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

Porcu, E.; Claringbould, A.; Lepik, K.; BIOS Consortium,; Richardson, T. G.; Santoni, F. A.; Franke, L.; Reymond, A.; Kutalik, Z.

doi:10.1101/2020.04.15.042986

bioRxiv · 10.1101/2020.04.15.042986

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

Porcu, E.·Claringbould, A.·Lepik, K.·BIOS Consortium,·Richardson, T. G.·Santoni, F. A.·Franke, L.·Reymond, A.·Kutalik, Z.

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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.

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Porcu, E., Claringbould, A., Lepik, K., BIOS Consortium,, Richardson, T. G., Santoni, F. A., Franke, L., Reymond, A., Kutalik, Z.. 2020-04-17. The role of gene expression on human sexual dimorphism: too early to call. https://doi.org/10.1101/2020.04.15.042986

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