Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits
Ekaterina A. Khramtsova,
Slavina B Goleva,
Gabriëlla AM Blokland,
Raymond K Walters,
Jonathan RI Coleman,
Anders D Børglum,
Thomas M Werge,
Phil H Lee,
Carol A. Mathews,
Roseann E Peterson,
Stacey J Winham,
Naomi R. Wray,
Howard J. Edenberg,
Stephen V Faraone,
Tracey L Petryshen,
Lauren A. Weiss,
Laramie E Duncan,
Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium,
Jill M Goldstein,
Jordan W Smoller,
Lea K. Davis
Posted 05 May 2020
bioRxiv DOI: 10.1101/2020.05.04.076042
Posted 05 May 2020
Background: The 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. Methods: Using 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. Results: With 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). Conclusions: Sex 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. ### Competing Interest Statement CM Bulik reports: Shire (grant recipient, Scientific Advisory Board member); Idorsia (consultant); Pearson (author, royalty recipient). EA Khramtsova is employed by Janssen Pharmaceutical Companies of Johnson and Johnson.
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