Identifying sex-specific genetic effects across 733 traits in UK Biobank

Abstract

\n Sex-specificity has been reported in a wide range of diseases and complex traits. While sex-specific genetic effects have been documented for certain traits, the genetic mechanisms underlying sex differences in most traits remain largely unexplored. With its large sample size and wide range of diseases and traits, the UK Biobank—a large, prospective cohort study containing health history, phenotypic measurements, and genetic data for over 500,000 individuals—provides an opportunity to explore sexually dimorphic genetic architectures in a large number of traits and diseases. Here, we present a sex-specific analysis of 733 sex-stratified complex trait GWAS for 361,194 white British individuals in the UK Biobank, and report 16 traits with significant sex-specific differences in heritability. These 16 candidate traits with sex-specific genetic effects belong to 5 distinct groups: body fat mass and distribution, blood pressure, creatinine levels, snoring, and birth weight. Using a systematic sex-specific discovery-replication analysis, we identify 47 (31 novel) loci showing sex-specific effects on the traits related with body fat mass/distribution, blood pressure, and birth weight, and discover 74 potential sex-specific biological pathways from the enrichment analyses based on associated genes from QTL analysis. In addition, we present further evidence for significant sex-specific genetic effects in 13 traits spanning three trait groups (body fat mass/distribution, blood pressure, and birth weight) by comparing the prediction performance of sex-specific polygenic risk scores.