Lipoprotein metabolism pathway genetic risk score is associated with distinct glaucoma phenotypes in a clinical biobank

Abstract

Purpose : Genes known to regulate lipid metabolism have been linked to primary open angle glaucoma (POAG) in prior genome wide association studies (GWAS). We aimed to further examine the relationship between lipoprotein metabolism and POAG using a lipoprotein metabolism pathway specific genetic risk score (GRS_lipid) and evaluate its association with glaucoma related phenotypes in a clinical biobank.

Methods : We constructed GRS_lipid using all independently associated single nucleotide polymorphisms (SNPs) in each gene in the lipoprotein pathway nominally associated with POAG in a prior GWAS (Genes: SNPs; ABCA1: rs4149274, rs2575874, rs2515613, ABCA1:RP11-217B7.2: rs1800977, LRP4: rs11039024, NPC2: 14:74952246, MAPT: rs242559, rs41543317, ITGB3: rs2317385). GRS_lipid was calculated in two ways: 1) unweighted: by summing the risk alleles and 2) weighted: by weighting risk alleles by the beta effect size obtained from a prior multi-ethnic POAG GWAS for 36,217 Mass General Brigham Biobank (MGBB) participants. GRS_lipid was normalized within each genotype-inferred ancestral group. Multivariable regression models adjusted for age and sex were used to evaluate the association between GRS_lipid and unadjusted intraocular pressure (IOP, mmHg), medication adjusted IOP and 9 visual field archetypes (AT) trained on a separate cohort of 263,707 visual fields from 34,331 glaucoma patients (Fig.1).

Results : Among 8,563 MGBB participants with ocular data available, the mean (SD) age was 67.5 (14.7) years and 53.2% were female. Each SD increase in unweighted GRS_lipid was associated with 0.16 (CI:0.05-0.26; p=0.003) increase in IOP, 0.21 (CI:0.07-0.35; p=0.003) increase in adjusted IOP and 0.005 (CI:0.000-0.011; p=0.049) increase in AT8 probability (Fig. 1). Each SD increase in weighted GRS_lipid was associated with 0.17 (CI:0.07-0.28; p=0.001) increase in IOP, 0.22 (CI:0.08-0.35; p=0.002) increase in adjusted IOP, 0.003 (CI:0.000-0.006; p=0.021) and 0.006 (CI:0.001-0.011; p=0.032) increase in AT4 and 8 probability, respectively (Fig. 1).

Conclusions : We found that lipoprotein metabolism pathway specific genetic risk score was associated with higher IOP and inferior paracentral and severe visual field loss archetypes in a large clinical biobank. Our results suggest that pathway specific GRS may have utility for glaucoma phenotyping and prognostication.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Figure 1