Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder

Abstract

Obsessive-compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D₁ and D₂ type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

Fig. 1. Manhattan plot of OCD GWAS meta-analysis.

The y axis represents −log₁₀ (P values) (two sided, not adjusted for multiple testing) for the association of variants with OCD using an inverse-variance-weighted fixed-effects model (n_cases = 53,660 and n_controls = 2,044,417). The x axis shows chromosomes 1–22. The horizontal red line represents the threshold for genome-wide significance ($P=5\times {10}^{-8})$. Index variants of genome-wide significant loci are highlighted as green diamonds.

Fig. 2. Gene-based, tissue and cell type enrichment analyses.

a, List of 25 genes that were implicated in at least two of the five different gene-based tests (significance indicated by gray dots) and passed the TWAS colocalization and/or SMR-HEIDI filters (significance indicated by orange dots). Conditionally independent (cond. ind.) genes within each locus are indicated by blue dots. b, Enrichment of OCD GWAS signal in human brain-related tissues from GTEx (version 8). No significant enrichment was observed in the peripheral tissues (not included in the figure). The horizontal bar size represents the significance of the enrichment measured using the MAGMA gene set enrichment test or partitioned LDSC. c, Top 20 groups of brain cell types (n = 35 total tested) enriched with OCD GWAS signal using MAGMA. Dots represent −log₁₀(P values) from MAGMA gene set enrichment tests of individual neuronal cell types from Zeisel et al.. Vertical crosses represent the mean −log₁₀(P value) observed for each brain cell type group. Blue crosses represent a significant enrichment of OCD GWAS signals (FDR across 35 groups, FDR < 0.05), while pink crosses indicate nonsignificant enrichment. Gray points represent the association (−log₁₀(P value)) for each single cell cluster (‘level 5’ analysis defined by Zeisel et al.) in a given cell type (for example, excitatory neurons, cerebral cortex). CCK, cholecystokinin-expressing; R-LM, stratum radiatum-stratum lacunosum-moleculare.

Fig. 3. Genetic correlations (r_G) between OCD and 112 phenotypes.

This includes psychiatric, substance use, cognition–socioeconomic status (SES), personality, psychological, neurological, autoimmune, cardiovascular (cardiovasc.), anthropomorphic–diet, fertility and other phenotypes. References and sample sizes of the corresponding summary statistics of the GWAS studies can be found in Supplementary Table 18. The OCD summary statistics are of the main meta-analysis (n_cases = 53,660 and n_controls = 2,044,417). Error bars represent the 95% confidence intervals for the genetic correlation estimates (r_G). Red circles indicate significant associations with a P value adjusted for multiple testing with the Benjamini–Hochberg procedure to control the FDR (<0.05). Black circles indicate associations that are not significant. a., after; ADHD, attention-deficit hyperactivity disorder; ALS, amyotrophic lateral sclerosis; BMI, body mass index; embarras., embarrassment; freq, frequency; fr., from; HDL, high-density lipoprotein; IQ, intelligence quotient; LDL, low-density lipoprotein; neurot., neuroticism; nr., number; PTSD, post-traumatic stress disorder; sat., satisfaction; VN, verbal-numerical.