Abstract:
BACKGROUND:Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder with a genetic risk component, yet identification of high-confidence risk genes has been challenging. In recent years, risk gene discovery in other complex psychiatric disorders has been achieved by studying rare de novo (DN) coding variants. METHODS:We performed whole-exome sequencing in 222 OCD parent-child trios (184 trios after quality control), comparing DN variant frequencies with 777 previously sequenced unaffected trios. We estimated the contribution of DN mutations to OCD risk and the number of genes involved. Finally, we looked for gene enrichment in other datasets and canonical pathways. RESULTS:DN likely gene disrupting and predicted damaging missense variants are enriched in OCD probands (rate ratio, 1.52; p = .0005) and contribute to risk. We identified 2 high-confidence risk genes, each containing 2 DN damaging variants in unrelated probands: CHD8 and SCUBE1. We estimate that 34% of DN damaging variants in OCD contribute to risk and that DN damaging variants in approximately 335 genes contribute to risk in 22% of OCD cases. Furthermore, genes harboring DN damaging variants in OCD are enriched for those reported in neurodevelopmental disorders, particularly Tourette's disorder and autism spectrum disorder. An exploratory network analysis reveals significant functional connectivity and enrichment in canonical pathways, biological processes, and disease networks. CONCLUSIONS:Our findings show a pathway toward systematic gene discovery in OCD via identification of DN damaging variants. Sequencing larger cohorts of OCD parent-child trios will reveal more OCD risk genes and will provide needed insights into underlying disease biology.
journal_name
Biol Psychiatryjournal_title
Biological psychiatryauthors
Cappi C,Oliphant ME,Péter Z,Zai G,Conceição do Rosário M,Sullivan CAW,Gupta AR,Hoffman EJ,Virdee M,Olfson E,Abdallah SB,Willsey AJ,Shavitt RG,Miguel EC,Kennedy JL,Richter MA,Fernandez TVdoi
10.1016/j.biopsych.2019.09.029subject
Has Abstractpub_date
2020-06-15 00:00:00pages
1035-1044issue
12eissn
0006-3223issn
1873-2402pii
S0006-3223(19)31779-2journal_volume
87pub_type
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