Multivariate Genome-wide Association Study of OCT-derived biomarkers for AMD in the Amish Eye Study

Abstract

Purpose : We previously reported that four OCT-derived biomarkers, for the presence of drusen volume greater than 0.03 mm³ in the central 3 mm ring (DV), intraretinal hyperreflective foci (IHRF), hyporeflective drusen cores (hDC), and subretinal drusenoid deposits (SDD), were associated with an increased risk for development of late age-related macular degeneration (AMD). Multivariate methods can increase the statistical power to detect associations in the case of shared genetic basis between phenotypes. In this study, we carried out a multivariate genome-wide association study (mvGWAS) of these biomarkers among Amish from Ohio, Indiana, and Pennsylvania aiming to identify genetic variants with effects on OCT-derived biomarkers of AMD.

Methods : We performed exome chip genotyping (Illumina MEGAex with custom content) and analyzed common SNPs (>5%) after extensive QC. The exact multivariate linear mixed model (mvLMM) implemented in the ‘Genome-wide Efficient Mixed Model Association algorithm’ (GEMMA) program was used to test for association. For each biomarker, mvGWAS was done for right and left eyes simultaneously (mvB1). The mean of right and left eyes was used for mvGWAS of all four OCT-derived biomarkers simultaneously (mvB4). We adjusted for relatedness, age at exam, and sex.

Results : After QC, 990 Amish adults with a familly history of AMD were included in the analyses. A total of 126 SNPs reached at least the suggestive level (p<2.5x10^-6) from all analyses, among which 97 from mvB1 only (13, 4, 80 for hDC, IHRF, DV respectively) and 18 from both mvB1 and mvB4. Additional 11 SNPs were identified only by mvB4, 8 of which are located in genes. There were 6 genome-wide significant (p<1.25x10^-8) SNPs in 4 gene loci (GPD2; p<7.2x10^-10, CFH; p<8.0x10^-10, LOC105373710; p<2.6x10^-9, CRACDL; p<9.5x10^-9) from mvB1 of DV and none from other biomarkers. Another SNP on chromosome 3 (ITPR1; p<7.4x10^-10) reached genome-wide significance from both mvB1 of DV and mvB4.

Conclusions : We identified a SNP in a known AMD gene (CFH) and several additional loci potentially associated with the OCT-derived biomarkers of AMD by analyzing multiple biomarkers simultaneously. These findings support the OCT-derived biomarkers as promising biomarkers for evaluating genetic cause of AMD, helping to elucidate the relationship between OCT-derived biomarkers and AMD as well as to advance our knowledge of the physiology in AMD.

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