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

Sumana R. Chintalapudi, Doaa Maria, Xiang Di Wang, Jessica N.Cooke Bailey, Rand Allingham, Murray Brilliant, Don Budenz, John Fingert, Douglas Gaasterland, Teresa Gaasterland, Jonathan L. Haines, Lisa Hark, Michael Hauser, Rob Igo, Jae Hee Kang, Peter Kraft, Richard Lee, Paul Lichter, Yutao Liu, Syoko Moroi & 43 others Louis R. Pasquale, Margaret Pericak-Vance, Anthony Realini, Doug Rhee, Julia R. Richards, Robert Ritch, Joel Schuman, William K. Scott, Kuldev Singh, Arthur Sit, Douglas Vollrath, Gadi Wollstein, Don Zack, Tin Aung, Peter Bonnemaijer, Cheng Yu Cheng, Jamie Craig, Cornelia Van Duijn, Puya Gharahkhani, Adriana Iglesias Gonzalez, Christopher J. Hammond, Alex Hewitt, Rene Hoehn, Fridbert Jonansson, Anthony Khawaja, Chiea Chuen Khor, Caroline C.W. Klaver, Andrew Lotery, David MacKey, Stuart MacGregor, Calvin Pang, Francesca Pasutto, Kári Stefansson, Gudmar Thorleifsson, Unnar Thorsteinsdottir, Veronique Vitart, Eranga Vithana, Terri Young, Tanja Zeller, Pirro G. Hysi, Janey L. Wiggs, Robert Williams, Monica Jablonski

Research output: Contribution to journalArticle

3 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 (US)
Article number1755
JournalNature communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

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

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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

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

Research output: Contribution to journalArticle

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, 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, R & Jablonski, M 2017, 'Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility', Nature communications, vol. 8, no. 1, 1755. https://doi.org/10.1038/s41467-017-00837-5
Chintalapudi, Sumana R. ; Maria, Doaa ; Di Wang, Xiang ; Bailey, Jessica N.Cooke ; Allingham, Rand ; Brilliant, Murray ; Budenz, Don ; Fingert, John ; Gaasterland, Douglas ; Gaasterland, Teresa ; Haines, Jonathan L. ; Hark, Lisa ; Hauser, Michael ; Igo, Rob ; Hee Kang, Jae ; Kraft, Peter ; Lee, Richard ; Lichter, Paul ; Liu, Yutao ; Moroi, Syoko ; Pasquale, Louis R. ; Pericak-Vance, Margaret ; Realini, Anthony ; Rhee, Doug ; Richards, Julia R. ; Ritch, Robert ; Schuman, Joel ; Scott, William K. ; Singh, Kuldev ; Sit, Arthur ; Vollrath, Douglas ; Wollstein, Gadi ; Zack, Don ; Aung, Tin ; Bonnemaijer, Peter ; Cheng, Cheng Yu ; Craig, Jamie ; Van Duijn, Cornelia ; Gharahkhani, Puya ; Iglesias Gonzalez, Adriana ; Hammond, Christopher J. ; Hewitt, Alex ; Hoehn, Rene ; Jonansson, Fridbert ; Khawaja, Anthony ; Chuen Khor, Chiea ; Klaver, Caroline C.W. ; Lotery, Andrew ; MacKey, David ; MacGregor, Stuart ; Pang, Calvin ; Pasutto, Francesca ; Stefansson, Kári ; Thorleifsson, Gudmar ; Thorsteinsdottir, Unnar ; Vitart, Veronique ; Vithana, Eranga ; Young, Terri ; Zeller, Tanja ; Hysi, Pirro G. ; Wiggs, Janey L. ; Williams, Robert ; Jablonski, Monica. / Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility. In: Nature communications. 2017 ; Vol. 8, No. 1.
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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.",
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AU - Allingham, Rand

AU - Brilliant, Murray

AU - Budenz, Don

AU - Fingert, John

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AU - Gaasterland, Teresa

AU - Haines, Jonathan L.

AU - Hark, Lisa

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AU - Scott, William K.

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AU - Sit, Arthur

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AU - Wollstein, Gadi

AU - Zack, Don

AU - Aung, Tin

AU - Bonnemaijer, Peter

AU - Cheng, Cheng Yu

AU - Craig, Jamie

AU - Van Duijn, Cornelia

AU - Gharahkhani, Puya

AU - Iglesias Gonzalez, Adriana

AU - Hammond, Christopher J.

AU - Hewitt, Alex

AU - Hoehn, Rene

AU - Jonansson, Fridbert

AU - Khawaja, Anthony

AU - Chuen Khor, Chiea

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AU - Vithana, Eranga

AU - Young, Terri

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AU - Wiggs, Janey L.

AU - Williams, Robert

AU - Jablonski, Monica

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