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

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.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.

• Authors: Hyun Ji Noh, Ruqi Tang, Jason Flannick, Colm O'Dushlaine, Ross Swofford, Daniel Howrigan, Diane P Genereux, Jeremy Johnson, Gerard van Grootheest, Edna Grünblatt, Erik Andersson, Diana R Djurfeldt, Paresh D Patel, Michele Koltookian, Christina M 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, Kerstin Lindblad-Toh
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 774 (10 17 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 29042551 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CTTNBP2 protein, human
• Calcium-Binding Proteins
• Carrier Proteins
• Cell Adhesion Molecules, Neuronal
• Membrane Transport Proteins
• NRXN1 protein, human
• Nerve Tissue Proteins
• Neural Cell Adhesion Molecules
• Proteins
• REEP3 protein, human

Topics

• Calcium-Binding Proteins
• Carrier Proteins (genetics, metabolism)
• Cell Adhesion Molecules, Neuronal (genetics, metabolism)
• Cohort Studies
• Humans
• Membrane Transport Proteins (genetics, metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Neural Cell Adhesion Molecules
• Obsessive-Compulsive Disorder (genetics, metabolism)
• Polymorphism, Single Nucleotide
• Proteins (genetics, metabolism)
• Signal Transduction
• Synapses (genetics, metabolism)