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Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits

Martin, Joanna ORCID:, Khramtsova, Ekaterina A., Goleva, Slavina B., Blokland, Gabriëlla A.M., Traglia, Michela, Walters, Raymond K., Hübel, Christopher, Coleman, Jonathan R. I., Breen, Gerome, Børglum, Anders D., Demontis, Ditte, Grove, Jakob, Werge, Thomas, Bralten, Janita, Bulik, Cynthia M., Lee, Phil H., Mathews, Carol A., Peterson, Roseann E., Winham, Stacey J., Wray, Naomi, Edenberg, Howard J., Guo, Wei, Yao, Yin, Neale, Benjamin M., Faraone, Stephen V., Petryshen, Tracey L., Weiss, Lauren A., Duncan, Laramie E., Goldstein, Jill M., Smoller, Jordan W., Stranger, Barbara E. and Davis, Lea K. 2021. Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits. Biological Psychiatry 89 (12) , pp. 1127-1137. 10.1016/j.biopsych.2020.12.024

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Background The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits. Methods Using European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in SNP-based heritability (SNP-h2) and genetic correlation (rg<1). For each trait, we computed per-SNP z-scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z-scores, to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations. Results We observed no consistent sex differences in SNP- h2. Between-sex, within-trait genetic correlations were high, although <1 for educational attainment and risk-taking behavior. We identified four genes with significant sex-differentiated effects across three traits. Several trait pairs shared sex-differentiated effects. The top genes with sex-differentiated effects were enriched for multiple gene sets, including neuron- and synapse-related sets. Most between-trait genetic correlation estimates were not significantly different between sexes, with exceptions (educational attainment and risk-taking behavior). Conclusions Sex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic, and unlikely to fully account for observed sex-differentiated attributes. Larger sample sizes are needed to identify sex-differentiated effects for most traits. For well-powered studies, we identified genes with sex-differentiated effects that were enriched for neuron-related and other biological functions. This work motivates further investigation of genetic and environmental influences on sex differences.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Elsevier
ISSN: 0006-3223
Funders: Wellcome Trust
Date of First Compliant Deposit: 1 February 2021
Date of Acceptance: 17 December 2020
Last Modified: 02 May 2023 11:49

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