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.
Highlights
Obsessive-compulsive disorder is a severe psychiatric disorder linked to abnormalities in glutamate signaling and the cortico-striatal circuit
Through Genome-wide association studies (GWAS) and targeted sequencing in dog breeds with exceptionally high rates of canine CD, we associated genes involved in synaptic functioning and adhesion with CD, including neural cadherin (CDH2), catenin alpha[2] (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP)[8, 9]
We compiled a list of 608 genes using three strategies (65 were implicated more than once) (Supplementary Table 1 and Supplementary Methods): (1) 263 “model-organism genes”, including 56 genes associated in canine CD GWAS and 222 genes implicated in murine-compulsive grooming
Summary
Obsessive-compulsive disorder is a severe psychiatric disorder linked to abnormalities in glutamate signaling and the cortico-striatal circuit. Genome-wide association studies (GWAS) implicate glutamate signaling and synaptic proteins[2, 3], but specific genes and variants have not been validated. Isolating and characterizing such genes are important for understanding the biology and developing treatments for this devastating disease. Through GWAS and targeted sequencing in dog breeds with exceptionally high rates of canine CD, we associated genes involved in synaptic functioning and adhesion with CD, including neural cadherin (CDH2), catenin alpha[2] (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP)[8, 9]. Genome-wide studies searching for de novo and inherited risk variants have confidently associated hundreds of genes with ASD; this set may be enriched for genes involved in OCD10
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