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De novo damaging coding mutations are strongly associated with obsessive-compulsive disorder and overlap with autism

By Carolina Cappi, Melody E Oliphant, Zsanett P├ęter, Gwyneth Zai, Catherine A. W. Sullivan, Abha R Gupta, Ellen J Hoffman, Manmeet Virdee, A. Jeremy Willsey, Roseli G Shavitt, Euripedes C Miguel, James L Kennedy, Margaret A Richter, Thomas V. Fernandez

Posted 21 Sep 2017
bioRxiv DOI: 10.1101/127712

Obsessive-compulsive disorder (OCD) is a debilitating developmental neuropsychiatric disorder with a genetic risk component, yet identification of high-confidence risk genes has been challenging. We performed whole-exome sequencing in 222 OCD parent-child trios (184 trios after quality control), finding strong evidence that de novo likely gene disrupting and predicted damaging missense variants contribute to OCD risk. Together, these de novo damaging variants are enriched in OCD probands (RR 1.52, p=0.0005). We identified two high-confidence risk genes, each containing two de novo damaging variants in unrelated probands: CHD8 (Chromodomain Helicase DNA Binding Protein 8) and SCUBE1 (Signal Peptide, CUB Domain And EGF Like Domain Containing 1). Based on our data, we estimate that 34% of de novo damaging variants seen in OCD contribute to risk, and that de novo damaging variants in approximately 335 genes contribute to risk in 22% of OCD cases. Furthermore, genes harboring de novo damaging variants in OCD are enriched for those reported in neurodevelopmental disorders, particularly autism spectrum disorders. An exploratory network analysis reveals significant functional connectivity and enrichment in canonical pathways related to immune response.

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