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
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).
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.
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.
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
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).
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.
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.
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