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

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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, Hewitt, A ORCID: 0000-0002-5123-5999, 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 and Jablonski, MM 2017 , 'Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility' , Nature Communications, vol. 8, no. 1 , pp. 1-12 , doi: 10.1038/s41467-017-00837-5.

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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.

Item Type: Article
Authors/Creators:Chintalapudi, SR and Maria, D and Di Wang, X and Bailey, JNC and Allingham, R and Brilliant, M and Budenz, D and Fingert, J and Gaasterland, D and Gaasterland, T and Haines, JL and Hark, L and Hauser, M and Igo, R and Hee Kang, J and Kraft, P and Lee, R and Lichter, P and Liu, Y and Moroi, S and Pasquale, LR and Pericak-Vance, M and Realini, A and Rhee, D and Richards, JR and Ritch, R and Schuman, J and Scott, WK and Singh, K and Sit, A and Vollrath, D and Wollstein, G and Zack, D and Aung, T and Bonnemaijer, P and Cheng, CY and Craig, J and Van Duijn, C and Gharahkhani, P and Iglesias Gonzalez, A and Hammond, CJ and Hewitt, A and Hoehn, R and Jonansson, F and Khawaja, A and Chuen Khor, C and Klaver, CCW and Lotery, A and MacKey, D and MacGregor, S and Pang, C and Pasutto, F and Stefansson, K and Thorleifsson, G and Thorsteinsdottir, U and Vitart, V and Vithana, E and Young, T and Zeller, T and Hysi, PG and Wiggs, JL and Williams, RW and Jablonski, MM
Keywords: Cacna2d1, intraocular pressure, glaucoma susceptibility, systems genetics, genetic variation
Journal or Publication Title: Nature Communications
Publisher: Nature Publishing Group
ISSN: 2041-1723
DOI / ID Number: 10.1038/s41467-017-00837-5
Copyright Information:

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

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