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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


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
Issue number1
Publication statusPublished - 1 Dec 2017

Bibliographical note

Funding Information:
We thank Dr. E. Geisert, Dr. L. Lu, and Mr. B. Orr for their assistance in generating the BXD microarray data sets that were used in these analyses. We also thank Dr. H. Lu for acquiring the IOP data sets and Dr. S. Surbhi for assistance with statistical analyses. We further thank S. Ganguli and A. Shepherd for discussion and technical assistance. We acknowledge the financial support from: the Center for Integrative and Translational Genomics at the University of Tennessee Health Science Center; NEI Grants R01EY021200, R01EY022305, and P30EY013080; NIAAA Grant U01AA01666; and a Stein Innovation Award and an unrestricted grant from Research to Prevent Blindness, Inc.

Publisher Copyright:
© 2017 The Author(s).


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