“The Genetic Architecture of Obsessive-Compulsive Disorder: Contribution of Liability to OCD From Alleles Across the Frequency Spectrum”, 2021-11-18 (; similar):
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 2 new homogeneous cohorts to estimate the heritability of OCD from inherited genetic variation and contrasted the results with those of previous studies.
Method: 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.
Conclusion: 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 prediction 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.
…The heritability of OCD, historically estimated by analysis of twin and family studies and within the context of the ACE model (A, additive genetic, also known as narrow-sense heritability; C, shared environment; and E, nonshared environment), is reported to be in the range of 35%–50% (1, 4, 8–14)…It is useful to compare the heritability results from family-based and SNP-based approaches. Family-based studies, being more direct, typically yield estimates of heritability with lower standard errors, whereas the inaccuracy of estimating distant relationships from genetic data tends to produce fuzzier estimates. Family-based estimates also tend to yield higher estimates of heritability because the familial covariance reflects both rare and common genetic variation, whereas SNP-based estimates mostly arise from covariance due to common genetic variants. Looking at the results summarized above, one might conclude that this is also operating for OCD, that is, that family-based studies are producing higher heritability estimates than SNP-based studies.
However, in an influential study of data from the International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) by Davis et al5 (1,061 case subjects, 4,236 control subjects, 373,846 SNPs), there was no evidence for heritability from SNPs with minor allele frequency (MAF) < 0.05, and over 60% of total heritability mapped to the most common variants (MAF >0.3). In addition, in a meta-analysis of data from the International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Study (OCGAS) (16), ~60% of heritability was accounted for by SNPs with MAF >0.4 in both the OCGAS sample alone and in the combined sample. If this observation were true, it could have profound implications for which evolutionary forces shaped this unusual mapping of risk alleles to their population frequency distribution. For example, balancing selection, where multiple alleles are maintained in the gene pool of a population at frequencies larger than expected from genetic drift alone, may play a role in OCD.