Faculty Opinions recommendation of Sex differences in the genetic architecture of obsessive-compulsive disorder.

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.© 2018 Wiley Periodicals, Inc. PMID: 30456828 Funding information This work was supported by: Biological Sciences Division at the University of Chicago, International NINDS NIH HHS, United States Grant ID: R01 NS040024 NIMH NIH HHS, United States Grant ID: R01 MH079494 NIMH NIH HHS, United States Grant ID: U01 MH109536 NIMH NIH HHS, United States Grant ID: R21 MH087748 NINDS NIH HHS, United States Grant ID: U01 NS040024 NIMH NIH HHS, United States Grant ID: R13 MH073250 NIMH NIH HHS, United States Grant ID: U01 MH109528 Intramural NIH HHS, United States Grant ID: ZIA MH002930-06 NIMH NIH HHS, United States Grant ID: U01 MH109539 NIMH NIH HHS, United States Grant ID: R01 MH079488 NIMH NIH HHS, United States Grant ID: P50 MH094267 NIMH NIH HHS, United States Grant ID: R01 MH071507 NIMH NIH HHS, United States Grant ID: K23 MH085057 NIMH NIH HHS, United States Grant ID: R01 MH079487 David Judah Foundation, International Grant ID: S40024 NCATS NIH HHS, United States Grant ID: UL1 TR000430 More Less keyboard_arrow_down