Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits
Joanna Martin, Ekaterina Khramtsova, Slavina B. Goleva, Gabriëlla A.M. Blokland, Michela Traglia, Raymond K. Walters, Christopher Hübel, Jonathan R. I. Coleman, Gerome Breen, Anders D. Børglum, Ditte Demontis, Jakob Grove, Thomas Werge, Janita Bralten, Cynthia M. Bulik, Phil H. Lee, Carol A. Mathews, Roseann E. 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, Barbara E. Stranger, Lea K. Davis, Martin Alda, Marco Bortolato, Christie L. Burton, Enda M. Byrne, Caitlin E. Carey, Lauren Erdman, Laura M. Huckins, Manuel Mattheisen, Elise Robinson, Eli Stahl
Abstract
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: < 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-based heritability. Between-sex, within-trait genetic correlations were high, although <1 for educational attainment and risk-taking behavior. We identified 4 genes with significant sex-differentiated effects across 3 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.