Genome-wide association study of obsessive-compulsive disorder

Abstract

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

Figure 1. Quantile-quantile (QQ) Plots of Observed versus Expected −log(p) Statistics for: (a) Trio samples, (b) Case-Control samples and, (c) Combined Trio-Case-Control Samples

Quantile-quantile (Q-Q) plots of observed versus expected −log (P) test statistics for: (a) trio samples; (b) case-control samples; and (c) combined trio-case-control samples. The 95% confidence interval of expected values is indicated in grey. Corresponding genomic control lambda values are indicated within each plot.

Figure 2. Manhattan Plots for: (a) Trio, (b) Case-Control and, (c) Combined Trio-Case-Control Samples

Manhattan plots of all genotyped single-nucleotide polymorphisms (SNPs) for (a) trio samples; (b) case-control samples; and (c) combined trio-case-control samples. Red and blue lines indicate significance thresholds of 5 ×10^-8 and 1 × 10^-5, respectively.

Figure 3. Locus Plots for SNPs rs6131295 (near BTBD3), rs11081062 (within DLGAP1) and rs297941 (near FAIM2)

Regional association plots of the best supported SNPs from the a) Trio, b) Case-Control and c) Trio-Case-Control analyses. Locations and observed -log (p-values) for genotyped SNPs are shown with circles. LD, in r², to the lowest p-value SNP in each plot is indicated using shading (dark blue, low LD, red-high LD). Light blue lines indicate the estimated recombination rate from HapMap release 22.

Figure 4. Enrichment analyses for Quantitative Trait Loci (QTLs) among GWAS Variants with p<0.01

Enrichment of (a) frontal lobe expression QTLs (p=0.001), (b) cerebellum expression QTLs (p=0.033), (c) parietal lobe expression QTLs (p=0.003), and (d) methylation QTLs (p<0.001) among GWAS SNPs with p<0.01 (N=5321). Distribution of the count of QTLs in 1,000 simulations are displayed, each matching the MAF distribution of the OCD–associated SNPs. The black dot identifies the observed eQTL or mQTL count in the OCD susceptibility–associated SNPs.