Limited evidence for blood eQTLs in human sexual dimorphism

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 s...

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Published in:Genome medicine Vol. 14; no. 1; pp. 89 - 13
Main Authors: Porcu, Eleonora, Claringbould, Annique, Weihs, Antoine, Lepik, Kaido, Richardson, Tom G., Völker, Uwe, Santoni, Federico A., Teumer, Alexander, Franke, Lude, Reymond, Alexandre, Kutalik, Zoltán
Format: Journal Article
Language:English
Published: London BioMed Central 11.08.2022
BioMed Central Ltd
Springer Nature B.V
BMC
Subjects:
Amyotrophic lateral sclerosis
Analysis
Biobanks
Bioinformatics
Biomedical and Life Sciences
Biomedicine
Blood
Cancer Research
Cohort analysis
Consortia
Diabetes
Female
Gender differences
Gene expression
Gene loci
Genes
Genome-wide association studies
Genome-Wide Association Study - methods
Genomes
Genomics
Human Genetics
Humans
Male
Medicine/Public Health
Metabolomics
Polymorphism, Single Nucleotide
Population
Quantitative genetics
Quantitative Trait Loci
Sex Characteristics
Sexes
Sexual dimorphism
Single nucleotide polymorphisms
Single-nucleotide polymorphism
Systems Biology
Testosterone
Transcriptome
Transcriptomes
Type 2 diabetes
Womens health
Netherlands
ISSN:1756-994X, 1756-994X
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Summary: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.
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ISSN:1756-994X
1756-994X
DOI:10.1186/s13073-022-01088-w