Associations of autozygosity with a broad range of human phenotypes

Abstract

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F_ROH) for >1.4 million individuals, we show that F_ROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F_ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F_ROH are confirmed within full-sibling pairs, where the variation in F_ROH is independent of all environmental confounding.

Fig. 1

Census of complex traits. Sample sizes are given for analyses of 57 representative phenotypes, arranged into 16 groups covering major organ systems and disease risk factors. HDL high-density lipoprotein, LDL low-density lipoprotein, hs-CRP high-sensitivity C-reactive protein, TNF-alpha tumour necrosis factor alpha, FEV1 forced expiratory volume in one second, FVC forced vital capacity, eGFR estimated glomerular filtration rate

Fig. 2

Mean F_ROH and F_IS for 234 ROHgen sub-cohorts. Each cohort is represented by a circle whose area is proportional to the approximate statistical power ($N{\sigma }_{F_{\mathrm{ROH}}}^2$) contributed to estimates of ${\beta }_{F_{\mathrm{ROH}}}$. Mean F_ROH can be considered as an estimate of total inbreeding relative to an unknown base generation, approximately tens of generations past. F_IS measures inbreeding in the current generation, with F_IS = 0 indicating random mating, F_IS > 0 indicating consanguinity, and F_IS < 0 inbreeding avoidance. In cohorts along the y-axis, such as the Polynesians and the Anabaptist isolates, autozygosity is primarily caused by small effective population size rather than preferential consanguineous unions. In contrast, in cohorts along the dotted unity line, all excess SNP homozygosity is accounted for by ROH, as expected of consanguinity within a large effective population. A small number of cohorts along the x-axis, such as Hispanic and mixed-race groups, show excess SNP homozygosity without elevated mean F_ROH, indicating population genetic structuring, caused for instance by admixture and known as the Wahlund effect. A few notable cohorts are labelled. BBJ Biobank Japan, BiB Born in Bradford, UKB UK Biobank, MESA Multiethnic Study of Atherosclerosis, TCGS Tehran Cardiometabolic Genetic Study

Fig. 3

Scope of inbreeding depression. a Effect of F_ROH on 25 quantitative traits. To facilitate comparison between traits, effect estimates are presented in units of within-sex standard deviations. Traits shown here reached Bonferroni-corrected significance of p = 0.0005 (=0.05/100 traits). Sample sizes, within-sex standard deviations, and effect estimates in measurement units are shown in Supplementary Data 9. FEV1 forced expiratory volume in one second. Traits are grouped by type. b Effect of F_ROH on eight binary traits with associated p values. Effect estimates are reported as ln(Odds-Ratio) for the offspring of first cousins, for which E(F_ROH) = 0.0625. Self-declared infertility is shown for information, although this trait does not reach Bonferroni corrected significant (${\mathrm{OR}}_{0.0625}$ = 2.6 ± 1.1, p = 0.0006). Numbers of cases and controls and effect estimates for all binary traits are shown in Supplementary Data 10. c Sex-specificity of ROH effects. The effect of F_ROH in men versus that in women is shown for 13 traits for which there was evidence of significant differences in the effects between sexes. For 11 of these 13 traits the magnitude of effect is greater in men than in women. Traits such as liver enzymes levels (alanine transaminase, gamma-glutamyl transferase) show sex-specific effects of opposite sign (positive in women, negative in men), which cancel out in the overall analysis. BMI body mass index, LDL low-density lipoprotein. All errors bars represent 95% confidence intervals

