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

Sumana R Chintalapudi,Monica M Jablonski,Doaa Maria,Janey L Wiggs,Robert W Williams,Jessica N Cooke Bailey,Xiang Di Wang,Pirro G Hysi

doi:10.1038/s41467-017-00837-5

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.

Highlights

Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role
Using stringent stepwise refinement based on expression quantitative trait locus (QTL) mapping, correlation analyses, and the analysis of single-nucleotide polymorphisms (SNPs), we identify a candidate gene that modulates intraocular pressure (IOP), and we combine mouse and human genetic data in an effort to validate the candidate gene
We have demonstrated that our top candidate gene—Cacna2d1—is critical for modulation of IOP in these strains

Summary

Results

To determine the candidate gene variants that modulate IOP within the Chr 5 locus, we used the following stringent criteria (Fig. 2e): (1) the gene is located within the confidence interval of the peak eQTL; (2) the gene has cis-modulation; (3) the expression level of the gene across BXD strains is significantly correlated with elevated IOP using both linear correlation and partial Pearson correlation analyses; (4) the gene functions within a network that could explain its role in modulating IOP; (5) the gene has sequence variants between parental strains at/near the region of the gene; (6) the gene is expressed in the eye and localized to an area associated with modulation of IOP; (7) the gene is associated with human POAG and/or elevated IOP either through GWAS or standard linkage studies; and (8) the gene has a biological association with glaucoma or its treatment. Categories that are statistically over-represented are shown with their normalized enrichment score (NES) listed next to the bars

10 Parents and F1s b

BXD strains

Discussion

Methods