Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis.

Two obsessive-compulsive disorder (OCD) genome-wide association studies (GWASs) have been published by independent OCD consortia, the International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and the OCD Collaborative Genetics Association Study (OCGAS), but many of the top-ranked signals were supported in only one study. We therefore conducted a meta-analysis from the two consortia, investigating a total of 2688 individuals of European ancestry with OCD and 7037 genomically matched controls. No single-nucleotide polymorphisms (SNPs) reached genome-wide significance. However, in comparison with the two individual GWASs, the distribution of P-values shifted toward significance. The top haplotypic blocks were tagged with rs4733767 (P=7.1 × 10-7; odds ratio (OR)=1.21; confidence interval (CI): 1.12-1.31, CASC8/CASC11), rs1030757 (P=1.1 × 10-6; OR=1.18; CI: 1.10-1.26, GRID2) and rs12504244 (P=1.6 × 10-6; OR=1.18; CI: 1.11-1.27, KIT). Variants located in or near the genes ASB13, RSPO4, DLGAP1, PTPRD, GRIK2, FAIM2 and CDH20, identified in linkage peaks and the original GWASs, were among the top signals. Polygenic risk scores for each individual study predicted case-control status in the other by explaining 0.9% (P=0.003) and 0.3% (P=0.0009) of the phenotypic variance in OCGAS and the European IOCDF-GC target samples, respectively. The common SNP heritability in the combined OCGAS and IOCDF-GC sample was estimated to be 0.28 (s.e.=0.04). Strikingly, ∼65% of the SNP-based heritability in the OCGAS sample was accounted for by SNPs with minor allele frequencies of ⩾40%. This joint analysis constituting the largest single OCD genome-wide study to date represents a major integrative step in elucidating the genetic causes of OCD

The serotonergic system in obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a psychiatric condition that is characterized by obsessive thoughts and compulsive behavior. Over the past decades, the involvement of the neurotransmitter serotonin (5-HT) in treatment and pathophysiology of OCD has been actively discussed. The therapeutic effects of selective serotonin reuptake inhibitors in OCD patients strongly implicate 5-HT in the reduction of OCD symptoms. However, the role of the 5-HT system in development and pathophysiology of OCD remains less clear. Here, we review neurochemical, genetic association, and receptor and transporter binding studies to shed more light on a potential dysfunction of the 5-HT system in OCD patients. Additionally, animal studies demonstrate that alterations of the 5-HT system can both induce and alleviate OCD-like symptoms. To provide more insight, future studies should take several factors into account: the heterogeneity of the disorder, the variety of genetic polymorphisms associated with OCD, and possible interactions with other neurotransmitter systems