Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits

Research output: Contribution to journalJournal articleResearchpeer-review

  • Joanna Martin
  • Ekaterina A. 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
  • Werge, Thomas
  • Janita Bralten
  • Cynthia M. Bulik
  • Phil H. Lee
  • Carol A. Mathews
  • Roseann E. Peterson
  • Stacey J. Winham
  • Naomi Wray
  • Howard J. Edenberg
  • Wei Guo
  • Yin Yao
  • 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
  • Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium

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 (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-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.

Original languageEnglish
JournalBiological Psychiatry
Volume89
Issue number12
Pages (from-to)1127-1137
ISSN0006-3223
DOIs
Publication statusPublished - 2021

Bibliographical note

Publisher Copyright:
© 2021 Society of Biological Psychiatry

    Research areas

  • Behavioral, Genetic correlation, GWAS, Heritability, Psychiatric, Sex differences

ID: 272237822