Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: a multi-cohort analysis

Abstract

Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 × 10^-27) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 × 10^-5); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.

Figure 1

Association of intraocular pressure and diastolic blood pressure gene variants with primary open-angle glaucoma (POAG; n=3853 cases) and the high-tension glaucoma (HTG; n=1774 cases) and normal tension glaucoma (NTG; n=725 cases) subtypes in the NEIGHBORHOOD consortium (n=37 333 total participants). Odds ratios and 95% confidence intervals (indicated with error bars) for association between 8 intraocular pressure loci (upper panel), and 27 diastolic blood pressure loci (bottom panel) and POAG (a), HTG (b), and NTG (c). SNPs with nominally significant associations are highlighted in red. P-values can be found in Supplementary Table 2. The full colour version of this figure is available at European Journal of Human Genetics online.

Figure 2

Heritability enrichment of selected glaucoma-related traits in various ocular tissues and the cochlea in NEIHBORHOOD and the International Glaucoma Genetics Consortium. See text for how tissue-specific SNP sets were assembled. Tissue categories with percent available GWAS SNPs are represented on the vertical axis. Heritability enrichment (E) estimates are presented on the horizontal axis along with tissue-specific heritability P-values. These P-values, as opposed to the E P-values, are provided here because they represent a more conservative estimate of significance that simultaneously accounts for all tissue categories. E estimates for IOP are derived from the IGGC, whereas similar estimates for HTG and NTG are from the NEIHBORHOOD. For a complete list of tissue-specific E values, E P-values and tissue-specific heritability P-values for all glaucoma traits, see Supplementary Table 5. NB: Ciliary refers to ciliary body. RPE=retinal pigment epithelium. IOP=intraocular pressure, HTG=high-tension glaucoma, NTG=normal tension glaucoma.