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Nat Commun DOI:10.1038/s41467-017-00831-x

Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder.

Publication TypeJournal Article
Year of Publication2017
AuthorsNoh, 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
JournalNat Commun
Date Published2017 10 17
KeywordsCarrier Proteins, Cell Adhesion Molecules, Neuronal, Cohort Studies, Humans, Membrane Transport Proteins, Nerve Tissue Proteins, Obsessive-Compulsive Disorder, Polymorphism, Single Nucleotide, Proteins, Signal Transduction, Synapses

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) 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 JournalNat Commun
PubMed ID29042551
PubMed Central IDPMC5645406
Grant ListR01 MH085321 / MH / NIMH NIH HHS / United States
R21 MH109938 / MH / NIMH NIH HHS / United States
/ / European Research Council / International