A Genome-Wide Association Study of Age-Related Cortical Cataract and Its Progression Identifies Novel Genes

Abstract

Purpose: Age-related cortical cataract is a common progressive disorder in the elderly. Despite importance of gene discovery for age-related cortical cataract, large-scale genome-wide association (GWA) studies have never been conducted.

Methods: We performed meta-analysis of GWA studies in Age Related Eye Disease Study (AREDS) and Blue Mountains Eye Study (BMES) with baseline measures of cortical lens opacity and annual change over time as a quantitative trait, using 3,364 unrelated subjects. Promising genes containing at least one GWA marker with P<10^-6 were further evaluated in single marker or gene-based replication using a cross-sectional measurement of cortical lens opacity from the Framingham Heart Study (FHS).

Results: Genome-wide significant associations (p<5x10^-8) were detected for baseline risk in BCL11A, near STAP2, and in NBPF22P (best SNP, rs79657645 in STAP2: meta-analysis p=1.3x10^-8). Markers influencing the rate of progression were genome-wide significant near LINC00536, in FGFR2, and in THBD (best SNP, rs1649201 in FGFR2: p=7.6x10^-9); FGFR2 is necessary for lens cell differentiation and cell survival. Among the top ranked genes in discovery, single marker tests in BCL11A, ITGA8, RAB31, STAP2, IGF2R, FGFR2, CNTN5, and THBD were significant with different markers (p<10^-3) in replication. Meta-analysis of discovery and replication sets in gene-based tests revealed that BCL11A, ITGA8, STAP2, FGFR2, and THBD were genome-wide significant (gene-based p<10^-6), while RAB31, CNTN5, and IGF2R were significant after multiple testing correction (gene-based p<8x10^-4). Two additional genes, KLHL8 and TMEM161B were also significant in gene-based tests with p<8x10^-4. A bioinformatic survey found ITGA8, FGFR2, and CNTN5 to play roles in axon guidance pathway, wherein EPHA2, a known gene for cortical cataract, is involved.

Conclusions: We discovered novel genome-wide significant genes for age-related cortical cataract enriched in axon guidance pathway.