Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits

Martin, J.; Khramtsova, E. A.; Goleva, S. B.; Blokland, G. A. M.; Traglia, M.; Walters, R. K.; Hübel, C.; Coleman, J. R. I.; Breen, G.; Borglum, A.; Demontis, D.; Grove, J.; Werge, T.; Bralten, J.; Bulik, C.; Lee, P. H.; Mathews, C. A.; Peterson, R. E.; Winham, S. J.; Wray, N. R.; Edenberg, H. J.; Guo, W.; Yao, Y.; Neale, B.; Faraone, S. V.; Petryshen, T. L.; Weiss, L.; Duncan, L.; Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium,; Goldstein, J. M.; Smoller, J. W.; Stranger, B.; Davis, L. K.

doi:10.1101/2020.05.04.076042

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bioRxiv · 10.1101/2020.05.04.076042

Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits

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Abstract

BackgroundThe 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. MethodsUsing 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. ResultsWith 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). ConclusionsSex 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.

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Martin, J., Khramtsova, E. A., Goleva, S. B., Blokland, G. A. M., Traglia, M., Walters, R. K., Hübel, C., Coleman, J. R. I., Breen, G., Borglum, A., Demontis, D., Grove, J., Werge, T., Bralten, J., Bulik, C., Lee, P. H., Mathews, C. A., Peterson, R. E., Winham, S. J., Wray, N. R., Edenberg, H. J., Guo, W., Yao, Y., Neale, B., Faraone, S. V., Petryshen, T. L., Weiss, L., Duncan, L., Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium,, Goldstein, J. M., Smoller, J. W., Stranger, B., Davis, L. K.. 2020-05-05. Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits. https://doi.org/10.1101/2020.05.04.076042

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