Childhood-onset obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with a strong genetic component. De novo variants (DNVs) have been shown to have a role in childhood-onset OCD, but to date, no DNV analysis has been performed in patients from a genetically isolated population. Here, we aimed to investigate the impact of rare de novo single nucleotide variants (dnSNVs) on childhood-onset OCD risk in the French-Canadian population. In a cohort of 36 French-Canadian trios comprised of 36 probands with childhood-onset OCD and 72 unaffected parents, we identified 34 dnSNVs harboured in 34 different genes. We found that four of these genes were previously associated with OCD, replicating their contribution to its risk. We also observed complete overlap between our 34 candidate genes and genes associated with eleven related neuropsychiatric disorders, supporting a shared underlying genetic susceptibility across psychopathologies. Among genes harbouring DNVs across three childhood-onset OCD cohorts, we observed an overrepresentation of genes involved in clathrin-dependent endocytosis (GO:0072583; p- adj=0.0498) and phosphatidylinositol binding (GO:0035091; p-adj=0.0431), offering potential biological mechanisms underlying childhood-onset OCD. No association was found between the number of dnSNVs in childhood-onset OCD probands and OCD symptom severity. Altogether, this study offers a framework for performing DNV analyses of complex disorders in genetically isolated populations. We have provided the first list of candidate childhood-onset OCD genes in the French-Canadian population.

The authors have declared no competing interest.

J.P.R received a doctoral student fellowship from the ALS Society of Canada and a CIHR Frederick Banting & Charles Best Canada Graduate Scholarship (FRN159279). Z.S. received a doctoral student fellowship from the Canadian Institutes of Health Research (CIHR) Frederick Banting & Charles Best Canada Graduate Scholarship (FRN260055) and the Transforming Autism Care Consortium, a thematic network supported by the Fonds de Recherche Quebec-Sante.

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Ethical approval was obtained from the McGill University Health Centre (MUHC) Centre for Applied Ethics Research Ethics Board (REB) Neurosciences-Psychiatry (NEUPSY) panel (IRB00010120).

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