Noh, Hyun Ji, Tang, Ruqi, Flannick, Jason, O'Dushlaine, Colm, Swofford, Ross ORCID: 0000-0003-3676-8479, Howrigan, Daniel, Genereux, Diane P., Johnson, Jeremy, van Grootheest, Gerard ORCID: 0000-0003-4350-6661, Grunblatt, Edna ORCID: 0000-0001-8505-7265, Andersson, Erik, Djurfeldt, Diana R., Patel, Paresh D., Koltookian, Michele, Hultman, Christina M., Pato, Michele T., Pato, Carlos N., Rasmussen, Steven A., Jenike, Michael A., Hanna, Gregory L., Stewart, S. Evelyn, Knowles, James A., Ruhrmann, Stephan ORCID: 0000-0002-6022-2364, Grabe, Hans-Joergen, Wagner, Michael ORCID: 0000-0003-2589-6440, Ruck, Christian, Mathews, Carol A., Walitza, Susanne ORCID: 0000-0002-8161-8683, Cath, Danielle C., Feng, Guoping, Karlsson, Elinor K. and Lindblad-Toh, Kerstin (2017). Integrating evolutionary and regulatory information with multispecies approach implicates genes and pathways in obsessive-compulsive disorder. Nat. Commun., 8. BERLIN: NATURE RESEARCH. ISSN 2041-1723

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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 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Noh, Hyun JiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tang, RuqiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flannick, JasonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Dushlaine, ColmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Swofford, RossUNSPECIFIEDorcid.org/0000-0003-3676-8479UNSPECIFIED
Howrigan, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Genereux, Diane P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnson, JeremyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Grootheest, GerardUNSPECIFIEDorcid.org/0000-0003-4350-6661UNSPECIFIED
Grunblatt, EdnaUNSPECIFIEDorcid.org/0000-0001-8505-7265UNSPECIFIED
Andersson, ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Djurfeldt, Diana R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patel, Paresh D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koltookian, MicheleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hultman, Christina M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pato, Michele T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pato, Carlos N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rasmussen, Steven A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jenike, Michael A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hanna, Gregory L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stewart, S. EvelynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knowles, James A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruhrmann, StephanUNSPECIFIEDorcid.org/0000-0002-6022-2364UNSPECIFIED
Grabe, Hans-JoergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, MichaelUNSPECIFIEDorcid.org/0000-0003-2589-6440UNSPECIFIED
Ruck, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mathews, Carol A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walitza, SusanneUNSPECIFIEDorcid.org/0000-0002-8161-8683UNSPECIFIED
Cath, Danielle C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feng, GuopingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karlsson, Elinor K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindblad-Toh, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-214130
DOI: 10.1038/s41467-017-00831-x
Journal or Publication Title: Nat. Commun.
Volume: 8
Date: 2017
Publisher: NATURE RESEARCH
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Faculty of Management, Economy and Social Sciences
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; CANDIDATE GENES; HERITABILITY; BEHAVIORS; CORTACTIN; CIRCUITRY; GENETICS; INSIGHTS; ELEMENTS; AUTISMMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21413

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