor C(x1019)G polymorphism and psychopathology より

crazyKorean3


A及びBの論文データとこの論文データから精神異常民族韓国人どもと白人・黒人・ヒスパニックの多型は確実に異なっている。絶対に間違いない!

④日本人と比べてどうか?
幸いにもネイチャー論文が見つかった。
Serotonin-1A receptor C-1019G polymorphism affects brain functional networks

論文そのものは、明日別にメモするが、サンプル数120で次のとおりである。
当然だが、中国人とほぼ完全に同じ多型構成である。

CC:68(56%)
CG:40(33%)
GG:12(10%)

遂に、韓国人という精神異常民族の顕著な分かり易い精神的形質である制御不能な怒りの決定的な証拠、我々日本人・中国人との感性面での決定的な差の証拠をみつけたぞ!ヤッホー!誰にでも理解できるはずだ!ヘテロ優性・劣性という言葉を看護師さんは理解しているはずだ!

推定値で我々日本人の20%程度が理解できる分かり易い韓国人という精神異常民族の遺伝的証拠を示せる!FDA論文に基づき非同義変異が他民族集団よりも多いという一般人は勿論、看護師さんでさえ理解不能であろう難しい内容ではない。万歳!万歳!

上記ネイチャー掲載論文では、下記論文と多型に関しては同じ結果としている。従って、サンプル数も多くなる。
Serotonin 1A receptor gene, schizophrenia and bipolar disorder: an association study and meta-analysis

今、日本で時折煽り運転云々がニュースサイトや動画サイトで見られるが、恐らくは、大部分が、在日韓国・朝鮮人どもの所業とみて間違いない。明確な証拠だ。それと同時に、韓国人どもが遺伝的に見た場合には、他の人類と感情制御面で明白に異なることの誰にでも分かり易い明確な証拠だ!

変異ではなく、多型の特異性だ!

このような明確な結果が出る韓国人という精神異常民族の特異性を改めて痛感する。株価操作で一儲けたくらんだようで、一カ月前ぐらいから、常温超電導する物質を韓国人どもが見つけた云々の内容をよく見かけるが、やはり、単なる株価操作のために嘘だった


Abstract

The present research examined the interaction between genes and culture as potential determinants of individuals’ locus of attention.

As the serotonin (5-HT) system has been associated with attentional focus and the ability to adapt to changes in reinforcement,

we examined the serotonin 1A receptor polymorphism (5-HTR1A). Koreans and European Americans were genotyped and reported their chronic locus of attention.

There was a significant interaction between 5-HTR1A genotype and culture in the locus of attention. Koreans reported attending to the field more than European Americans, and this cultural difference was moderated by 5-HTR1A.

There was a linear pattern such that those homozygous for the G allele, which is associated with reduced ability to adapt to changes in reinforcement, more strongly endorsed the culturally reinforced mode of thinking than those homozygous for the C allele, with those heterozygous in the middle. 


CULTURE, SEROTONIN RECEPTOR POLYMORPHISM AND LOCUS OF ATTENTION

A large body of research in psychology has demonstrated that there are systematic factors that influence individuals’ modes of thinking. These cognitive differences, namely holistic vs analytic modes of thinking, are fostered by culture, as holistic thinking is more prevalent in Eastern cultural contexts, whereas analytic thinking is more prevalent in Western cultural contexts (Nisbett et al., 2001).

There is increasing empirical evidence suggesting a significant role for genes in influencing particular psychological outcomes, such as personality, social behaviors and proneness to psychological illnesses (e.g. Lesch et al.1996; Bachner-Melman et al.2005; Ben Zion et al.2006).

Thus, the possibility of a genetic basis for culturally variable psychological tendencies, such as holistic vs analytic mode of thinking is viable. Yet, research suggests that environmental input can significantly interact with the effect of genes (e.g. Caspi et al.2003; Bakermans-Kranenburg and van IJzendoorn, 2006; Taylor et al.2006; Eisenberg et al.2008; Kim-Cohen and Gold, 2009; but see also Risch et al.2009 for the case of 5-HTTLPR), and culture represents a potentially important source of environmental input.

