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

Nat Commun. 2017 Oct 17;8(1):774. doi: 10.1038/s41467-017-00831-x.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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