Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder.
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Noh HJ, 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, M Hultman C, Pato MT, Pato CN, Rasmussen SA, Jenike MA, Hanna GL, Stewart SE, Knowles JA, Ruhrmann S, Grabe HJ, Wagner M, Rück C, Mathews CA, Walitza S, Cath DC, Feng G, Karlsson EK, Lindblad-Toh K
Nat Commun 8 (1) 774 [2017-10-17; online 2017-10-17]
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
PubMed 29042551
DOI 10.1038/s41467-017-00831-x
Crossref 10.1038/s41467-017-00831-x
pii: 10.1038/s41467-017-00831-x
pmc: PMC5645406