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Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits

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  • Joanna Martin, Cardiff University
  • ,
  • Ekaterina A. Khramtsova, University of Chicago, Johnson & Johnson
  • ,
  • Slavina B. Goleva, Vanderbilt University
  • ,
  • Gabriëlla A.M. Blokland, Harvard University, Maastricht University
  • ,
  • Michela Traglia, University of California at San Francisco
  • ,
  • Raymond K. Walters, Harvard University, Broad Institute
  • ,
  • Christopher Hübel
  • Jonathan R.I. Coleman, King's College London, South London and Maudsley NHS Foundation Trust
  • ,
  • Gerome Breen, King's College London, South London and Maudsley NHS Foundation Trust
  • ,
  • Anders D. Børglum
  • Ditte Demontis
  • Jakob Grove
  • Thomas Werge, Mental Health Services Capital Region of Denmark, University of Copenhagen, H. Lundbeck A/S
  • ,
  • Janita Bralten, Radboud University Nijmegen
  • ,
  • Cynthia M. Bulik, University of North Carolina, Karolinska Institutet
  • ,
  • Phil H. Lee, Harvard University
  • ,
  • Carol A. Mathews, University of Florida
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  • Roseann E. Peterson, Virginia Commonwealth University
  • ,
  • Stacey J. Winham, Mayo Clinic Rochester, MN
  • ,
  • Naomi Wray, University of Queensland
  • ,
  • Howard J. Edenberg, Indiana University - Purdue University Indianapolis
  • ,
  • Wei Guo, National Institutes of Health
  • ,
  • Yin Yao, Fudan University
  • ,
  • Benjamin M. Neale, Harvard University
  • ,
  • Stephen V. Faraone, SUNY Upstate Medical University
  • ,
  • Tracey L. Petryshen, Harvard University
  • ,
  • Lauren A. Weiss, University of California at San Francisco
  • ,
  • Laramie E. Duncan, Stanford University
  • ,
  • Jill M. Goldstein, Harvard University
  • ,
  • Jordan W. Smoller, Harvard University
  • ,
  • Barbara E. Stranger, University of Chicago, Northwestern University
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  • Lea K. Davis, Vanderbilt University, Department of Psychiatry and Behavioral Sciences
  • ,
  • 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
Issue12
Pages (from-to)1127-1137
Number of pages11
ISSN0006-3223
DOIs
Publication statusPublished - Jun 2021

Bibliographical note

Publisher Copyright:
© 2021 Society of Biological Psychiatry

    Research areas

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

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