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

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Abstract
Obsessive–compulsive disorder (OCD) and chronic tic disorders (CTDs) are highly heritable. Rare mutations confer large risks for OCD and CTDs but only four high-confidence (hc) genes have been identified. Here we analyzed whole-exome sequencing data from 3,964 individuals with OCD, CTDs or both, including 2,418 trios. We found an excess in cases of de novo and rare protein-damaging mutations and identified 36 hc genes (false discovery rate < 0.1), including four previously identified hc genes ( CELSR3, CHD8, SCUBE1 and WWC1 ) and four genes that overlap with OCD genome-wide association study loci ( BRWD1 , CELSR3 , QRICH1 and SYNE1 ). Risk genes are shared among OCD, CTDs and other neurodevelopmental conditions. Transcriptomic and network analyses highlight mechanistic convergence and increased risk gene expression in postnatal cerebellum, prenatal and postnatal cortex and striatum. Dozens of large-effect OCD and CTD genes offer insights into pathogenesis and a path forward for illuminating pathophysiology and identifying novel treatment targets.
Funding Information
  • National Institute of Mental Health (R01MH115963)
  • National Institute of Mental Health (R25MH060482)
  • National Institute of Mental Health (K08MH128665)
  • National Institute of Mental Health (K99MH128540)
  • National Institute of Mental Health (R01MH115959)
  • National Institute of Mental Health (K23MH126193)
  • National Institute of Mental Health (K23MH066284)
  • National Institute of Mental Health (R01MH135899)
  • National Institute of Mental Health (R01MH130609)
  • National Institute of Mental Health (R01MH116038)
  • National Institute of Mental Health (R01MH115962)
  • National Institute of Mental Health (R01MH115961)
  • National Institute of Mental Health (R01MH115960)
  • National Institute of Mental Health (R01MH115993)
  • National Institute of Mental Health (R01MH115958)
  • National Institute of Mental Health (K23MH125018)
  • National Institute of Mental Health (R01MH115958)
  • National Institute of Mental Health (R01MH114927)
  • New Venture Fund/Foundation for OCD Research, Overlook International Fund
  • Harvey L. and Maud C. Sorensen Foundation Career Award in Child & Adolescent Psychiatry
  • Tourette Association of America (Young Investigator Award)
  • Tourette Association of America (Young Investigator Award)
  • New Venture Fund/Foundation for OCD Research

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