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

International Glaucoma Genetics Consortium

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number1755
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017

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intraocular pressure
glaucoma
Intraocular Pressure
Glaucoma
magnetic permeability
Genes
Pressure effects
Polymorphism
genome
Genome-Wide Association Study
polymorphism
nucleotides
Human Genome
pressure effects
Nucleotides
genes
Haplotypes
Single Nucleotide Polymorphism
mice
Molecular Biology

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title = "Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility",
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.",
author = "{International Glaucoma Genetics Consortium} and Chintalapudi, {Sumana R.} and Doaa Maria and {Di Wang}, Xiang and Bailey, {Jessica N.Cooke} and Rand Allingham and Murray Brilliant and Don Budenz and John Fingert and Douglas Gaasterland and Teresa Gaasterland and Haines, {Jonathan L.} and Lisa Hark and Michael Hauser and Rob Igo and {Hee Kang}, Jae and Peter Kraft and Richard Lee and Paul Lichter and Yutao Liu and Syoko Moroi and Pasquale, {Louis R.} and Margaret Pericak-Vance and Anthony Realini and Doug Rhee and Richards, {Julia R.} and Robert Ritch and Joel Schuman and Scott, {William K.} and Kuldev Singh and Arthur Sit and Douglas Vollrath and Gadi Wollstein and Don Zack and Tin Aung and Peter Bonnemaijer and Cheng, {Cheng Yu} and Jamie Craig and {Van Duijn}, Cornelia and Puya Gharahkhani and {Iglesias Gonzalez}, Adriana and Hammond, {Christopher J.} and Alex Hewitt and Rene Hoehn and Fridbert Jonansson and Anthony Khawaja and {Chuen Khor}, Chiea and Klaver, {Caroline C.W.} and Andrew Lotery and David MacKey and Stuart MacGregor and Calvin Pang and Francesca Pasutto and K{\'a}ri Stefansson and Gudmar Thorleifsson and Unnar Thorsteinsdottir and Veronique Vitart and Eranga Vithana and Terri Young and Tanja Zeller and Hysi, {Pirro G.} and Wiggs, {Janey L.} and Williams, {Robert W.} and Jablonski, {Monica M.}",
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Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility. / International Glaucoma Genetics Consortium.

In: Nature Communications, Vol. 8, No. 1, 1755, 01.12.2017.

Research output: Contribution to journalArticle

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AU - International Glaucoma Genetics Consortium

AU - Chintalapudi, Sumana R.

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AU - Allingham, Rand

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AU - Hammond, Christopher J.

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AU - Hoehn, Rene

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AU - Pang, Calvin

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AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnar

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