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

Sumana R. Chintalapudi, Doaa Maria, Xiang Wang, Jessica N. Cooke Bailey, Pirro G. Hysi, Janey L. Wiggs, Robert W. Williams and Monica M. Jablonski ()
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Sumana R. Chintalapudi: The University of Tennessee Health Science Center
Doaa Maria: The University of Tennessee Health Science Center
Xiang Wang: The University of Tennessee Health Science Center
Jessica N. Cooke Bailey: Case Western Reserve University School of Medicine
Pirro G. Hysi: King’s College London
Janey L. Wiggs: Harvard Medical School, Massachusetts Eye and Ear Infirmary
Robert W. Williams: The University of Tennessee Health Science Center
Monica M. Jablonski: The University of Tennessee Health Science Center

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00837-5

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