Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder
Name
s41467-017-00831-x.pdf
Size
1.93 MB
Format
Adobe PDF
Checksum (MD5)
4bd27084083c438dc7680d71ec6e8a16
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
Date Issued
October 2017
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
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)
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Terms of Use
Creative Commons Attribution 4.0 International License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/s41467-017-00831-x
