Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits

Joanna Martin*, Ekaterina A. Khramtsova, Slavina B. Goleva, Gabriella A. M. Blokland, Michela Traglia, Raymond K. Walters, Christopher Hubel, Jonathan R. Coleman, Gerome Breen, Anders D. Borglum, Ditte Demontis, Jakob Grove, Thomas Werge, Janita Bralten, Cynthia M. Bulik, Phil H. Lee, Carol A. Mathews, Roseann E. Peterson, Stacey J. Winham, Naomi WrayHoward J. Edenberg, Wei Guo, Yin Yao, Benjamin M. Neale, Stephen Faraone, Tracey L. Petryshen, Lauren A. Weiss, Laramie E. Duncan, Jill M. Goldstein, Jordan W. Smoller, Barbara E. Stranger, Lea K. Davis*, Schizophrenia Working Group of the Psychiatric Genomics Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 single nucleotide polymorphism (SNP)-based heritability and genetic correlation (r(g) < 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

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.

Original languageEnglish
Pages (from-to)1127-1137
Number of pages11
JournalBiological Psychiatry
Issue number12
Publication statusPublished - 15 Jun 2021


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