Journal Article

DZNE-2020-05887

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder.

Noh, H. J. (Corresponding author) ; Tang, R. ; Flannick, J. ; O'Dushlaine, C. ; Swofford, R. ; Howrigan, D. ; Genereux, D. P. ; Johnson, J. ; van Grootheest, G. ; Grünblatt, E. ; Andersson, E. ; Djurfeldt, D. R. ; Patel, P. D. ; Koltookian, M. ; M Hultman, C. ; Pato, M. T. ; Pato, C. N. ; Rasmussen, S. A. ; Jenike, M. A. ; Hanna, G. L. ; Stewart, S. E. ; Knowles, J. A. ; Ruhrmann, S. ; Grabe, H.Extern* ; Wagner, M.DZNE* ; Rück, C. ; Mathews, C. A. ; Walitza, S. ; Cath, D. C. ; Feng, G. ; Karlsson, E. K. ; Lindblad-Toh, K.

2017
Nature Publishing Group UK [London]

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Please use a persistent id in citations: 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.

Keyword(s): Calcium-Binding Proteins (MeSH) ; Carrier Proteins: genetics (MeSH) ; Carrier Proteins: metabolism (MeSH) ; Cell Adhesion Molecules, Neuronal: genetics (MeSH) ; Cell Adhesion Molecules, Neuronal: metabolism (MeSH) ; Cohort Studies (MeSH) ; Humans (MeSH) ; Membrane Transport Proteins: genetics (MeSH) ; Membrane Transport Proteins: metabolism (MeSH) ; Nerve Tissue Proteins: genetics (MeSH) ; Nerve Tissue Proteins: metabolism (MeSH) ; Obsessive-Compulsive Disorder: genetics (MeSH) ; Obsessive-Compulsive Disorder: metabolism (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Proteins: genetics (MeSH) ; Proteins: metabolism (MeSH) ; Signal Transduction (MeSH) ; Synapses: genetics (MeSH) ; Synapses: metabolism (MeSH) ; Neural Cell Adhesion Molecules (MeSH) ; CTTNBP2 protein, human ; Carrier Proteins ; Cell Adhesion Molecules, Neuronal ; Membrane Transport Proteins ; NRXN1 protein, human ; Nerve Tissue Proteins ; Proteins ; REEP3 protein, human

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Contributing Institute(s):

1. Neuropsychology (AG Wagner)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2017

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; ; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; IF >= 15 ; JCR ; SCOPUS ; Web of Science Core Collection ; Zoological Record

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