Whole-exome sequencing in individuals with obsessive-compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes

Excess of de novo and rare protein-damaging mutations, with converging expression in postnatal cerebellum, prenatal and postnatal cortex and striatum

Whole-exome sequencing of 3,964 individuals with obsessive-compulsive disorder, chronic tic disorders or both, including 2,418 trios, showed an excess of de novo and rare protein-damaging mutations. Thirty-six high-confidence genes were identified at a false discovery rate below 0.1, including the four previously known genes — CELSR3, CHD8, SCUBE1 and WWC1 — and four overlapping obsessive-compulsive disorder GWAS loci: BRWD1, CELSR3, QRICH1 and SYNE1. Risk genes are shared with other neurodevelopmental conditions. Transcriptomic and network analyses highlight mechanistic convergence and increased risk gene expression in postnatal cerebellum, prenatal and postnatal cortex, and striatum.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Going from four to thirty-six high-confidence genes changes the scale of what can be interpreted in severe obsessive-compulsive disorder or Tourette syndrome with associated neurodevelopmental features. The overlap with neurodevelopmental genes confirms these are not genetically isolated entities, which argues for reanalysing such exomes against a broader gene list rather than by psychiatric label. The nature of the finding matters, though: these are large-effect risk genes, not Mendelian genes, and returning them to individual patients remains delicate.

Analysis by Dr Thibaut Benquey