Extreme inbreeding in a European ancestry sample from the contemporary UK population

Loic Yengo et.al

03 Nature communications September 2019

バイオバンクＵＫのデータから、FROH>0.1を基準に、極度の近親交配即ち近親相姦を125例、0.03%検出している。 しかし、その具体的影響に関しては、推計に過ぎない。

気の重いテーマであるが、少なくとも、高麗前期の朝鮮半島の支配層では、極端な近親交配が一般的であったことは確実である。
複数の集団遺伝学論文が示すところの現代朝鮮人DNAの異様性の原因は、過去の歴史において、朝鮮半島で日本と中国とは異なる事象が生じたことを意味する。可能性が最も高いのは、やはり、何処をどう見ても、高麗前期の近親婚と高麗末期から李氏朝鮮時代の奴婢制である。


Abstract

In most human societies, there are taboos and laws banning mating between first- and second-degree relatives, but actual prevalence and effects on health and fitness are poorly quantified.

Here, we leverage a large observational study of ~450,000 participants of European ancestry from the UK Biobank (UKB) to quantify extreme inbreeding (EI) and its consequences. 

We use genotyped SNPs to detect large runs of homozygosity (ROH) and call EI when >10% of an individual’s genome comprise ROHs.

We estimate a prevalence of EI of ~0.03%, i.e., ~1/3652. EI cases have phenotypic means between 0.3 and 0.7 standard deviation below the population mean for 7 traits, including stature and cognitive ability, consistent with inbreeding depression estimated from individuals with low levels of inbreeding.

Results
Prevalence of EI in European descents from the UKB

 Following guidelines from the American College of Medical Genetics and Genomics (ACMG)26,27, EI was called for individuals with FROH > 0.1. The use of both FROH as a measure of inbreeding and of this threshold are recommended by the ACMG for detecting suspected consanguinity between parents.

Table 1 Mean number and length of runs of homozygosity (ROHs) detected in participants from the UK Biobank (UKB), including extreme inbreeding (EI) cases (defined as FROH > 0.1) and unrelated EI controls (defined as FROH < 0.01). We also report the mean and length of ROHs in simulated data under various mating types

From: Extreme inbreeding in a European ancestry sample from the contemporary UK population

 

Sample size

Mean number of ROHs per individual (SD)

Mean length of ROHs in Mb (SD)

Mean FROH (SD)

Observed ROHs in UKB participantsa

 EI cases (FROH > 0.1)

125

33.6 (10.3)

14.8 (15.6)

0.172 (.07)

 Unrelated EI controls (FROH < 0.01)

345,276

4.9 (2.2)

2.1 (0.8)

0.003 (.002)

ROHs from simulated data under various mating types

 Parent–offspring mating (PO)

19,062

38.1 (5.9)

17.6 (18.5)

0.253 (.054)

 Fullsibs mating (FS)

19,065

45.2 (5.9)

14.9 (15.4)

0.254 (.046)

 Halfsibs mating (HS)

19,048

25.0 (5.5)

13.6 (15.1)

0.128 (.040)

 Uncle/aunt–niece/nephew mating (AV)

19,108

28.3 (5.6)

12.0 (13.0)

0.127 (.036)

 Grandparent–grandchild mating (GP)

19,025

24.9 (5.4)

13.6 (15.1)

0.128 (.039)

 Double first cousins mating (DC)

19,080

31.6 (5.7)

10.8 (11.3)

0.128 (.032)

 First cousins mating (FC)

19,061

18.1 (4.7)

9.6 (10.9)

0.065 (.025)

 Mating between unrelated parents (UN)

18,912

4.8 (2.1)

2.0 (0.7)

0.004 (.002)

 Mating type 1 (MT1: PO or FS)

38,127

41.7 (6.9)

16.1 (16.9)

0.254 (.050)

 Mating type 2 (MT2: HS or AV or GP or DC)

76,261

27.4 (6.1)

12.4 (13.6)

0.128 (.037)

 Mixture of MT1 and MT2 mating (Mixture proportion: 54/125)

139,310

33.6 (9.6)

14.0 (15.2)

0.182 (.075)

  1. SD standard deviation
  2. aMean differences between EI cases and controls are statistically significant at p < 10−10

Fig. 3

From: Extreme inbreeding in a European ancestry sample from the contemporary UK population

