Abstract
Obsessive-compulsive disorder (OCD) is a complex psychiatric disorder with a substantial genetic contribution. While the specific variants underlying OCD's heritability are still unknown, findings from genome-wide association studies (GWAS) corroborate the importance of common SNPs explaining the phenotypic variance in OCD. Investigating associations between the genetic liability for OCD, as reflected by a polygenic risk score (PRS), and potential endophenotypes of the disorder, such as the personality trait harm avoidance, may aid the understanding of functional pathways from genes to diagnostic phenotypes. We derived PRS for OCD at several P-value thresholds based on the latest Psychiatric Genomics Consortium OCD GWAS (2688 cases, 7037 controls) in an independent sample of OCD patients (n=180), their unaffected first-degree relatives (n=108) and healthy controls (n=200). Using linear regression, we tested whether these PRS are associated with the personality trait harm avoidance. Results showed that OCD PRS significantly predicted OCD status, with patients having the highest scores and relatives having intermediate scores. Furthermore, the genetic risk for OCD was associated with harm avoidance across the entire sample, and among OCD patients. As indicated by mediation analyses, harm avoidance mediated the association between the OCD PRS and OCD caseness. These results were observed at multiple P-value thresholds and persisted after the exclusion of patients with a current comorbid major depressive or anxiety disorder. Our findings support the polygenic nature of OCD and further validate harm avoidance as a candidate endophenotype and diathesis of OCD.
Highlights
Obsessive-compulsive disorder (OCD) is a debilitating and often chronic psychiatric disorder characterized by obsessions and/or compulsions, which affects 1–3% of the population worldwide [1]
Using PLINK [49], polygenic scores were calculated for each individual in our target sample from the number of risk alleles carried for each selected single nucleotide polymorphism (SNP), weighted by the log (OR) provided by the Psychiatric Genomics Consortium (PGC) GWAS, and averaged across all SNPs
This resulted in eight continuous PRS that reflect the genetic risk for OCD at different PT thresholds for each individual in our target sample based on the GWAS results of the discovery sample
Summary
Obsessive-compulsive disorder (OCD) is a debilitating and often chronic psychiatric disorder characterized by obsessions (intrusive unwanted thoughts or images) and/or compulsions (ritualized repetitive behaviors), which affects 1–3% of the population worldwide [1]. OCD is familial, with first-degree relatives having an approximately fivefold increased risk of being affected by the disease [2,3,4]. The majority of the genetic variability underlying the heritability estimates from family studies in OCD seems to be captured by GWAS. Investigating endophenotypes, which are heritable, quantitative traits associated with the disease and observed in unaffected relatives of patients, may aid the understanding of functional pathways from genes to diagnostic phenotypes [15]. Since endophenotypes are supposed to share underlying genetic factors with the clinical disorder, they should be associated with specific genetic risk variants for the disease [16] and represent genetically driven vulnerability factors
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