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

Abstract

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.

Figure 1.

Manhattan plot of genotyped and imputed single-nucleotide polymorphisms (SNPs) for 2,688 OCD cases and 7,031 controls from the IOCDF-GC, OCGAS, and GPC consortia. Red line indicates the genome-wide significance threshold of p=5×10⁻⁸.

Figure 2.. Polygenic Risk Score Analysis in OCD.

The variance explained in two target samples (OCTR, consisting of 630cases and 630 pseudo-controls; IOEU, consisting of 1032 cases and 4100 controls) is based on risk scores derived from an aggregated sum of weighted single-nucleotide polymorphism risk allele effect sizes estimated from the discovery samples (IOCDF-GC without IOAJ, consisting of 1623 cases and 5113 controls; OCGAS, consisting of 974 cases and 663 controls) at eight significance thresholds. The numbers of SNPs used at each significance thresholds for PRS were listed on the top of the corresponding bars. The y-axis indicates Nagelkerke’s pseudo R².