Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population
Strom, N. I.; Burton, C. L.; Iyegbe, C.; Silzer, T.; Antonyan, L.; Pool, R.; Lemire, M.; Crowley, J. J.; Hottenga, J.-J.; Ivanov, V. Z.; Larsson, H.; Lichtenstein, P.; Magnusson, P.; Rueck, C.; Schachar, R.; Wu, H. M.; Cath, D.; Crosbie, J.; Mataix-Cols, D.; Boomsma, D. I.; Mattheisen, M.; Meier, S. M.; Smit, D. J.; Arnold, P. D.
Show abstract
While 1-2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more ([~]15-40%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations on the SNP or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 x10-5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin-mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33% - 43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.
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