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

Hyun Ji Noh (), Ruqi Tang, Jason Flannick, Colm O’Dushlaine, Ross Swofford, Daniel Howrigan, Diane P. Genereux, Jeremy Johnson, Gerard Grootheest, Edna Grünblatt, Erik Andersson, Diana R. Djurfeldt, Paresh D. Patel, Michele Koltookian, Christina Hultman, Michele T. Pato, Carlos N. Pato, Steven A. Rasmussen, Michael A. Jenike, Gregory L. Hanna, S. Evelyn Stewart, James A. Knowles, Stephan Ruhrmann, Hans-Jörgen Grabe, Michael Wagner, Christian Rück, Carol A. Mathews, Susanne Walitza, Daniëlle C. Cath, Guoping Feng, Elinor K. Karlsson () and Kerstin Lindblad-Toh ()
Additional contact information
Hyun Ji Noh: Broad Institute of MIT and Harvard
Ruqi Tang: Broad Institute of MIT and Harvard
Jason Flannick: Broad Institute of MIT and Harvard
Colm O’Dushlaine: Broad Institute of MIT and Harvard
Ross Swofford: Broad Institute of MIT and Harvard
Daniel Howrigan: Broad Institute of MIT and Harvard
Diane P. Genereux: Broad Institute of MIT and Harvard
Jeremy Johnson: Broad Institute of MIT and Harvard
Gerard Grootheest: VU University Medical Center
Edna Grünblatt: University Hospital of Psychiatry Zurich, University of Zurich
Erik Andersson: Karolinska Institutet Tomtebodavägen 18A
Diana R. Djurfeldt: Karolinska Institutet Tomtebodavägen 18A
Paresh D. Patel: University of Michigan
Michele Koltookian: Broad Institute of MIT and Harvard
Christina Hultman: Karolinska Institutet
Michele T. Pato: USC
Carlos N. Pato: USC
Steven A. Rasmussen: Brown Medical School
Michael A. Jenike: Harvard Medical School
Gregory L. Hanna: University of Michigan
S. Evelyn Stewart: BC Mental Health & Addictions Research Institute, UBC
James A. Knowles: USC
Stephan Ruhrmann: University of Cologne
Hans-Jörgen Grabe: University of Medicine Greifswald
Michael Wagner: University of Bonn
Christian Rück: Karolinska Institutet Tomtebodavägen 18A
Carol A. Mathews: University of Florida
Susanne Walitza: University Hospital of Psychiatry Zurich, University of Zurich
Daniëlle C. Cath: Utrecht University
Guoping Feng: Massachusetts Institute of Technology
Elinor K. Karlsson: Broad Institute of MIT and Harvard
Kerstin Lindblad-Toh: Broad Institute of MIT and Harvard

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00831-x

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