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

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posted on 2023-05-19, 19:05 authored by Chintalapudi, SR, Maria, D, Di Wang, X, Bailey, JNC, Allingham, R, Brilliant, M, Budenz, D, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, JL, Hark, L, Hauser, M, Igo, R, Hee Kang, J, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pasquale, LR, Pericak-Vance, M, Realini, A, Rhee, D, Richards, JR, Ritch, R, Schuman, J, Scott, WK, Singh, K, Sit, A, Vollrath, D, Wollstein, G, Zack, D, Aung, T, Bonnemaijer, P, Cheng, CY, Craig, J, Van Duijn, C, Gharahkhani, P, Iglesias Gonzalez, A, Hammond, CJ, Alexander HewittAlexander Hewitt, Hoehn, R, Jonansson, F, Khawaja, A, Chuen Khor, C, Klaver, CCW, 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, PG, Wiggs, JL, Williams, RW, Jablonski, MM
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.

History

Publication title

Nature Communications

Volume

8

Article number

1755

Number

1755

Pagination

1-12

ISSN

2041-1723

Department/School

Menzies Institute for Medical Research

Publisher

Nature Publishing Group

Place of publication

United Kingdom

Rights statement

© 2017 The Authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

Repository Status

  • Open

Socio-economic Objectives

Clinical health not elsewhere classified

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