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Integrating evolutionary and regulatory information with multispecies approach implicates genes and pathways in obsessive-compulsive disorder
Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA.;MIT, McGovern Inst Brain Res, Dept Brain & Cognit Sci, 43 Vassar St, Cambridge, MA 02139 USA.;Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, 145 Shandong Middle Rd, Shanghai 200001, Peoples R China..
Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 774Article in journal (Refereed) Published
Abstract [en]

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 x 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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 8, article id 774
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Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-340126DOI: 10.1038/s41467-017-00831-xISI: 000413116100001PubMedID: 29042551OAI: oai:DiVA.org:uu-340126DiVA, id: diva2:1179265
Funder
Swedish Research Council, K2013-61P-22168NIH (National Institute of Health), 1R21MH109938-01
Note

Elinor K. Karlsson and Kerstin Lindblad-Toh contributed equally to this work

Available from: 2018-01-31 Created: 2018-01-31 Last updated: 2018-02-01Bibliographically approved

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