Genome-wide association study of pediatric obsessive-compulsive traits: shared genetic risk between traits and disorder

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 (r_g = 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.

Fig. 1. Distribution of OC trait measures.

Histograms of A Toronto Obsessive-Compulsive Scale (TOCS) total score, B total score for collapsed TOCS items (all negative scores converted to zero for each item) and C the Child Behavior Checklist – Obsessive-Compulsive Scale (CBCL-OCS). n = 5018.

Fig. 2. Genome-wide significant locus in PTPRD associated with OC traits in Spit for Science.

A Manhattan plot for GWAS of the TOCS standardized total score. rs7856850 in one of the introns of PTPRD surpassed the genome-wide threshold (p = 5 × 10⁻⁸; gray line). B Locus zoom plot for the genome-wide significant locus from the GWAS of the TOCS standardized total score. C QQ Plot for the GWAS of the TOCS standardized total score. n = 5018.

Fig. 3. Validation of locus in PTPRD in OCD samples.

Forrest plot of genome-wide significant variant (rs7856850) across all the replication samples and sub-samples: (1) IOCDF/OCGAS (International Obsessive-Compulsive Disorder Foundation Collaborative and OCD Collaborative Genetics Association Studies samples), (2) CHOP (Philadelphia Neurodevelopmental Cohort (PNC) from the Children’s Hospital of Philadelphia, and (3) Michigan/Toronto OCD Imaging Genomics Study. Total cases: 3369; total controls: 8611. OR = odds ratio.

Fig. 4. OC traits in the community and OCD share polygenic risk.

A Variance explained (R²) in OCD case/control status in replication samples by polygenic risk for OC traits from Spit for Science B variance explained in OC traits in Spit for Science sample by polygenic risk for OCD from replication samples across a range of prior proportion of causal variants (ρ). Analyses conducted using LDpred. *p < 0.01.