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

• Published in: Molecular psychiatry 2018-05, Vol.23 (5), p.1181-1188
• Main Author: International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS)
• Format: Article
• Language: English
• Subjects: 45; 45/43; 631/208; 692/699/476; Alleles; Behavioral Sciences; Biological Psychology; Case-Control Studies; Collaboration; Consortia; European Continental Ancestry Group - genetics; Female; Gene frequency; Gene Frequency - genetics; Genetic Linkage; Genetic Predisposition to Disease - genetics; Genetics; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Heritability; Humans; Male; Medicine; Medicine & Public Health; Meta-analysis; Multifactorial Inheritance - genetics; Neoplasm Proteins - genetics; Neurosciences; Neuroses; Obsessive compulsive disorder; Obsessive-Compulsive Disorder - genetics; Obsessive-Compulsive Disorder - metabolism; original-article; Pharmacotherapy; Polymorphism; Polymorphism, Single Nucleotide - genetics; Psychiatry; Receptors, Glutamate - genetics; RNA, Long Noncoding - genetics; Single-nucleotide polymorphism; Systematic review
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2017.154

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.