A Rutgers-led consortium has expanded the genetic map of obsessive-compulsive disorder and tic disorders, revealing 36 high-confidence risk genes and suggesting new directions for treatment research.
A Rutgers-led consortium has turned a sparse genetic trail into a much denser map of risk for obsessive-compulsive disorder and chronic tic disorders, reporting in Nature Neuroscience on 1 September that it had identified 36 high-confidence, large-effect genes linked to one or both conditions, (nature.com) a jump the authors have described elsewhere as a tenfold expansion from the four such genes previously regarded as firmly established. Reuters, in a 2 September write-up, (currently.att.yahoo.com) presented the finding as a possible route to new treatments rather than a near-term clinical test.
The scale of the dataset helps explain why the paper is drawing attention. The team analysed 3,964 affected people, including 2,418 parent-proband trios and 1,546 singletons, with comparison data from 1,734 neurotypical sibling-parent trios and 2,380 European-ancestry parents used as singleton controls; about 36% of the case trios and 70% of the case singletons were newly sequenced for the project, (news.mdspire.com) and the disorder-specific analyses produced 12 high-confidence genes for OCD and 10 for chronic tic disorders before a combined analysis yielded 34, bringing the overall tally to 36.
One reason the result matters is that it treats OCD and chronic tic disorders, including Tourette syndrome, as overlapping biology rather than wholly separate silos, (medicalxpress.com) and 30 of the 36 genes drew evidence from both disorders. The estimated effects were large, with the authors putting the average odds ratio at 57, but the mutations were uncommon: damaging de novo or other rare likely gene-disrupting variants appeared in only about 3% to 8% of affected patients, (nature.com) which means the work is more immediately useful for understanding mechanism than for offering a simple screening answer to families.
The biological picture is also sharper than the usual claim that psychiatric disorders are “in the brain”. The paper’s transcriptomic analyses pointed to increased risk-gene expression in the postnatal cerebellum and in prenatal and postnatal cortex and striatum, while cell-type analyses highlighted telencephalic projecting excitatory neurons and also implicated striatal medium spiny neurons, (nature.com) giving researchers a more precise sense of where disrupted signalling, movement control and habit formation may intersect.
Some of the strongest clues lay outside OCD and tics themselves. The newly implicated genes overlapped established risk genes for autism spectrum disorder, developmental delay or intellectual disability, and schizophrenia, (nature.com) while four genes – BRWD1, CELSR3, QRICH1 and SYNE1 – also coincided with loci highlighted by common-variant OCD genome-wide studies. That convergence between rare-variant and common-variant evidence strengthens the case that at least part of the signal reflects shared underlying biology rather than statistical noise.
Jay Tischfield, the Rutgers geneticist and senior co-author, said the enlarged target list could give drug developers far more to work with than the “couple of strong genes” known before, and told Reuters and Rutgers that scientists now had “over 30 targets” to pursue, (medicalxpress.com) while his colleague Gary Heiman said the work “dramatically expands the catalog of shared risk genes” and illuminates circuits involved in impulse control, movement and habit formation. (medicalxpress.com) The shift in emphasis is important: the researchers are arguing less for a one-gene, one-disorder model than for networks of genes acting across connected brain systems.
The breadth of the collaboration is another part of the story. Rutgers said more than 30 research teams across the United States, Canada, Europe, South Korea and South America contributed to the project, and Newswise reported that participating centres included the University of California campuses in San Francisco and Los Angeles, Harvard Medical School and McLean Hospital, Johns Hopkins, Yale, Baylor, the University of Washington and McGill’s Montreal Neurological Institute-Hospital, (medicalxpress.com) while Rutgers researchers helped design the study, curate clinical data and oversee sequencing. According to Newswise, funding included support from the US National Institutes of Health, the New Venture Fund/Foundation for OCD Research and the New Jersey Center for Tourette Syndrome, making clear that this was a long-build effort rather than a quick single-lab result.
Even so, the study is not a final answer. MDSpire noted that the analyses were not designed as an independent replication, focused on rare coding variants rather than copy-number, non-coding or mitochondrial changes, and were constrained by incomplete clinical information; its singleton analysis was also limited to people of European ancestry, (news.mdspire.com) so the next phase is likely to involve working out which of these mutations alter brain development, in whom, and whether any of the pathways they expose can be targeted safely enough to matter in the clinic. For patients and families, that is less dramatic than the headline number, but it is where the real test of the discovery will lie.
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