{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T04:25:32Z","timestamp":1775363132642,"version":"3.50.1"},"reference-count":57,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T00:00:00Z","timestamp":1651708800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014370","name":"Simons Foundation Autism Research Initiative","doi-asserted-by":"publisher","award":["734069LW"],"award-info":[{"award-number":["734069LW"]}],"id":[{"id":"10.13039\/100014370","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01MH114924"],"award-info":[{"award-number":["R01MH114924"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"Phenotypic differences across sexes are pervasive, but the genetic architecture of sex differences within and across phenotypes is mostly unknown. In this study, we aimed to improve detection power for sex-differentially contributing SNPs previously demonstrated to be enriched in disease association, and we investigate their functions in health, pathophysiology, and genetic function. We leveraged GIANT and UK Biobank summary statistics and defined a set of 2,320 independent SNPs having sexually dimorphic effects within and across biometric traits (MAF > 0.001, P<\/jats:italic> < 5x10-8<\/jats:sup>). Biometric trait sex-heterogeneous SNPs (sex-het SNPs)<\/jats:italic> showed enrichment in association signals for 20 out of 33 diseases\/traits at 5% alpha compared to sex-homogeneous matched SNPs (empP<\/jats:italic> < 0.001), and were significantly overrepresented in muscle, skeletal and stem cell development processes, and in calcium channel and microtubule complexes (FDR<\/jats:italic> < 0.05, empP<\/jats:italic> < 0.05). Interestingly, we found that sex-het SNPs<\/jats:italic> significantly map to predicted expression quantitative trait loci (Pr-eQTLs<\/jats:italic>) across brain and other tissues, methylation quantitative trait loci (meQTLs<\/jats:italic>) during development, and transcription start sites, compared to sex-homogeneous SNPs<\/jats:italic>. Finally, we verified that the sex-het disease\/trait enrichment was not explained by Pr-eQTL<\/jats:italic> enrichment alone, as sex-het Pr-eQTLs<\/jats:italic> were more enriched than matched sex-homogeneous Pr-eQTLs<\/jats:italic>. We conclude that genetic polymorphisms with sexually dimorphic effects on biometric traits not only contribute to fundamental embryogenic processes, but later in life play an outsized role in disease risk. These sex-het SNPs disproportionately influence gene expression and have a greater influence on disorders of body and brain than other expression-regulatory variation. Together, our data emphasize the genetic underpinnings of sexual dimorphism and its role in human health.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010147","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T17:35:19Z","timestamp":1651772119000},"page":"e1010147","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Sex-heterogeneous SNPs disproportionately influence gene expression and health"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3361-4602","authenticated-orcid":true,"given":"Michela","family":"Traglia","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2170-7374","authenticated-orcid":true,"given":"Margaux","family":"Bout","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren A.","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,5,5]]},"reference":[{"key":"pgen.1010147.ref001","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/nrg2415","article-title":"Sex-specific genetic architecture of human disease","volume":"9","author":"C Ober","year":"2008","journal-title":"Nat Rev Genet"},{"key":"pgen.1010147.ref002","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/s41576-018-0083-1","article-title":"The role of sex in the genomics of human complex traits","volume":"20","author":"EA Khramtsova","year":"2019","journal-title":"Nat Rev Genet"},{"key":"pgen.1010147.ref003","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/j.biopsych.2020.12.024","article-title":"Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits","author":"J Martin","year":"2021","journal-title":"Biol Psychiatry"},{"key":"pgen.1010147.ref004","doi-asserted-by":"crossref","DOI":"10.1093\/hmg\/dds304","article-title":"Genome-wide meta-analysis of common variant differences between men and women","volume":"21","author":"V Boraska","year":"2012","journal-title":"Hum Mol Genet"},{"key":"pgen.1010147.ref005","article-title":"Sexual differences in genetic architecture in UK Biobank.","author":"E Bernabeu","year":"2020","journal-title":"bioRxiv"},{"key":"pgen.1010147.ref006","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1006425","article-title":"Pleiotropic Mechanisms Indicated for Sex Differences in Autism.","volume":"12","author":"I Mitra","year":"2016","journal-title":"PLoS Genet."},{"key":"pgen.1010147.ref007","doi-asserted-by":"crossref","DOI":"10.1534\/genetics.116.193623","article-title":"Genetic Mechanisms Leading to Sex Differences Across Common Diseases and Anthropometric Traits","volume":"205","author":"M Traglia","year":"2017","journal-title":"Genetics"},{"key":"pgen.1010147.ref008","article-title":"Meta-analysis of genome-wide association studies for height and body mass index in ~700,000 individuals of European ancestry.","author":"L Yengo","year":"2018","journal-title":"Meta-analysis genome-wide Assoc Stud Height body mass index ~700 000 Individ Eur ancestry."},{"key":"pgen.1010147.ref009","article-title":"The Combination of Estimates from Different Experiments","author":"WG Cochran","year":"1954","journal-title":"Biometrics"},{"key":"pgen.1010147.ref010","article-title":"MAGMA: Generalized Gene-Set Analysis of GWAS Data.","author":"CA de Leeuw","year":"2015","journal-title":"PLoS Comput Biol."},{"key":"pgen.1010147.ref011","article-title":"Functional mapping and annotation of genetic associations with FUMA.","author":"K Watanabe","year":"2017","journal-title":"Nat Commun."},{"key":"pgen.1010147.ref012","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1210\/me.2009-0103","article-title":"Androgen-responsive gene database: integrated knowledge on androgen-responsive genes","volume":"23","author":"M Jiang","year":"2009","journal-title":"Mol Endocrinol"},{"key":"pgen.1010147.ref013","doi-asserted-by":"crossref","first-page":"D533","DOI":"10.1093\/nar\/gkh083","article-title":"ERGDB: Estrogen Responsive Genes Database","volume":"32","author":"S Tang","year":"2004","journal-title":"Nucleic Acids Res"},{"key":"pgen.1010147.ref014","first-page":"014241","article-title":"Partitioning heritability by functional category using GWAS summary statistics.","author":"HK Finucane","year":"2015","journal-title":"bioRxiv"},{"key":"pgen.1010147.ref015","article-title":"The Avon Longitudinal Study of Parents and Children (ALSPAC): an update on the enrolled sample of index children in 2019 [version 1; 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