|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Noh, HJi, Tang, R, Flannick, J, O'Dushlaine, C, Swofford, R, Howrigan, D, Genereux, DP, Johnson, J, van Grootheest, G, Grünblatt, E, Andersson, E, Djurfeldt, DR, Patel, PD, Koltookian, M, Hultman, CM, Pato, MT, Pato, CN, Rasmussen, SA, Jenike, MA, Hanna, GL, S Stewart, E, Knowles, JA, Ruhrmann, S, Grabe, H-J, Wagner, M, Rück, C, Mathews, CA, Walitza, S, Cath, DC, Feng, G, Karlsson, EK, Lindblad-Toh, K|
|Date Published||2017 Oct 17|
Obsessive-compulsive disorder is a severe psychiatric disorder linked to abnormalities in glutamate signaling and the cortico-striatal circuit. We sequenced coding and regulatory elements for 608 genes potentially involved in obsessive-compulsive disorder in human, dog, and mouse. Using a new method that prioritizes likely functional variants, we compared 592 cases to 560 controls and found four strongly associated genes, validated in a larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains. CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants, of which at least six (35%) alter transcription factor-DNA binding in neuroblastoma cells. NRXN1 achieves genome-wide significance (p = 6.37 × 10(-11)) when we include 33,370 population-matched controls. Our findings suggest synaptic adhesion as a key component in compulsive behaviors, and show that targeted sequencing plus functional annotation can identify potentially causative variants, even when genomic data are limited.Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with symptoms including intrusive thoughts and time-consuming repetitive behaviors. Here Noh and colleagues identify genes enriched for functional variants associated with increased risk of OCD.
|Alternate Journal||Nat Commun|