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

Sumana R Chintalapudi; Doaa Maria; Xiang Di Wang; Jessica N Cooke Bailey; Pirro G Hysi; Janey L Wiggs; Robert W Williams; Monica M Jablonski; NEIGHBORHOOD consortium

doi:10.1038/s41467-017-00837-5

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

Journal article

Open access

Peer reviewed

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

Sumana R Chintalapudi, Doaa Maria, Xiang Di Wang, Jessica N Cooke Bailey, Pirro G Hysi, Janey L Wiggs, Robert W Williams, Monica M Jablonski and NEIGHBORHOOD consortium

Nature communications, Vol.8(1), 1755

11/24/2017

DOI: 10.1038/s41467-017-00837-5

PMCID: PMC5701146

PMID: 29176626

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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.

Genetic Predisposition to Disease

Genome-Wide Association Study

Calcium Channels - metabolism

Glaucoma, Open-Angle - genetics

Intraocular Pressure

Humans

Mice, Inbred C57BL

Glaucoma, Open-Angle - physiopathology

Male

Animals

Female

Glaucoma, Open-Angle - metabolism

Mice, Inbred DBA

Aged

Mice

Polymorphism, Single Nucleotide

Calcium Channels - genetics

Cohort Studies

Disease Models, Animal

Details

Title: Subtitle: Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility
Creators: Sumana R Chintalapudi - Department of Ophthalmology, The Hamilton Eye Institute, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
Doaa Maria - Department of Pharmaceutics, College of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
Xiang Di Wang - Department of Ophthalmology, The Hamilton Eye Institute, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
Jessica N Cooke Bailey - Department of Epidemiology and Biostatistics, Institute of Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
Pirro G Hysi - Department of Twin Research and Genetic Epidemiology, King's College London, London, WC2R 2LS, UK
Janey L Wiggs - Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, 02298, USA
Robert W Williams - Department of Genetics, Genomics and Informatics, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
Monica M Jablonski - Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA. mjablonski@uthsc.edu
NEIGHBORHOOD consortium
Contributors: John H Fingert (Contributor) - University of Iowa, Ophthalmology and Visual Sciences
Resource Type: Journal article
Publication Details: Nature communications, Vol.8(1), 1755
DOI: 10.1038/s41467-017-00837-5
PMID: 29176626
PMCID: PMC5701146
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: England
Grant note: P30 EY013080 / NEI NIH HHS R21 EY028671 / NEI NIH HHS R01 EY021200 / NEI NIH HHS R01 EY022305 / NEI NIH HHS
Language: English
Date published: 11/24/2017
Academic Unit: Ophthalmology and Visual Sciences
Record Identifier: 9983980071802771

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