Evidence for sex-specific genetic architectures across a spectrum of human complex traits

Abstract

Background: Sex differences are a common feature of human traits; however, the role sex determination plays in human genetic variation remains unclear. The presence of gene-by-sex (GxS) interactions implies that trait genetic architecture differs between men and women. Here, we show that GxS interactions and genetic heterogeneity among sexes are small but common features of a range of high-level complex traits.

Results: We analyzed 19 complex traits measured in 54,040 unrelated men and 59,820 unrelated women from the UK Biobank cohort to estimate autosomal genetic correlations and heritability differences between men and women. For 13 of the 19 traits examined, there is evidence that the trait measured is genetically different between males and females. We find that estimates of genetic correlations, based on ~114,000 unrelated individuals and ~19,000 related individuals from the same cohort, are largely consistent. Genetic predictors using a sex-specific model that incorporated GxS interactions led to a relative improvement of up to 4 % (mean 1.4 % across all relevant phenotypes) over those provided by a sex-agnostic model. This further supports the hypothesis of the presence of sexual genetic heterogeneity across high-level phenotypes.

Conclusions: The sex-specific environment seems to play a role in changing genotype expression across a range of human complex traits. Further studies of GxS interactions for high-level human traits may shed light on the molecular mechanisms that lead to biological differences between men and women. However, this may be a challenging endeavour due to the likely small effects of the interactions at individual loci.

Keywords: Gene-by-sex interactions; Genomic prediction; Sex-specific genetic architecture.

Fig. 1

Differences in variance components between the sexes. The fold difference between male and female genetic and residual variance components as estimated using common SNPs in unrelated white British individuals. Values larger than one indicate a larger variance in males, values smaller than one a larger variance in females

Fig. 2

Effect of relatedness and SNP density on estimates of heritability and genetic correlations. Estimates of male and female heritability obtained using common variants in unrelated individuals against those obtained using a related individuals and common variants or b including common and rare variants for unrelated individuals. c Comparison of estimates of genetic correlations between these two alternative analyses with the estimates obtained on the main set of unrelated individuals with common variants