Limited evidence for blood eQTLs in human sexual dimorphism

Eleonora Porcu; Annique Claringbould; Antoine Weihs; Kaido Lepik; BIOS Consortium; Tom G Richardson; Uwe Völker; Federico A Santoni; Alexander Teumer; Lude Franke; Alexandre Reymond; Zoltán Kutalik

doi:10.1186/s13073-022-01088-w

Limited evidence for blood eQTLs in human sexual dimorphism

Genome Med. 2022 Aug 11;14(1):89. doi: 10.1186/s13073-022-01088-w.

Authors

Eleonora Porcu^{1

2

3}, Annique Claringbould^{4

5}, Antoine Weihs⁶, Kaido Lepik^{7

8}; BIOS Consortium; Tom G Richardson^{9

10}, Uwe Völker^{11

12}, Federico A Santoni^{13

14}, Alexander Teumer^{12

15}, Lude Franke⁴, Alexandre Reymond^#¹⁶, Zoltán Kutalik^#^{17

18

19}

Affiliations

¹ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. [email protected].
² Swiss Institute of Bioinformatics, Lausanne, Switzerland. [email protected].
³ University Center for Primary Care and Public Health, Lausanne, Switzerland. [email protected].
⁴ University Medical Centre Groningen, Groningen, the Netherlands.
⁵ Structural and Computational Biology Unit, European Molecular Biology Laboratories (EMBL), Heidelberg, Germany.
⁶ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁷ Institute of Computer Science, University of Tartu, Tartu, Estonia.
⁸ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁹ MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁰ Novo Nordisk Research Centre Oxford, Old Road Campus, Oxford, OX3 7DQ, UK.
¹¹ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
¹² DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
¹³ Endocrine, Diabetes, and Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
¹⁴ Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
¹⁵ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁶ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. [email protected].
¹⁷ Swiss Institute of Bioinformatics, Lausanne, Switzerland. [email protected].
¹⁸ University Center for Primary Care and Public Health, Lausanne, Switzerland. [email protected].
¹⁹ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland. [email protected].

^# Contributed equally.

Abstract

Background: 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.

Methods: To explore this scenario, we combined sex-specific whole blood RNA-seq eQTL data from 3447 European individuals included in BIOS Consortium and GWAS data from UK Biobank. Next, to test the presence of sex-biased causal effect of gene expression on complex traits, we performed sex-specific transcriptome-wide Mendelian randomization (TWMR) analyses on the two most sexually dimorphic traits, waist-to-hip ratio (WHR) and testosterone levels. Finally, we performed power analysis to calculate the GWAS sample size needed to observe sex-specific trait associations driven by sex-biased eQTLs.

Results: Among 9 million SNP-gene pairs showing sex-combined associations, we found 18 genes with significant sex-biased cis-eQTLs (FDR 5%). Our phenome-wide association study of the 18 top sex-biased eQTLs on >700 traits unraveled that these eQTLs do not systematically translate into detectable sex-biased trait-associations. In addition, we observed that sex-specific causal effects of gene expression on complex traits are not driven by sex-specific eQTLs. Power analyses using real eQTL- and causal-effect sizes showed that millions of samples would be necessary to observe sex-biased trait associations that are fully driven by sex-biased cis-eQTLs. Compensatory effects may further hamper their detection.

Conclusions: Our results suggest that sex-specific eQTLs in whole blood do not translate to detectable sex-specific trait associations of complex diseases, and vice versa that the observed sex-specific trait associations cannot be explained by sex-specific eQTLs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Female
Genome-Wide Association Study* / methods
Humans
Male
Polymorphism, Single Nucleotide
Quantitative Trait Loci*
Sex Characteristics
Transcriptome

Abstract

Publication types

MeSH terms

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