The Genetic Architecture of Obsessive-Compulsive Disorder: Contribution of Liability to OCD From Alleles Across the Frequency Spectrum.
paper
Cited
Public
- Authors
- Mahjani, Behrang; Klei, Lambertus; Mattheisen, Manuel; Halvorsen, Matthew W; Reichenberg, Abraham; Roeder, Kathryn; Pedersen, Nancy L; Boberg, Julia; de Schipper, Elles; Bulik, Cynthia M; Landén, Mikael; Fundín, Bengt; Mataix-Cols, David; Sandin, Sven; Hultman, Christina M; Crowley, James J; Buxbaum, Joseph D; Rück, Christian; Devlin, Bernie; Grice, Dorothy E
- Year
- 2022
- Journal
- The American journal of psychiatry
- PMID
- 34789012
- DOI
- 10.1176/appi.ajp.2021.21010101
- PMCID
- PMC8897260
OBJECTIVE: Obsessive-compulsive disorder (OCD) is known to be substantially heritable; however, the contribution of genetic variation across the allele frequency spectrum to this heritability remains uncertain. The authors used two new homogeneous cohorts to estimate the heritability of OCD from inherited genetic variation and contrasted the results with those of previous studies. METHODS: The sample consisted of 2,090 Swedish-born individuals diagnosed with OCD and 4,567 control subjects, 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, the authors estimated the heritability of OCD, both overall and partitioned according to MAF bins. RESULTS: Narrow-sense heritability of OCD was estimated at 29% (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 10% of heritability, and estimated heritability per MAF bin roughly followed expectations based on a simple model for SNP-based heritability. CONCLUSIONS: These 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" (also referred to as the "polygenic model"), where risk is influenced by a large number of loci across the genome and across MAF bins.
Estimates of heritability partitioned by MAF bins from the results in A) this study, B) Davis et al. (5) and, C) weighted averages (weights proportional to the inverse of variance) of this study and Davis et al. In each panel, we also show the estimate of heritability for each bin from 1000G data, presented as the mean of heritability for that bin for ten samples of size 180K SNP, where sampling from each bin was proportional to the percentage of SNPs in that bin from 1000G data. Note that the SE for this latter analysis is the standard error of the sample mean for the ten samples and is not directly comparable to the SNP-based SE. Correlations with 1000G data were 0.99, p-value<0.001, for panel A; 0.04, p-value=0.94, for panel B; and 0.94, p-value=0.005, for panel C.
Estimates of heritability partitioned by chromosome. A) The observed heritability by chromosome length and the 95% confidence interval (CI) for the regressed line (adjusted R2=0.27, p-value=0.008); B) The observed heritability by expected heritability and the 95% CI for the regressed line (adjusted R2=0.23, p-value=0.014); C) The weighted average observed heritability by chromosome length and the 95% CI for the regressed line (average over this manuscript and Davis et al. study) (adjusted R2=0.31, p-value=0.004), the results for chromosome 21 and 22 are overlapping; and D) The weighted average heritability by expected heritability and the 95% CI for the regressed line (adjusted R2=0.22, p-value=0.0161). The dashed lines have slope one and intercept zero (observed=expected).
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| Name | Type |
|---|---|
| 1000 Genomes Project | cohort |
| 184,296 largely independent SNPs local | variant |
| 405,105 high quality genotyped SNPs local | variant |
| affected individuals | cohort |
| age of onset | phenotype |
| anorexia nervosa | phenotype |
| anxiety | phenotype |
| ASD | phenotype |
| autism | phenotype |
| autism spectrum disorder | phenotype |
| autosomal SNPs | cohort |
| cases | cohort |
| combined data local | cohort |
| common risk variation local | variant |
| common SNP variation local | variant |
| common variants | cohort |
| common variation | variant |
| compulsive symptoms local | phenotype |
| control individuals | cohort |
| controls | cohort |
| Davis et al. local | cohort |
| Davis et al. study local | cohort |
| Davis et al. Study local | cohort |
| Davis study local | cohort |
| De novo protein truncating variants local | variant |
| EGOS | cohort |
| EGOS cohort local | cohort |
| European ancestry | cohort |
| European genetic ancestry individuals local | cohort |
| Evolutionarily-constrained genes local | gene |
| families | cohort |
| full sample | cohort |
| GenomeStudio local | drug |
| heritability | phenotype |
| high-effect genes local | gene |
| high-frequency alleles (MAF>0.3) local | variant |
| histone genes | gene |
| HLA | gene |
| LifeGene local | cohort |
| LifeGene-ANGI local | cohort |
| LifeGene-ANGI-Wave-1 local | cohort |
| LifeGene-ANGI-Wave-1 controls local | cohort |
| LifeGene-ANGI-Wave-2 local | cohort |
| LifeGene-ANGI-Wave-2 controls local | cohort |
| LifeGene-EGOS local | cohort |
| LifeGene-EGOS controls local | cohort |
| LifeGene-NORDiC local | cohort |
| low-frequency alleles (MAF<0.05) local | variant |
| low MAF SNPs | variant |
| major depressive disorder | phenotype |
| NORDiC local | cohort |
| NORDiC cohort local | cohort |
| obsessive-compulsive disorder | phenotype |
| OCD | phenotype |
| OCD Collaborative Genetics Association Study | cohort |
| OCD subtypes local | phenotype |
| OCGAS | cohort |
| optmatch local | drug |
| our study | cohort |
| pairmatch local | drug |
| R local | drug |
| rare risk variants local | variant |
| rare risk variation local | variant |
| rare variant | cohort |
| rare variation | cohort |
| risk allele | cohort |
| schizophrenia | phenotype |
| sex | phenotype |
| SNP | cohort |
| SNP-based heritability | phenotype |
| SNP-based studies local | cohort |
| SNPs (MAF < 0.05) local | variant |
| SNPs (MAF > 0.4) local | variant |
| SNPs with MAF > 0.05 local | variant |
| Sweden | cohort |
| Swedish families local | cohort |
| Swedish individuals | cohort |
| Swedish National Patient Register local | cohort |
| Swedish national registers local | cohort |
| Swedish population | cohort |
| tics | phenotype |
| unaffected individuals | cohort |
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In this knowledge base
External
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| Genetic Underpinnings of Obsessive-Compulsive Disorder With and Without Tics: Implications of Genetic Heterogeneity on Clinical Management. | Zouki JJ et al. | — | 2026 | → |
| Polygenic risk scores for pediatric obsessive-compulsive symptoms: Mediating effects in samples clinically diagnosed with mental disorders. | Antonyan L et al. | — | 2026 | → |
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| Characterizing Rare DNA Copy-Number Variants in Pediatric Obsessive-Compulsive Disorder. | Abdallah SB et al. | — | 2025 | → |
| Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder. | Strom NI et al. | — | 2025 | → |
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| Clinical characteristics of probands with obsessive-compulsive disorder from simplex and multiplex families. | Lima MO et al. | — | 2024 | → |
| Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder | Strom NI et al. | — | 2024 | — |
| Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population. | Strom NI et al. | — | 2024 | → |
| The genetics of trichotillomania and excoriation disorder: A systematic review. | Reid M et al. | — | 2024 | → |
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