Year: 2018
Type: article
Study design: Observational Study
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.
DOI: 10.1002/ajmg.b.32687
Language: English
Subfield: Clinical Psychology
Field: Psychology
Domain: Social Sciences
Open Access status: green
Funders: International OCD Foundation, University of Chicago, Georgia Clinical and Translational Science Alliance, National Institutes of Health, Directorate for Biological Sciences, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences
Awards: G1022082625, Developing Statistics Methods to Detect Common and Rare Genetics Variants in Human Complex Pedigrees, 2/7 Psychiatric Genomics Consortium: Finding Actionable Variation, Translational phenomics and genomics of Gilles de la Tourette Syndrome, G1600157729, OCD Collaborative Genetics Association Study, G2048194553, Identifying Intermediate Phenotypes for Compulsive Hoarding, G2725772924, OC Foundation Genetics Collaborative Conference, 1/7 Psychiatric Genomics Consortium: Finding actionable variation, G3480170010, Re-Engineering Translational Research at the University of Chicago, G4128221539, G4218682071, G4258172611, 3/7 Psychiatric Genomics Consortium: Finding actionable variation, Obsessive-compulsive disorder (OCD) Collaborative Genetics Association Study, A Genetic Linkage Study of GTS, Conte Center for Computational Systems Genomics of Neuropsychiatric Phenotypes, A GENETIC LINKAGE STUDY OF GTS, OCD Collaborative Genetics Association Study, G6491617417, G6743951032, G736887315, OCD Collaborative Genetics Association Study, Obsessive-compulsive disorder (OCD) Collaborative Genetics Association Study, G8631870757, G9000108065, G9000334782, Training the Science of Child Mental Health Treatment
OpenAlex ID: W2950198531