Exon-focused genome-wide association study of obsessive-compulsive disorder and shared polygenic risk with schizophrenia

Abstract

Common single-nucleotide polymorphisms (SNPs) account for a large proportion of the heritability of obsessive-compulsivedisorder (OCD). Co-ocurrence of OCD and schizophrenia is commoner than expected based on their respective prevalences,complicating the clinical management of patients. This study addresses two main objectives: to identify particular genes associatedwith OCD by SNP-based and gene-based tests; and to test the existence of a polygenic risk shared with schizophrenia. The primaryanalysis was an exon-focused genome-wide association study of 370 OCD cases and 443 controls from Spain. A polygenic riskmodel based on the Psychiatric Genetics Consortium schizophrenia data set (PGC-SCZ2) was tested in our OCD data. A polygenicrisk model based on our OCD data was tested on previous data of schizophrenia from our group. The most significant association atthe gene-based test was found atDNM3(P= 7.9 × 10−5), a gene involved in synaptic vesicle endocytosis. The polygenic risk modelfrom PGC-SCZ2 data was strongly associated with disease status in our OCD sample, reaching its most significant value afterremoval of the major histocompatibility complex region (lowestP= 2.3 × 10−6, explaining 3.7% of the variance). The sharedpolygenic risk was confirmed in our schizophrenia data. In conclusion,DNM3may be involved in risk to OCD. The shared polygenicrisk between schizophrenia and OCD may be partially responsible for the frequent comorbidity of both disorders, explainingepidemiological data on cross-disorder risk. This common etiology may have clinical implications.