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Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

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Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility. / Chintalapudi, Sumana R; Maria, Doaa; Di Wang, Xiang; Bailey, Jessica N Cooke; Hysi, Pirro G; Wiggs, Janey L; Williams, Robert W; Jablonski, Monica M; NEIGHBORHOOD Consortium.

In: NAT COMMUN, Vol. 8, No. 1, 1755, 24.11.2017.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Chintalapudi, SR, Maria, D, Di Wang, X, Bailey, JNC, Hysi, PG, Wiggs, JL, Williams, RW, Jablonski, MM & NEIGHBORHOOD Consortium 2017, 'Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility', NAT COMMUN, vol. 8, no. 1, 1755. https://doi.org/10.1038/s41467-017-00837-5

APA

Chintalapudi, S. R., Maria, D., Di Wang, X., Bailey, J. N. C., Hysi, P. G., Wiggs, J. L., Williams, R. W., Jablonski, M. M., & NEIGHBORHOOD Consortium (2017). Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility. NAT COMMUN, 8(1), [1755]. https://doi.org/10.1038/s41467-017-00837-5

Vancouver

Chintalapudi SR, Maria D, Di Wang X, Bailey JNC, Hysi PG, Wiggs JL et al. Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility. NAT COMMUN. 2017 Nov 24;8(1). 1755. https://doi.org/10.1038/s41467-017-00837-5

Bibtex

@article{8f9739bb934d44099865d1c2ac850825,
title = "Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility",
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.",
keywords = "Aged, Animals, Calcium Channels/genetics, Cohort Studies, Disease Models, Animal, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glaucoma, Open-Angle/genetics, Humans, Intraocular Pressure, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Polymorphism, Single Nucleotide",
author = "Chintalapudi, {Sumana R} and Doaa Maria and {Di Wang}, Xiang and Bailey, {Jessica N Cooke} and Hysi, {Pirro G} and Wiggs, {Janey L} and Williams, {Robert W} and Jablonski, {Monica M} and {NEIGHBORHOOD Consortium} and Tanja Zeller",
year = "2017",
month = nov,
day = "24",
doi = "10.1038/s41467-017-00837-5",
language = "English",
volume = "8",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

TY - JOUR

T1 - Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

AU - Chintalapudi, Sumana R

AU - Maria, Doaa

AU - Di Wang, Xiang

AU - Bailey, Jessica N Cooke

AU - Hysi, Pirro G

AU - Wiggs, Janey L

AU - Williams, Robert W

AU - Jablonski, Monica M

AU - NEIGHBORHOOD Consortium

AU - Zeller, Tanja

PY - 2017/11/24

Y1 - 2017/11/24

N2 - 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.

AB - 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.

KW - Aged

KW - Animals

KW - Calcium Channels/genetics

KW - Cohort Studies

KW - Disease Models, Animal

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Glaucoma, Open-Angle/genetics

KW - Humans

KW - Intraocular Pressure

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Inbred DBA

KW - Polymorphism, Single Nucleotide

U2 - 10.1038/s41467-017-00837-5

DO - 10.1038/s41467-017-00837-5

M3 - SCORING: Journal article

C2 - 29176626

VL - 8

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

M1 - 1755

ER -