Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder, 2025, Strom et al.

SNT Gatchaman

SNT Gatchaman

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Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder
Strom, Nora I. and 207 others

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.

Link | PDF (Nature Genetics) [Open Access]
 
The most significant SNP (rs78587207 (P = 5.28 × 10−12)) identified in the GWAS is located on chr11q12.1 and has been previously associated with several traits, including neuropsychiatric phenotypes such as depressive symptoms and neuroticism. Gene-based analyses identified four putative causal genes within this locus. The closest gene to rs78587207 is CTNND1, which encodes the cell adhesion molecule p120 catenin. This gene was associated with OCD using three gene-based tests (mBAT-combo, TWAS and PWAS), and we found strong evidence for colocalization of the TWAS signal for CTNND1 in the dlPFC. The dlPFC has been consistently implicated in the neural circuitry of OCD as well as in compulsivity more broadly as part of the cortico–striatal–thalamo–cortical circuitry. The protein product of CTNND1 is a regulator of cell–cell adhesion and has a crucial role in gene transcription, Rho GTPase activity and cytoskeletal organization.
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Other credible causal genes in the locus include CLP1 (cleavage factor polyribonucleotide kinase subunit 1), TMX2 (thioredoxin-related transmembrane protein 2) and ZDHHC5 (zinc finger DHHC type palmitoyltransferase 5). Rare genetic mutations CLP1 are associated with pontocerebellar hypoplasia type 10, a very rare autosomal recessive neurodegenerative disease characterized by brain atrophy and delayed myelination resulting in intellectual disability. TMX2 is associated with increased risk of neurodevelopmental disorders with microcephaly, cortical malformations, spasticity and congenital nervous system abnormalities. ZDHHC5 is broadly expressed in the brain, including the frontal cortex.
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We identified a total of 25 credible causal genes based on robust evidence using multiple positional and functionally informed gene-based approaches. Notably, DLGAP1, which has been previously implicated in OCD pathogenesis, was not identified in either the GWAS or in the gene-based analyses.
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(DLGAP1 was one of the top hits in Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis)

Four other genes identified through these analyses are located in the MHC locus, a region on chromosome 6 that has a major role in the adaptive immune system and has been repeatedly linked to major psychiatric disorders. The newly identified MHC association for OCD is noteworthy given evidence linking OCD with autoimmune disorders. Genetic pleiotropy may underlie this connection, with variants predisposing individuals to both autoimmune conditions and OCD. Furthermore, some OCD subtypes, such as pediatric acute-onset neuropsychiatric disorders associated with Streptococcus and pediatric acute-onset neuropsychiatric syndrome, may have autoimmune origins. Nevertheless, we were surprised to discover several negative genetic correlations between OCD and autoimmune disorders such as Crohn’s disease, ulcerative colitis and inflammatory bowel disease in our analyses, suggesting that there is heterogeneity (and perhaps pleiotropy) in the genetic relationships between autoimmune disorders and OCD.
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