Fig. 4

Inbreeding depression caused by ROH. a Effect of different ROH lengths on height, compared with the effect of SNP homozygosity outside of ROH. The effects of shorter (<5 Mb) and longer (>5 Mb) ROH per unit length are similar and strongly negative, whereas the effect of homozygosity outside ROH is much weaker. The pattern is similar for other traits (Supplementary Fig. 11a; Supplementary Data 14). b ${\mathit{F}}_{\mathbf{ROH}}$ is more strongly associated than ${\mathit{F}}_{\mathbf{GRM}}$ in a bivariate model of height. Meta-analysed effect estimates, and 95% confidence intervals, are shown for a bivariate model of height ($\mathrm{Height}~F_{\mathrm{ROH}}+F_{\mathrm{GRM}}$). The reduction in height is more strongly associated with $F_{\mathrm{ROH}}$ than $F_{\mathrm{GRM}}$, as predicted if the causal variants are in weak LD with the common SNPs used to calculate $F_{\mathrm{GRM}}$ (Supplementary Note 5). The pattern is similar for other traits (Supplementary Fig. 15a, b; Supplementary Data 22). c F_ROH is a lower variance estimator of the inbreeding coefficient than F_GRM. The ratio of ${\beta }_{F_{\mathrm{GRM}}}:{\beta }_{F_{\mathrm{ROH}}}$ is plotted against $\frac{\mathrm{var}\left(F_{\mathrm{ROH}}\right)}{\mathrm{var}\left(F_{\mathrm{GRM}}\right)}$ for all traits in all cohorts. When the variation of $F_{\mathrm{GRM}}$ which is independent of $F_{\mathrm{ROH}}$ has no effect on traits, ${\widehat{\beta }}_{F_{\mathrm{GRM}}}$ is downwardly biased by a factor of $\frac{\mathrm{var}\left(F_{\mathrm{ROH}}\right)}{\mathrm{var}\left(F_{\mathrm{GRM}}\right)}$ (Supplementary Note 4). A linear maximum likelihood fit, shown in red, has a gradient consistent with unity [1.01; 95% CI 0.84–1.18], as expected when the difference between $F_{\mathrm{GRM}}$ and $F_{\mathrm{ROH}}$ is not informative about the excess homozygosity at causal variants (Supplementary Note 5). d F_ROH is a better predictor of rare variant homozygosity than F_GRM. The excess homozygosities of SNPs, extracted from UK Biobank imputed genotypes, were calculated at seven discrete minor allele frequencies ($F_{\mathrm{MAF}}$), and regressed on two estimators of inbreeding in a bivariate statistical model (see Supplementary Note 5). The homozygosity of common SNPs is better predicted by $F_{\mathrm{GRM}}$, but rare variant homozygosity is better predicted by $F_{\mathrm{ROH}}$. The results from real data (Fig. 4b, Supplementary Figs 15a, b and Supplementary Data 22) are consistent with those simulated here, if the causal variants are predominantly rare. All errors bars represent 95% confidence intervals

Fig. 5

Evidence ROH effects are un-confounded. a Linear decrease in height with increasing F_ROH. Average heights (in metres) is plotted in bins of increasing F_ROH. The limits of each bin are shown by red dotted lines, and correspond to the offspring of increasing degree unions left-to-right. The overall estimate of ${\beta }_{F_{\mathrm{ROH}}}$ is shown as a solid black line. Subjects with kinship equal to offspring of full-sibling or parent–child unions are significantly shorter than those of avuncular or half-sibling unions who in turn are significantly shorter than those of first-cousin unions. b Linear decrease in odds of ever having children with increasing F_ROH. Linear model approximations of ln(Odds-Ratio) for ever having children (1 = parous, 0 = childless) are plotted in bins of increasing F_ROH. A strong relationship is evident, extending beyond the offspring of first cousins. c ROH effects are consistent in adoptees. The ratios of effect estimates, ${\beta }_{F_{\mathrm{ROH}}}$, between adoptees and all individuals are presented by trait. All traits are directionally consistent and overall show a strongly significant difference from zero (average = 0.78, 95% CI 0.56–1.00, p = 2 × 10⁻¹²). FEV1 forced expiratory volume in one second. d ROH effects are consistent in full siblings. The ratios of effect estimates within full siblings to effects in all individuals (${\beta }_{F_{\mathrm{ROH}\text{\_}\mathrm{wSibs}}}:{\beta }_{F_{\mathrm{ROH}}}$) are presented by trait. Twenty-three of 29 estimates are directionally consistent and overall show a significant difference from zero (average = 0.78, 95% CI 0.53–1.04, p = 7 × 10⁻¹⁰). BMI body mass index. All errors bars represent 95% confidence intervals