Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits

Joanna Martin; Ekaterina A. Khramtsova; Slavina B. Goleva; Gabriëlla A.M. Blokland; Michela Traglia; Raymond Kenney Walters; Christopher Hübel; Jonathan R. I. Coleman; Gerome D. Breen; Anders Dupont Børglum; Ditte Demontis; Jakob Grove; Thomas Mears Werge; Janita Bralten; Cynthia Marie Bulik; Phil Hyoun Lee; Carol A. Mathews; Roseann Elizabeth Peterson; Stacey J. Winham; Naomi R. Wray; Howard J. Edenberg; Wei Guo; Yin Yao Shugart; Benjamin M. Neale; Stephen V. Faraone; Tracey L. Petryshen; Lauren A. Weiss; Laramie E. Duncan; Jill M. Goldstein; Jordan W. Smoller

doi:10.1016/j.biopsych.2020.12.024

GeneticsBiological PsychiatryJan 10, 2021

Peer-reviewed journal article

Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits

Joanna Martin iD, Ekaterina A. Khramtsova iD, Slavina B. Goleva iD, Gabriëlla A.M. Blokland iD, Michela Traglia iD, Raymond Kenney Walters iD, Christopher Hübel iD, Jonathan R. I. Coleman iD, Gerome D. Breen iD, Anders Dupont Børglum iD, Ditte Demontis iD, Jakob Grove iD, Thomas Mears Werge iD, Janita Bralten iD, Cynthia Marie Bulik iD, Phil Hyoun Lee iD, Carol A. Mathews iD, Roseann Elizabeth Peterson iD, Stacey J. Winham iD, Naomi R. Wray iD, Howard J. Edenberg iD, Wei Guo iD, Yin Yao Shugart iD, Benjamin M. Neale iD, Stephen V. Faraone iD, , Eli Stahl iD

Abstract

BackgroundThe origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations across these traits, we tested for a sex-differentiated genetic architecture within and between traits. MethodsUsing genome-wide association study (GWAS) summary statistics for 20 neuropsychiatric and behavioral traits, we tested for differences in SNP-based heritability (h2) and genetic correlation (rg<1) between sexes. For each trait, we computed z-scores from sex-stratified GWAS regression coefficients and identified genes with sex-differentiated effects. We calculated Pearson correlation coefficients between z-scores for each trait pair, to assess whether specific pairs share variants with sex-differentiated effects. Finally, we tested for sex differences in between-trait genetic correlations. ResultsWith current sample sizes (and power), we found no significant, consistent sex differences in SNP-based h2. Between-sex, within-trait genetic correlations were consistently high, although significantly less than 1 for educational attainment and risk-taking behavior. We identified genome-wide significant genes with sex-differentiated effects for eight traits. Several trait pairs shared sex-differentiated effects. The top 0.1% of genes with sex-differentiated effects across traits overlapped with neuron- and synapse-related gene sets. Most between-trait genetic correlation estimates were similar across sex, with several exceptions (e.g. educational attainment & risk-taking behavior). ConclusionsSex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic, requiring large sample sizes. Genes with sex-differentiated effects are enriched for neuron-related gene sets. This work motivates further investigation of genetic, as well as environmental, influences on sex differences.

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