Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder
Author(s)Noh, Hyun Ji; Flannick, Jason; O’Dushlaine, Colm; Swofford, Ross; Howrigan, Daniel; Genereux, Diane P.; Johnson, Jeremy; van Grootheest, Gerard; Grünblatt, Edna; Andersson, Erik; Djurfeldt, Diana R.; Patel, Paresh D.; Koltookian, Michele; M. Hultman, Christina; Pato, Michele T.; Pato, Carlos N.; Rasmussen, Steven A.; Jenike, Michael A.; Hanna, Gregory L.; Stewart, S. Evelyn; Knowles, James A.; Ruhrmann, Stephan; Grabe, Hans-Jörgen; Wagner, Michael; Rück, Christian; Mathews, Carol A.; Walitza, Susanne; Cath, Daniëlle C.; Lindblad-Toh, Kerstin; Tang, Ruqi; Feng, Guoping; Karlsson, Elinor; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Nature Publishing Group
Noh, Hyun Ji et al. “Integrating Evolutionary and Regulatory Information with a Multispecies Approach Implicates Genes and Pathways in Obsessive-Compulsive Disorder.” Nature Communications 8, 1 (October 2017): 774 © 2017 The Author(s)
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