SEX-STRATIFIED ANALYSIS OF OBSESSIVE-COMPULSIVE DISORDER REVEALS MINOR DIFFERENCES IN GENETIC ARCHITECTURE

Obsessive-Compulsive Disorder (OCD), a heritable neurobehavioral disorder, demonstrates sexual dimorphism in age of onset and clinical presentation, suggesting a possible sex difference in genetic architecture. Here, we present the first genome-wide assessment of sex-specific genetic architecture of OCD on currently the largest OCD cohort available from the Psychiatric Genomics Consortium (total cases and controls N=9,870 after quality control, 1:1.4 male/female ratio). First, we performed a sex-stratified meta-GWAS to identify specific autosomal and sex chromosome genetic variants differentially associated to OCD risk in each of the sexes. Second, we assessed whether the most heterogeneous OCD risk alleles and top (p<10-3) sex-specific genome-wide associations are involved in gene regulation to elucidate the biological mechanisms by which those variants may impact dimorphism. Third, we used heritability analysis to (a) assess the proportion of overall OCD heritability explained by the X chromosome, and (b) to test for evidence of variable liability threshold for OCD between males and females. Lastly, we performed a sex-stratified genetic correlation analysis with other traits which may play a role in OCD development (e.g. brain volumes), show sexual dimorphisms (e.g. autism, Tourette's syndrome, etc.) or are known to be differential clinical symptoms in OCD (e.g. smoking, alcohol consumption, etc.). There were no genome-wide significant associations in either sex. Sex heterogenous SNPs (including and excluding SNPs in the HLA region) were strongly enriched for immune expression quantitative trait loci (p<0.001). Top associations were significantly enriched for brain eQTLs (p=0.003) in females and for immune eQTLs (p=0.003) in males. Using DAPPLE, we identified 10 genes implicated by heterogeneous OCD risk brain eQTLs (FDR<0.05) that showed significantly more network connectivity than expected by chance. There were no differences between sexes in OCD heritability (h2male=0.23, se=0.08; h2female=0.24, se=0.06). The X chromosome contributed 6.7% to total heritability which is not statistically different from expectation. The genetic correlation between sexes is high: GCTA GREML (1.0, se=0.27). Although OCD demonstrated significant genetic correlation with many traits, there were no statistically significant differences between sexes when corrected for multiple testing. We present the first genome-wide assessment of sex-specific genetic architecture of OCD. We identified minor sex differences in genetic architecture of OCD, and although the sex-stratified sample size is likely too small to identify variants with small effect, we have developed a robust analytic pipeline for sex-stratified genetic analysis which will be applied in the near future to OCD as larger cohorts become available. The pipeline will also be applied to additional phenotypes where a sex bias in genetic effects may influence trait variation. This will enable a deeper understanding of how genetic variants may regulate biological processes influencing sex-biased phenotypes.