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; 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 W. Williams; Monica M. Jablonski

doi:10.1038/s41467-017-00837-5

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 MoroiLouis 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 W. Williams, Monica M. Jablonski

Ophthalmology

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

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 language	English (US)
Article number	1755
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00837-5
State	Published - Dec 1 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Chintalapudi, S. R., Maria, D., Di Wang, X., Bailey, J. N. C., Allingham, R., Brilliant, M., Budenz, D., Fingert, J., Gaasterland, D., Gaasterland, T., Haines, J. L., Hark, L., Hauser, M., Igo, R., Hee Kang, J., Kraft, P., Lee, R., Lichter, P., Liu, Y., ... Jablonski, M. M. (2017). Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility. Nature communications, 8(1), Article 1755. https://doi.org/10.1038/s41467-017-00837-5

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, RW & Jablonski, MM 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

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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 = "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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AU - Chintalapudi, Sumana R.

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AU - Di Wang, Xiang

AU - Bailey, Jessica N.Cooke

AU - Allingham, Rand

AU - Brilliant, Murray

AU - Budenz, Don

AU - Fingert, John

AU - Gaasterland, Douglas

AU - Gaasterland, Teresa

AU - Haines, Jonathan L.

AU - Hark, Lisa

AU - Hauser, Michael

AU - Igo, Rob

AU - Hee Kang, Jae

AU - Kraft, Peter

AU - Lee, Richard

AU - Lichter, Paul

AU - Liu, Yutao

AU - Moroi, Syoko

AU - Pasquale, Louis R.

AU - Pericak-Vance, Margaret

AU - Realini, Anthony

AU - Rhee, Doug

AU - Richards, Julia R.

AU - Ritch, Robert

AU - Schuman, Joel

AU - Scott, William K.

AU - Singh, Kuldev

AU - Sit, Arthur

AU - Vollrath, Douglas

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

AU - Klaver, Caroline C.W.

AU - Lotery, Andrew

AU - MacKey, David

AU - MacGregor, Stuart

AU - Pang, Calvin

AU - Pasutto, Francesca

AU - Stefansson, Kári

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnar

AU - Vitart, Veronique

AU - Vithana, Eranga

AU - Young, Terri

AU - Zeller, Tanja

AU - Hysi, Pirro G.

AU - Wiggs, Janey L.

AU - Williams, Robert W.

AU - Jablonski, Monica M.

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N2 - 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.

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

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