The genetic architecture of obsessive-compulsive disorder: alleles across the frequency spectrum contribute liability to OCD

Abstract

ObjectiveObsessive-compulsive disorder (OCD) is known to be substantially heritable; however, the contribution of common genetic variation across the allele frequency spectrum to this heritability remains uncertain. We use two new, homogenous cohorts to estimate heritability of OCD from common genetic variation and contrast results with prior studies.MethodsThe sample consisted of 2096 Swedish-born individuals diagnosed with OCD and 4609 controls, all genotyped for common genetic variants, specifically >400,000 single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 0.01. Using genotypes of these SNPs to estimate distant familial relationships among individuals, we estimated heritability of OCD, both overall and partitioned according to MAF bins.ResultsWe estimated narrow-sense heritability of 28% (SE=4%). The estimate was robust, varying only modestly under different models. Contrary to an earlier study, however, SNPs with MAF between 0.01 and 0.05 accounted for 8% of heritability and estimated heritability per bin roughly follows expectations based on a simple model for SNP-based heritability.ConclusionsThese results indicate that common inherited risk variation (MAF ≥ 0.01) accounts for most of the heritable variation in OCD. SNPs with low MAF contribute meaningfully to the heritability of OCD and the results are consistent with expectation under the “infinitesimal model,” where risk is influenced by a large number of loci across the genome and across MAF bins.

Genetics of obsessive-compulsive disorder

“…Compulsive symptoms rather than obsessive symptoms had higher SNP heritability and genetic correlations with OCD (Smit et al, 2019 ). Heritability for SNPs with a minor allele frequency between 0.1% and 5% for OCD is reported to be 0% (Davis et al, 2013 ); however, these results are not yet replicated (Mahjani et al, 2021 ). Given that twin- and SNP-based heritability estimates are in a similar range, particularly for adult OCD (van Grootheest, Cath, Beekman, & Boomsma, 2005 ), this suggests that common genetic variants account for a substantial portion of the variance for OCD (Davis et al, 2013 ).…”

A dimensional perspective on the genetics of obsessive-compulsive disorder

“…Modern genomic methods demonstrated that the genetic contribution to OCD is primarily polygenic, meaning that hundreds or thousands of genetic variants each contribute a very small amount to the overall genetic predisposition to OCD [50,53]. There is some evidence from copy number variants studies and wholeexome sequencing studies that rare variants exerting larger effects Fig.…”

OCD symptom severity and comorbid psychiatric diagnoses in a Swedish genetic epidemiological obsessive-compulsive disorder cohort

“…All samples were genotyped using the Global Screening Array and analyzed for common genetic variation (B. Mahjani et al, 2021). All samples are currently going through wholeexome sequencing to detect rare structural variation and single nucleotide variation.…”