The role of gene expression on human sexual dimorphism: too early to call

Abstract The genetic underpinning of sexual dimorphism is very poorly understood. The prevalence of many diseases differs between men and women, which could be in part caused by sex-specific genetic effects. Nevertheless, only a few published genome-wide association studies (GWAS) were performed separately in each sex. The reported enrichment of expression quantitative trait loci (eQTLs) among GWAS–associated SNPs suggests a potential role of sex-specific eQTLs in the sex-specific genetic mechanism underlying complex traits. To explore this scenario, we performed a genome-wide analysis of sex-specific whole blood RNA-seq eQTLs from 3,447 individuals. Among 9 million SNP-gene pairs showing sex-combined associations, we found 18 genes with significant sex-specific cis -eQTLs (FDR 5%). Our phenome-wide association study of the 18 top sex-specific eQTLs on >700 traits unraveled that these eQTLs do not systematically translate into detectable sex-specific trait-associations. Power analyses using real eQTL- and causal effect sizes showed that millions of samples would be necessary to observe sex-specific trait associations that are fully driven by sex-specific cis -eQTLs. Compensatory effects may further hamper their detection. In line with this observation, we confirmed that the sex-specific trait-associations detected so far are not driven by sex-specific cis -eQTLs.