Abstract
Using a novel trait-based measure, we examined genetic variants associated with obsessive-compulsive (OC) traits and tested whether OC traits and obsessive-compulsive disorder (OCD) shared genetic risk. We conducted a genome-wide association analysis (GWAS) of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of all currently available OCD cases. Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses. A locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p = 2.48 × 10−8). rs7856850 was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). The direction of effect was the same as in the community sample. Polygenic risk scores from OC traits were significantly associated with OCD in case/control datasets and vice versa (p’s < 0.01). OC traits were highly, but not significantly, genetically correlated with OCD (rg = 0.71, p = 0.062). We report the first validated genome-wide significant variant for OC traits in PTPRD, downstream of the most significant locus in a previous OCD GWAS. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the feasibility and power of using trait-based approaches in community samples for genetic discovery.
Highlights
Obsessive-compulsive disorder (OCD) is a common (1–2% prevalence)[1] psychiatric disorder characterized by intrusive, recurrent thoughts and repeated, ritualized behaviors
Rs7856850 in PTPRD was significantly associated with Toronto Obsessive-Compulsive Scale (TOCS) total scores at the genome-wide level (p = 2.48 × 10−8, β = 0.14, s.e. = 0.025, R2 = 0.618%: Fig. 2A, most significant loci listed in Supplemental Table S1)
Several variants in this region that approached genome-wide significance were in linkage disequilibrium (LD) with rs7856850, which was genotyped on both the HumanCore and OMNI arrays (Fig. 2B)
Summary
Obsessive-compulsive disorder (OCD) is a common (1–2% prevalence)[1] psychiatric disorder characterized by intrusive, recurrent thoughts and repeated, ritualized behaviors. Up to 50% of OCD cases have a childhoodonset (before the age of 18)[2], which is more heritable than (GWAS) in clinical samples with mixed ages of OCD-. Onset and a meta-analysis of these studies did not identify genome-wide significant loci[4,5,6]. The most significant loci from previous GWAS include SNPs within DLGAP1, BTBD3, GRID2, and one close to PTPRD. Using obsessive-compulsive (OC) symptoms rather than a clinical diagnosis, a study of adult twins identified a genomewide significant SNP in MEF2B (rs8100480)[7]. This SNP was not replicated in an independent sample[5].
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