Genome-wide multi-ethnic meta-analyses identify new loci associated with age-related nuclear cataract

Abstract

Purpose : A recent genome wide association study (GWAS) meta-analysis identified two loci associated with age-related nuclear cataract in Asian populations. The aim of this study is to further elucidate the genetic causes of this condition by conducting a GWAS meta-analysis in 14,151 individuals from European and Asian ancestry.

Methods : Nuclear cataract severity was measured in 7,352 individuals of European ancestry and 6,799 of Asian ancestry, over the age of 40 years, from the following cohorts: TwinsUK, Age-Related Eye Disease Study, Blue Mountain Eye Study, Rotterdam Study I, Singapore Malay Eye Study, Singapore Indian Eye Study, and the Singapore Chinese Eye Studies. Lens photos were taken from individuals’ eyes following standard procedures, and cataract was graded following established grading systems. Genome-wide genotyping was performed using Illumina platforms and imputed against the 1000 Genomes. Nuclear cataract was treated as quantitative trait and GWAS were performed separately in each cohort adjusting for age, sex and principal components. In the TwinsUK cohort family structure was also taken into account. Fixed effect inverse variance meta-analyses were carried in the European and Asian samples separately followed by combined analyses. Variants showing high heterogeneity (p<1x10^-4) were excluded.

Results : In the European cohorts, the most strongly associated variants were located at chromosome 3q26 (p=4.4x10^-9). In the Asian cohorts, in addition to the previously identified variants in CRYAA (p=3.6x10^-17), another locus located at chromosome 13q12 was also found associated at genome-wide significance level (p=2.2x10^-8). The combined analysis yielded one additional locus at chromosome 11q23 reaching genome-wide significance level (p=4.2x10^-11).

Conclusions : This is the largest meta-analysis of GWAS for age-related nuclear cataract to date. We identified at least 3 new loci associated with this trait and confirmed the association with variants in CRYAA. We also found common variants for age-related cataract in genes previously found to have rare mutations causing congenital cataract. The results offer additional insights into the pathogenesis of nuclear cataract in Asians.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.