Limited evidence for blood eQTLs in human sexual dimorphism.

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

Journal

Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844

Informations de publication

Date de publication:
11 08 2022
Historique:
received: 20 10 2021
accepted: 14 07 2022
entrez: 11 8 2022
pubmed: 12 8 2022
medline: 16 8 2022
Statut: epublish

Résumé

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 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. 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1186/s13073-022-01088-w PMID: 35953856 PMC: PMC9373355
pubmed: 35953856
doi: 10.1186/s13073-022-01088-w
pii: 10.1186/s13073-022-01088-w
pmc: PMC9373355
doi:

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

89

Subventions

Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom

Informations de copyright

© 2022. The Author(s).

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Auteurs

Eleonora Porcu (E)

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. eleonora.porcu@unil.ch.
Swiss Institute of Bioinformatics, Lausanne, Switzerland. eleonora.porcu@unil.ch.
University Center for Primary Care and Public Health, Lausanne, Switzerland. eleonora.porcu@unil.ch.
ORCID: 0000-0003-2878-7485

Annique Claringbould (A)

University Medical Centre Groningen, Groningen, the Netherlands.
Structural and Computational Biology Unit, European Molecular Biology Laboratories (EMBL), Heidelberg, Germany.

Antoine Weihs (A)

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.

Kaido Lepik (K)

Institute of Computer Science, University of Tartu, Tartu, Estonia.
Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.

Tom G Richardson (TG)

MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Novo Nordisk Research Centre Oxford, Old Road Campus, Oxford, OX3 7DQ, UK.

Uwe Völker (U)

Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.

Federico A Santoni (FA)

Endocrine, Diabetes, and Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.

Alexander Teumer (A)

DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

Lude Franke (L)

University Medical Centre Groningen, Groningen, the Netherlands.

Alexandre Reymond (A)

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. alexandre.reymond@unil.ch.

Zoltán Kutalik (Z)

Swiss Institute of Bioinformatics, Lausanne, Switzerland. zoltan.kutalik@unil.ch.
University Center for Primary Care and Public Health, Lausanne, Switzerland. zoltan.kutalik@unil.ch.
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland. zoltan.kutalik@unil.ch.

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Classifications MeSH

questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Limited evidence for blood eQTLs in human...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Limited evidence for blood eQTLs in human...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Limited evidence for blood eQTLs in human...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › Locus de caractère quantitatif › Limited evidence for blood eQTLs in human...
questionsmedicales.fr › Phénomènes physiologiques des appareils urinaire et reproducteur › Phénomènes physiologiques de la reproduction › Caractères sexuels › Limited evidence for blood eQTLs in human...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Transcriptome › Limited evidence for blood eQTLs in human...