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Title: Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility
Authors: Chintalapudi, S.R
Maria, D
Di Wang, X
Bailey, J.N.C
Allingham, R 
Brilliant, M
Budenz, D
Fingert, J
Gaasterland, D
Gaasterland, T
Haines, J.L
Hark, L
Hauser, M 
Igo, R
Hee Kang, J
Kraft, P
Lee, R
Lichter, P
Liu, Y
Moroi, S
Pasquale, L.R
Pericak-Vance, M
Realini, A
Rhee, D
Richards, J.R
Ritch, R
Schuman, J
Scott, W.K
Singh, K
Sit, A
Vollrath, D
Wollstein, G
Zack, D
Aung, T 
Bonnemaijer, P
Cheng, C.-Y
Craig, J
Van Duijn, C
Gharahkhani, P
Iglesias Gonzalez, A
Hammond, C.J
Hewitt, A
Hoehn, R
Jonansson, F
Khawaja, A
Chuen Khor, C 
Klaver, C.C.W
Lotery, A
MacKey, D
MacGregor, S
Pang, C
Pasutto, F
Stefansson, K
Thorleifsson, G
Thorsteinsdottir, U
Vitart, V
Vithana, E 
Young, T
Zeller, T
Hysi, P.G
Wiggs, J.L
Williams, R.W
Jablonski, M.M
Keywords: cacna2d1 protein
unclassified drug
CACNA2D1 protein, human
CACNA2D1 protein, mouse
calcium channel
chemical binding
genetic analysis
genetic variation
nervous system disorder
polymerase chain reaction
risk factor
animal experiment
animal model
animal tissue
case report
cellular distribution
clinical article
controlled study
drug protein binding
genetic association
genetic susceptibility
genetic variability
genetic variation
genome-wide association study
human tissue
intraocular pressure
open angle glaucoma
protein function
quantitative trait locus
single nucleotide polymorphism
C57BL mouse
cohort analysis
DBA mouse
disease model
genetic predisposition
Calcium Channels
Cohort Studies
Disease Models, Animal
Genetic Predisposition to Disease
Genome-Wide Association Study
Glaucoma, Open-Angle
Intraocular Pressure
Mice, Inbred C57BL
Mice, Inbred DBA
Polymorphism, Single Nucleotide
Issue Date: 2017
Publisher: Nature Publishing Group
Citation: Chintalapudi, S.R, Maria, D, Di Wang, X, Bailey, J.N.C, Allingham, R, Brilliant, M, Budenz, D, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, J.L, Hark, L, Hauser, M, Igo, R, Hee Kang, J, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pasquale, L.R, Pericak-Vance, M, Realini, A, Rhee, D, Richards, J.R, Ritch, R, Schuman, J, Scott, W.K, Singh, K, Sit, A, Vollrath, D, Wollstein, G, Zack, D, Aung, T, Bonnemaijer, P, Cheng, C.-Y, Craig, J, Van Duijn, C, Gharahkhani, P, Iglesias Gonzalez, A, Hammond, C.J, Hewitt, A, Hoehn, R, Jonansson, F, Khawaja, A, Chuen Khor, C, Klaver, C.C.W, Lotery, A, MacKey, D, MacGregor, S, Pang, C, Pasutto, F, Stefansson, K, Thorleifsson, G, Thorsteinsdottir, U, Vitart, V, Vithana, E, Young, T, Zeller, T, Hysi, P.G, Wiggs, J.L, Williams, R.W, Jablonski, M.M (2017). Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility. Nature Communications 8 (1) : 1755. ScholarBank@NUS Repository.
Abstract: Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets. © 2017 The Author(s).
Source Title: Nature Communications
ISSN: 2041-1723
DOI: 10.1038/s41467-017-00837-5
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