title: Genetic Mechanisms Leading to Sex Differences Across Common Diseases and Anthropometric Traits.
abstract: Common diseases often show sex differences in prevalence, onset, symptomology, treatment, or prognosis. Although studies have been performed to evaluate sex differences at specific SNP associations, this work aims to comprehensively survey a number of complex heritable diseases and anthropometric traits. Potential genetically encoded sex differences we investigated include differential genetic liability thresholds or distributions, gene-sex interaction at autosomal loci, major contribution of the X-chromosome, or gene-environment interactions reflected in genes responsive to androgens or estrogens. Finally, we tested the overlap between sex-differential association with anthropometric traits and disease risk. We utilized complementary approaches of assessing GWAS association enrichment and SNP-based heritability estimation to explore explicit sex differences, as well as enrichment in sex-implicated functional categories. We do not find consistent increased genetic load in the lower-prevalence sex, or a disproportionate role for the X-chromosome in disease risk, despite sex-heterogeneity on the X for several traits. We find that all anthropometric traits show less than complete correlation between the genetic contribution to males and females, and find a convincing example of autosome-wide genome-sex interaction in multiple sclerosis (P = 1 × 10-9). We also find some evidence for hormone-responsive gene enrichment, and striking evidence of the contribution of sex-differential anthropometric associations to common disease risk, implying that general mechanisms of sexual dimorphism determining secondary sex characteristics have shared effects on disease risk.
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, California 94143.
authors.forename: Michela
authors.identifier: 0000-0002-5700-135X
authors.initials: M
authors.lastname: Traglia
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, California 94143.
authors.forename: Dina
authors.initials: D
authors.lastname: Bseiso
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142.|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115.|Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gusev
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, California 94143.
authors.forename: Brigid
authors.initials: B
authors.lastname: Adviento
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94158.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Park
authors.affiliation: Department of Epidemiology and Biostatistics and The Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, California 94158.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Mefford
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94158.
authors.forename: Noah
authors.initials: N
authors.lastname: Zaitlen
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, California 94143 Lauren.Weiss@ucsf.edu.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Weiss
mesh_terms: D049628:Body Size / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D040741:Genetic Load; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D012727:Sex Characteristics
keywords: gene–sex interactions; heritability; hormone-responsive genes; sex differences; sex heterogeneity