In the present study, we examine how a particular gene (5-HTR1A) and culture interact to produce specific modes of thinking that are known to vary systematically across cultures.

Culture and locus of attention

It has been well documented that there are reliable differences in the modes of thinking between people from Eastern cultural contexts and people from Western cultural contexts (Nisbett et al., 2001).

People from east-Asian cultural contexts tend to adopt a holistic style of reasoning that is characterized by the tendency to attend to the entire field and attribute the causes of a social event to external situational factors.

In contrast, people from Western cultural contexts tend to adopt an analytic style of reasoning that is characterized by the tendency to attend primarily to focal information, and attribute causes of a social event to internal and dispositional factors (Nisbett et al.2001).

Moreover, there is strong evidence that these differences are sensitive to cultural and environmental factors and are thus, culturally based.

In short, holistic vs analytic mode of thinking—locus of attention in particular—is a strategy to direct cultural participants’ attention to culturally important tasks posed by their environment. In the present study, we examined the interaction between a genetic factor and culture as potential determinants of individuals’ chronic locus of attention.

Gene X culture interaction and modes of thinking

Much research has found that the serotonin (5-HT) system is implicated in an array of cognitive effects including attention, cognitive flexibility and long-term memory (see Schmitt et al., 2006 for review).

More specifically, these findings come from human studies, all of them conducted in Western cultures that utilize acute tryptophan (TRP) depletion (ATD). 

ATD involves orally administering an amino acid suspension without L-TRP, the only precursor for 5-HT in the brain, which reduces TRP transport into the brain by increasing competition for active transport sites across the blood−brain barrier.

ATD results in temporarily lower levels of 5-HT activity in the brain. 

ATD studies demonstrate that under the condition of 5-HT depletion, people show an increased ability to attend to relevant stimuli while ignoring irrelevant information (Schmitt et al.2000; Ahveninen et al.2002), and also show an increased ability to direct and focus cognitive activity on specific stimuli over a prolonged period of time (Ramaekers et al.1995).

In particular, we examined the gene by culture interaction focusing on the C(-1019)G 5-HTR1A gene. 5-HTR1A is an autoinhibitor of 5-HT release.

The G allele of the C(−1019)G polymorphism prevents binding of putative repressor proteins, leading to enhanced gene expression and reduced serotonergic neurotransmission (Lemonde et al.2003; Huang et al.2004), and has been tied to neuroticism and depression (Lemonde et al.2003; Strobel et al.2003; Huang et al.2004).

In the present research, we investigated the extent to which cultural factors play a role in the association between different genotypes of 5-HTR1A and cognitive functioning.

In the present study, we assessed people’s mode of thinking using the Analysis-Holism Scale (AHS) (Choi et al.2007), a validated scale that has been shown to predict cognitive differences.

METHOD

Participants

【引用省略するが、
①韓国人149(平均年齢:24.91)韓国で
②ヨーロッパ系アメリカ人140(平均年齢:26.97)アメリカで】

RESULTS

Genotype

Koreans and European Americans differed in their allelic distribution. Among Koreans, there was a higher proportion of G alleles (7 C/C, 52 C/G and 90 G/G) than among European Americans (34 C/C, 65 C/G and 41 G/G), χ2(2, N = 289) = 37.31, P < 0.001.


This difference is consistent with distributions found in previous observations (Lemonde et al., 2003 for European Americans and Yu et al., 2006 for Asians). Both groups resulted in Hardy−Weinberg equilibrium, χ2(2, N = 149) = 0.01, P = 0.99 for Koreans and χ2(2, N = 140) = 0.58, P = 0.75 for European Americans.

Gene X culture interactions

The ANOVA on locus of attention showed that there was a significant main effect of culture, F(1, 280) = 33.74, P < 0.001, such that Koreans (M = 5.49, s.d. = 0.70) reported attending more to the context than European Americans (M = 4.59, s.d. = 0.97) did.

【ここ以降は、心理学の分析である】

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