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The Genetic Architecture of Obsessive-Compulsive Disorder: Contribution of Liability to OCD From Alleles Across the
Behrang Mahjani1, Lambertus Klei1, Manuel Mattheisen1
1Seaver Autism Center for Research and Treatment (Mahjani, Reichenberg, Sandin, Buxbaum, Grice),Division of Tics, Obsessive-Compulsive Disorder (OCD), and Related Disorders (Mahjani, Grice), Department of Psychiatry (Mahjani, Reichenberg, Sandin, Buxbaum, Grice),Mindich Child Health and Development Institute (Reichenberg, Buxbaum, Grice),Department of Genetics and Genomic Sciences (Buxbaum),Department of Neuroscience (Buxbaum), and Friedman Brain Institute (Buxbaum, Grice), Icahn School of Medicine at Mount Sinai, New York; Department of Medical Epidemiology and Biostatistics (Mahjani, Mattheisen, Halvorsen, Pedersen, Bulik, Landén, Fundín, Sandin, Hultman, Crowley) and Center for Psychiatry Research, Department of Clinical Neuroscience (Boberg, de Schipper, Mataix-Cols, Rück), Karolinska Institutet, Stockholm; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh (Klei, Devlin); Department of Psychiatry and Department of Community Health and Epidemiology, Dalhousie University, Halifax, Canada (Mattheisen); Department of Biomedicine-Human Genetics and the iSEQ Center, Aarhus University, Aarhus, Denmark (Mattheisen); Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Munich (Mattheisen); Department of Genetics (Halvorsen, Crowley) Department of Psychiatry (Bulik), and Department of Nutrition (Bulik), University of North Carolina at Chapel Hill; Department of Statistics and the Computational Biology Department, Carnegie Mellon University, Pittsburgh (Roeder); Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden (Landén); Health Care Services, Region Stockholm, Stockholm (Rück).
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.
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