Genetic meta-analysis of obsessive–compulsive disorder and self-report compulsive symptoms

Dirk J. A. Smit, Danielle Cath, Nuno R. Zilhão, Hill F. Ip, Damiaan Denys, Anouk den Braber, Eco J. C. de Geus, Karin J. H. Verweij, Jouke-Jan Hottenga, Dorret I. Boomsma

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We investigated whether obsessive–compulsive (OC) symptoms from a population-based sample could be analyzed to detect genetic variants influencing obsessive–compulsive disorder (OCD). We performed a genome-wide association studies (GWAS) on the obsession (rumination and impulsions) and compulsion (checking, washing, and ordering/precision) subscales of an abbreviated version of the Padua Inventory (N = 8,267 with genome-wide genotyping and phenotyping). The compulsion subscale showed a substantial and significant positive genetic correlation with an OCD case–control GWAS (rG = 0.61, p =.017) previously published by the Psychiatric Genomics Consortium (PGC-OCD). The obsession subscale and the total Padua score showed no significant genetic correlations (rG = −0.02 and rG = 0.42, respectively). A meta-analysis of the compulsive symptoms GWAS with the PGC-OCD revealed no genome-wide significant Single-Nucleotide Polymorphisms (SNPs combined N = 17,992, indicating that the power is still low for individual SNP effects). A gene-based association analysis, however, yielded two novel genes (WDR7 and ADCK1). The top 250 genes in the gene-based test also showed a significant increase in enrichment for psychiatric and brain-expressed genes. S-Predixcan testing showed that for genes expressed in hippocampus, amygdala, and caudate nucleus significance increased in the meta-analysis with compulsive symptoms compared to the original PGC-OCD GWAS. Thus, the inclusion of dimensional symptom data in genome-wide association on clinical case–control GWAS of OCD may be useful to find genes for OCD if the data are based on quantitative indices of compulsive behavior. SNP-level power increases were limited, but aggregate, gene-level analyses showed increased enrichment for brain-expressed genes related to psychiatric disorders, and increased association with gene expression in brain tissues with known emotional, reward processing, memory, and fear-formation functions.
Original languageEnglish
Pages (from-to)208-216
Number of pages9
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Issue number4
Early online date2019
Publication statusPublished - 1 Jun 2020

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