What is the inheritance pattern most commonly associated with Obsessive-Compulsive Disorder (OCD)?

Inheritance Pattern of Obsessive-Compulsive Disorder

OCD follows a complex polygenic inheritance pattern with multiple genes of small effect contributing to disease risk, rather than a simple Mendelian pattern, though some evidence suggests Mendelian-dominant transmission may occur in specific family subsets.

Polygenic Architecture

The genetic basis of OCD is fundamentally polygenic, meaning risk is distributed across many genetic variants throughout the genome rather than being caused by a single gene 1, 2.

• Approximately 11,500 genetic variants explain 90% of OCD genetic heritability, with each individual variant contributing only a small effect to overall risk 2
• Genome-wide association studies have identified 30 independent genome-wide significant loci associated with OCD, including variants in glutamatergic genes and the major histocompatibility complex (MHC) region 1, 2
• Common inherited genetic variation (minor allele frequency ≥0.01) accounts for most heritable variation in OCD, with SNPs across the frequency spectrum contributing meaningfully 3

Heritability Estimates

Twin studies demonstrate that additive genetic effects account for approximately 40% of variance in obsessive-compulsive symptoms, with non-shared environmental factors accounting for ~51% 1.

• Narrow-sense heritability of OCD from common genetic variants is estimated at 29% (SE=4%) 3
• The heritability pattern roughly follows the "infinitesimal model" (polygenic model), where risk is influenced by a large number of loci across the genome 3
• Early-onset OCD with tics may have higher heritability than other OCD subtypes 1

Evidence for Major Gene Effects in Specific Families

While the overall pattern is polygenic, complex segregation analysis of 153 families provided compelling evidence for a major gene effect in a subset of families 4.

• A Mendelian-dominant model with significant sex effects best explained observed data in family studies, though this applies to specific family subsets rather than OCD broadly 4
• Stratification by proband sex revealed that families with female probands and families with male probands both showed patterns consistent with Mendelian-dominant inheritance with residual familial effects 4
• This suggests genetic heterogeneity, where some families may have major gene effects while the broader population shows polygenic inheritance 4

Copy Number Variants and De Novo Mutations

OCD shows a 3.3-fold increased burden of large deletions associated with other neurodevelopmental disorders 1.

• Half of these deletions were located in 16p13.11, with three confirmed as de novo 1
• The overall de novo rate of large copy number variants (CNVs) in OCD is 1.4%, midway between rates in healthy controls and autism spectrum disorders 1

Gene-Environment Interactions

The inheritance pattern is further complicated by gene-environment interactions 1.

• Environmental factors including adverse perinatal events, birth complications, and stressful or traumatic events have been identified as potential risk factors 1
• These environmental factors likely interact with genetic susceptibility to influence OCD development 1

Clinical Implications

No single inheritance pattern applies to all OCD cases—the disorder shows genetic heterogeneity with predominantly polygenic architecture in the general population, but possible major gene effects in specific families 3, 2, 4.

• Genetic counseling should emphasize the complex, multifactorial nature of OCD inheritance rather than simple Mendelian ratios
• The 40% heritability from additive genetic effects provides a practical estimate for discussing familial risk 1
• Specific candidate genes identified include DLGAP1, WDR6, DALRD3, and CTNND1, though these represent only small pieces of the overall genetic architecture 2, 5