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

View ORCID ProfileEleonora Porcu, Annique Claringbould, Kaido Lepik, BIOS Consortium, Tom G. Richardson, Federico A. Santoni, Lude Franke, Alexandre Reymond, Zoltán Kutalik
doi: https://doi.org/10.1101/2020.04.15.042986
Eleonora Porcu
1Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
2Swiss Institute of Bioinformatics, Lausanne Switzerland
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  • ORCID record for Eleonora Porcu
  • For correspondence: eleonora.porcu@unil.ch alexandre.reymond@unil.ch zoltan.kutalik@unil.ch
Annique Claringbould
3University Medical Centre Groningen, Groningen, the Netherlands
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Kaido Lepik
4University Center for Primary Care and Public Health, Lausanne, Switzerland
5Institute of Computer Science, University of Tartu, Tartu, Estonia
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Tom G. Richardson
6MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, United Kingdom
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Federico A. Santoni
7Endocrine, Diabetes, and Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
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Lude Franke
3University Medical Centre Groningen, Groningen, the Netherlands
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Alexandre Reymond
1Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
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  • For correspondence: eleonora.porcu@unil.ch alexandre.reymond@unil.ch zoltan.kutalik@unil.ch
Zoltán Kutalik
2Swiss Institute of Bioinformatics, Lausanne Switzerland
4University Center for Primary Care and Public Health, Lausanne, Switzerland
8Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
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  • For correspondence: eleonora.porcu@unil.ch alexandre.reymond@unil.ch zoltan.kutalik@unil.ch
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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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* These authors jointly supervised this work: Alexandre Reymond and Zoltán Kutalik

  • ↵† A full list of consortium members appears at the end of the paper.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted April 17, 2020.
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The role of gene expression on human sexual dimorphism: too early to call
Eleonora Porcu, Annique Claringbould, Kaido Lepik, BIOS Consortium, Tom G. Richardson, Federico A. Santoni, Lude Franke, Alexandre Reymond, Zoltán Kutalik
bioRxiv 2020.04.15.042986; doi: https://doi.org/10.1101/2020.04.15.042986
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The role of gene expression on human sexual dimorphism: too early to call
Eleonora Porcu, Annique Claringbould, Kaido Lepik, BIOS Consortium, Tom G. Richardson, Federico A. Santoni, Lude Franke, Alexandre Reymond, Zoltán Kutalik
bioRxiv 2020.04.15.042986; doi: https://doi.org/10.1101/2020.04.15.042986

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