Fig. 3

Chromosomal and positional distribution of runs of homozygosity (ROHs) detected in 125 EI cases (FROH > 0.1). Each row, with possibly multiple segments, represents a unique participant. Segments are groups by autosomal chromosomes from chromosome 1 (bottom of each panel) to chromosome 22 (top of each panel) ROHs are grouped in 6 length categories: between 1.5 and 5 Mb (a), between 5 and 10 Mb (b), between 10 and 20 Mb (c), between 20 and 50 Mb (d), between 50 and 100 Mb (e), and above 100 Mb (f). f also show inbreeding coefficients of individuals harbouring the largest ROHs

Table 3 Association between extreme inbreeding (EI) and multiple traits measured in UK Biobank participants (125 EI cases vs. 345,276 EI controls)

From: Extreme inbreeding in a European ancestry sample from the contemporary UK population

Traits (unit: trait SD)

Mean in EI cases

Mean in controls

Effect size (unit: trait SD)

Extrapolated effect size (unit: trait SD for 100% inbreeding)

Standard error (s.e.)

p Value

PEF
peak expiratory flow

−0.651

0.005

−0.656

−3.88

0.099

2.8 × 10−11

Height
standing height

−0.404

0.012

−0.417

−2.46

0.090

3.2 × 10−6

HGS
handgrip strength

−0.395

0.004

−0.441

−2.35

0.091

1.2 × 10−5

FIS
fluid intelligence score

−0.570

0.010

−0.581

−3.43

0.152

1.4 × 10−4

MTCIM
mean time to correctly identify matches

−0.334

0.003

−0.337

−1.99

0.091

2.0 × 10−4

AA
auditory acuity

−0.557

0.002

−0.559

−3.31

0.164

6.7 × 10−4

EA
number of years of education or educational attainment

−0.260

0.023

−0.283

−1.67

0.089

1.5 × 10−3

VA
visual acuity

0.370

0.003

−0.373

−2.21

0.179

0.037

NCh
number of children

−0.230

−0.009

−0.221

−1.31

0.089

0.013

HWR
hip-to-waist ratio

−0.640

0.005

−0.170

−1.01

0.090

0.058

Polygenic predictor of EA*

−0.259

−0.262

4.9 × 10−4

N/A

0.018

0.978

   

RR [log(RR)]

 

s.e. of log(RR)

P-value

NCh
number of children 

1.54

1.78

0.23 [−1.46]

N/A

0.302

1.3 × 10−6

NDIS
number of diseases diagnosed

12.2

6.90

1.44 [0.36]

N/A

0.089

3.6 × 10−5

NDIS*

13.9

8.90

1.34 [0.29]

N/A

0.083

4.4 × 10−4

NDIS parents

2.16

2.24

0.96 [−0.04]

N/A

0.065

0.507

  1. Mean FROH is ~0.172 (SD: 0.067) in EI cases and ~0.003 (SD: 0.002) in EI controls. Effect sizes were estimated using either linear regression or overdispersed Poisson regression (latter for the following traits NCh, NDIS, NDIS* and NDIS parents) of the trait on the EI binary status. Extrapolated effect sizes in trait SD for 100% inbreeding were obtained by dividing estimated effect size by the difference in mean FROH between EI cases and EI controls, i.e., ~0.17. Traits analysed, include peak expiratory flow (PEF), standing height, handgrip strength (HGS), fluid intelligence score (FIS), mean time to correctly identify matches (MTCIM), auditory acuity (AA), number of years of education or educational attainment (EA), visual acuity (VA), number of children (NCh), hip-to-waist ratio (HWR), number of diseases diagnosed (NDIS) based on the International Classification of Diseases, Tenth Revision (ICD10). NDIS* refers to NDIS in individuals with at least one disease diagnosed. We also compared the number of disease-groups UKB participants reported their parents to be affected with (NDIS parents). RR relative risk, SD standard deviation. Estimates were adjusted for age at recruitment, recruitment centre (treated as a categorical factor), sex, year of birth (treated as a continuous variable), genotyping batch (treated as a factor), socioeconomic status measured by the Townsend deprivation index and population structure measured by ten genetic principal components estimated from HM3 SNPs. Polygenic predictor of EA was calculated using summary statistics from the Lee et al. (2018) study (excluding the UKB) and also adjusted for ten principal components. Inbreeding load for NCh was estimated as B = −log(RR) = 1.46 (95% confidence interval: [0.87–2.05]).