Obsessive–compulsive disorder (OCD)is a chronic psychiatric disease affecting around 1 to 3% of the population. It is characterized by compulsion and obsessions and has a substantial heritable component. Twin-based heritability estimates range from 27 to 47% in adults and from 45 to 65% in children. Single Nucleotide Polymorphism (SNP) based heritability is estimated to be between 28 and 37%.
This study combined data from 2 unpublished OCD genome-wide association studies (GWAS) along with additional cohort data to conduct a large-scale and well-established GWAS of OCD. This led to a 20-fold increase in the OCD cases compared to the previously published studies. Secondary analyses included functional and positive fine mapping of genes and SNPs, transcriptome and protein-wide association analyses, structural equation modelling, genetic correlation with other traits, and single-cell enrichment.
This study analyzed genomic data from 28 cohorts, comprising 2,044,427 controls of European ancestry and 53,660 OCD cases. It found that genomic inflation was due to the polygenic signal and is significantly influenced by population structure. Genomic structural equation modeling (GenomicSEM) was used to stimulate the combined genetic architecture of 4 groups, which include OCS and multivariate GWAS of a common factor. Genetic correlations were estimated by using cross-trait LDSC31, nd significant SNPs were mapped to genes for gene-based analyses.
This study conducted transcriptome-wide association research of OCD by using gene expression weights from PsychENCODE and linkage disequilibrium data from the 1000 Genomes Project Phase 3. The PsyOPS gene prioritization method was used to rank the genes in significant genome-wide loci. Protein-wide association studies (PWAS) utilized protein expression data from human brain samples. This study discovered an increase in loss-of-function mutations in OCD patients compared to controls, especially in loss-of-function intolerant genes. A total of 251 genes with common risk variants for OCD were identified.
A GWAS meta-analysis of 28 OCD control cases of European ancestry identified 30 genome-wide significant loci among 1672 SNPs, which exceeded the genome-wide significance threshold. The study found no statistically significant heterogeneity in individual cohorts for 30 genome-wide significant loci. Genome-wide analyses revealed that sample ascertaining impacted the results at a genome-wide scale. The study prioritized potential risk genes for OCD by using six positional and functional quantitative trait locus (QTL) gene-based mapping methods. From the 48 genes implicated by at least two methods, they prioritized causal genes for OCD using colocalization (TWAS-COLOC) and Summary-data-based Mendelian Randomization with HEIDI-outlier test (SMR-HEIDI) tests. Only 2 of these 25 genes were prioritized by both TWAS-COLOC and SMR-HEIDI. The study highlights the importance of understanding the genetic basis of OCD and the potential role of these genes in the development of this condition.
The OCD GWAS has identified 30 significant loci, which explain 6.7% of the variation in OCD risk, a reduction from the 28% previously reported. This reduction aligns with findings in related psychiatric disorders like depression or attention deficit hyperactivity disorder (ADHD). Approximately 11,500 causal variants account for 90% of the SNP-based heritability of OCD, suggesting that OCD is more polygenic than other complex traits but less polygenic than major depression and educational attainment.
This study has identified 25 credible causal genes associated with OCD, which include DLGAP1, WDR6, DALRD3, CELSR3, and the MHC locus. The shared genetic risk factors between OCD and other psychiatric disorders offer further insights into the etiology of OCD. Future studies will require ancestrally diverse samples, sex-specific analyses, and clinical phenotyping to understand genetic and clinical relationships further.
Reference: Strom NI, Gerring ZF, Galimberti M, et al. Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder. Nat Genet. 2025. doi:10.1038/s41588-025-02189-z
