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

Sumana Chintalapudi, Maria Doaa, Xiang Wang, Jessica Cooke Bailey, Tin Aung, Peter Bonnemaijer, Cheng-Yu Cheng, Jamie Craig, Pirro Hysi, Janey Wiggs, Robert Williams, Monica Jablonski

    Research output: Contribution to journalArticle

    8 Citations (Scopus)

    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.

    Original languageEnglish
    Article number1755
    Number of pages12
    JournalNature Communications
    Volume8
    Issue number1
    DOIs
    Publication statusE-pub ahead of print - 2017

    Fingerprint Dive into the research topics of 'Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility'. Together they form a unique fingerprint.

  • Cite this

    Chintalapudi, S., Doaa, M., Wang, X., Cooke Bailey, J., Aung, T., Bonnemaijer, P., Cheng, C-Y., Craig, J., Hysi, P., Wiggs, J., Williams, R., & Jablonski, M. (2017). Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility. Nature Communications, 8(1), [1755]. https://doi.org/10.1038/s41467-017-00837-5