Researchers may have identified 36 high-confidence, large-effect risk genes that could contribute to obsessive-compulsive disorder and chronic tic disorders.
The researchers used whole-exome sequencing data from 3,964 patients with obsessive-compulsive disorder (OCD), chronic tic disorders (CTD), or both, including 2,418 parent-proband trios and 1,546 singletons. Control data included 1,734 neurotypical sibling-parent trios and 2,380 parents of European ancestry used as singleton controls. About 36% of case trios and 70% of case singletons were newly sequenced for the study. The researchers evaluated rare de novo and other rare protein-damaging variants for enrichment and used gene-level analyses to identify genes associated with OCD, CTDs, or the disorders combined.
The analyses identified 12 high-confidence risk genes for OCD and 10 for CTDs. When the researchers combined data from the 2 disorders, they identified 34 high-confidence genes. Overall, 36 genes met the high-confidence threshold in at least 1 analysis compared with 4 high-confidence genes previously identified. The researchers estimated that about 7% to 8% of the patients with OCD and/or CTDs carried at least 1 risk-contributing de novo damaging variant, while approximately 3% of patients with OCD in the singleton analysis carried a rare likely gene-disrupting variant.
The findings indicated substantial genetic overlap between OCD and CTDs. For instance, 83% (n = 30) of the genes received evidence from patients with both disorders. Four genes—BRWD1, CELSR3, QRICH1, and SYNE1—also overlapped with genes implicated by common-variant OCD loci. The high-confidence OCD and CTD genes overlapped with established risk genes for autism spectrum disorder, developmental delay or intellectual disability, and schizophrenia.
Gene expression and cell type analyses provided additional evidence of potential biological convergence. High-confidence genes from the combined OCD and CTD analysis showed increased postnatal expression in the cerebellum, while broader sets of implicated genes showed prenatal enrichment across several brain regions. Cell-type analyses implicated telencephalic projecting excitatory neurons, with additional evidence involving striatal medium spiny neurons.
The study had several limitations. Previously reported samples were incorporated into the analysis, meaning the study was not designed as an independent replication of earlier gene associations. The analyses focused on rare coding single-nucleotide variants and small insertions and deletions and did not assess other potentially relevant types of genetic variation, including copy-number, noncoding, and mitochondrial variants. Genotype-phenotype analyses were limited by incomplete clinical information and small subgroup sizes, and the singleton analyses were restricted to patients of European ancestry.
The findings expanded the number of high-confidence, large-effect genes implicated in OCD and CTDs and supported shared genetic and neurobiological features across the disorders, although further research is needed to characterize the functional consequences of the implicated mutations.
“Overall, our results introduce a tenfold increase in the number of bona fide large-effect risk genes contributing to obsessions, compulsions and tics,” wrote lead study author Belinda Wang, of the Department of Psychiatry and Behavioral Sciences at the University of California, San Francisco Weill Institute for Neurosciences, and colleagues.
Full disclosures of the study authors can be found in the study.
Source: Nature Neuroscience
