Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder
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Author
Noh, Hyun Ji
Tang, Ruqi
Flannick, Jason
O’Dushlaine, Colm
Swofford, Ross
Howrigan, Daniel
Genereux, Diane P.
Johnson, Jeremy
van Grootheest, Gerard
Grünblatt, Edna
Andersson, Erik
Djurfeldt, Diana R.
Patel, Paresh D.
Koltookian, Michele
M. Hultman, Christina
Pato, Michele T.
Pato, Carlos N.
Rasmussen, Steven A.
Hanna, Gregory L.
Stewart, S. Evelyn
Knowles, James A.
Ruhrmann, Stephan
Grabe, Hans-Jörgen
Wagner, Michael
Rück, Christian
Mathews, Carol A.
Walitza, Susanne
Cath, Daniëlle C.
Feng, Guoping
Karlsson, Elinor K.
Lindblad-Toh, Kerstin
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/s41467-017-00831-xMetadata
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Noh, H. J., R. Tang, J. Flannick, C. O’Dushlaine, R. Swofford, D. Howrigan, D. P. Genereux, et al. 2017. “Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder.” Nature Communications 8 (1): 774. doi:10.1038/s41467-017-00831-x. http://dx.doi.org/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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645406/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492221
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