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Research Letter
December 1, 2021

Deletion of Loss-of-Function–Intolerant Genes and Risk of 5 Psychiatric Disorders

Author Affiliations
  • 1Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
  • 2Deep Genomics Inc, Toronto, Ontario, Canada
  • 3The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada
  • 4Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada
  • 5UHC Sainte-Justine Research Center, Montreal, Quebec, Canada
  • 6Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  • 7McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada
  • 8Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  • 9Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
  • 10Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
  • 11Department of Physiology, University of Toronto, Toronto, Ontario, Canada
JAMA Psychiatry. 2022;79(1):78-81. doi:10.1001/jamapsychiatry.2021.3211

Copy number variants (CNVs) are key etiological contributors to neuropsychiatric disorders. Most psychiatric CNV studies have focused on several dozen loci,1 collectively comprising less than 2% of the genome, where CNVs spontaneously recur sufficiently often to have individually detectable psychiatric associations. We hypothesized that knowledge of gene function could guide the search for nonrecurrent CNVs across the remaining 98%. Specifically, probability of loss-of-function intolerance (pLI) and loss-of-function observed/expected upper bound fraction (LOEUF),2 2 gene-level metrics of variation constraint against protein-truncating variants, have been reported to be uniquely associated with the cognitive consequences of CNVs.3 Here, we show that pLI and LOEUF are similarly associated with the psychiatric consequences of both recurrent and nonrecurrent gene deletions.

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