Sex differences in the genetic architecture of obsessive-compulsive disorder

Abstract

Obsessive-compulsive disorder (OCD) is a highly heritable complex phenotype that demonstrates sex differences in age of onset and clinical presentation, suggesting a possible sex difference in underlying genetic architecture. We present the first genome-wide characterization of the sex-specific genetic architecture of OCD, utilizing the largest set of OCD cases and controls available from the Psychiatric Genomics Consortium. We assessed evidence for several mechanisms that may contribute to sex differences including a sex-dependent liability threshold, the presence of individual sex-specific risk variants on the autosomes and the X chromosome, and sex-specific pleiotropic effects. Furthermore, we tested the hypothesis that genetic heterogeneity between the sexes may obscure associations in a sex-combined genome-wide association study. We observed a strong genetic correlation between male and female OCD and no evidence for a sex-dependent liability threshold model, suggesting that sex-combined analysis does not suffer from widespread loss of power because of genetic heterogeneity between the sexes. While we did not detect any significant sex-specific genome-wide single nucleotide polymorphisms (SNP) associations, we did identify two significant gene-based associations in females: GRID2 and GRP135, which showed no association in males. We observed that the SNPs with sexually differentiated effects showed an enrichment of regulatory variants influencing expression of genes in brain and immune tissues. These findings suggest that future studies with larger sample sizes hold great promise for the identification of sex-specific genetic risk factors for OCD.

Keywords: genetics; genome-wide association study; obsessive compulsive disorder; sex differences; sex-specific analysis; sex-specific genetic architecture.

Figure 1.

Manhattan and quantile-quantile plots for sex-stratified meta-GWAS. Meta-GWAS was run separately for females (1525 cases and 4307 controls) and males (1249 cases and 2789 controls) on ~5.5 million imputed SNPs (MAF>5%). (A) The peaks pointing up on the plot are the results for female analysis and the peaks pointing down are the results for male analysis. Although not genome-wide significant, several suggestive peaks can be observed in one sex and not observed in the other. (B) Quantile-quantile plot for sex-stratified and combined meta-GWAS. (C) Scatter plot of -log10(p-value) for female OCD assications (x-axis) versus male OCD associations (y-axis). Contour lines colored from red to blue indicate decreasing data density.

Figure 2.

eQTL enrichment in the brain and immune tissues for combined, female-specific, male-specific top associations (10⁻³) and SNPs with Sexually Differentiated Effect SNPs (SDEs), excluding and including SNPs in the HLA region. Only variants with more than 500 individuals in the GWAS are included here. Light green bars represent each immune tissue or cell type: whole blood, monocytes, and cd4+ T cells, while the dark green represents enrichment in a combination of the three immune tissues. Light blue bars represent each brain tissue, while the dark blue represents enrichment in a combination of ten brain tissues, or all ten brain tissues minus cerebellum. The black dashed line represents a p-value of 0.05. The red dashed line represents the significant p-value threshold (0.00357) after accounting for 14 eQTL datasets tested.