RT Journal Article SR Electronic T1 De novo damaging coding mutations are strongly associated with obsessive-compulsive disorder and overlap with autism JF bioRxiv FD Cold Spring Harbor Laboratory SP 127712 DO 10.1101/127712 A1 Carolina Cappi A1 Melody E. Oliphant A1 Zsanett Péter A1 Gwyneth Zai A1 Catherine A. W. Sullivan A1 Abha R. Gupta A1 Ellen J. Hoffman A1 Manmeet Virdee A1 A. Jeremy Willsey A1 Roseli G. Shavitt A1 Euripedes C. Miguel A1 James L. Kennedy A1 Margaret A. Richter A1 Thomas V. Fernandez YR 2017 UL http://biorxiv.org/content/early/2017/09/21/127712.abstract AB 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.SIGNIFICANCE STATEMENT Decades of genetic studies in obsessive-compulsive disorder (OCD) have yet to provide reproducible, statistically significant findings. Following an approach that has led to tremendous success in gene discovery for several neuropsychiatric disorders, here we report findings from DNA whole-exome sequencing of patients with OCD and their parents. We find strong evidence for the contribution of spontaneous, or de novo, predicted-damaging genetic variants to OCD risk, identify two high-confidence risk genes, and detect significant overlap with genes previously identified in autism. These results change the status quo of OCD genetics by identifying novel OCD risk genes, clarifying the genetic landscape of OCD with respect to de novo variation, and suggesting underlying biological pathways that will improve our understanding of OCD biology.