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 |
|---|---|
| Article number | 1755 |
| Journal | Nature Communications |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Dec 2017 |
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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 journal › Article
TY - JOUR
T1 - Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility
AU - International Glaucoma Genetics Consortium
AU - Chintalapudi, Sumana R.
AU - Maria, Doaa
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.
PY - 2017/12/1
Y1 - 2017/12/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85035018930&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-00837-5
DO - 10.1038/s41467-017-00837-5
M3 - Article
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1755
ER -