Strong Evidence for Association With Age-Related Cataract at a Candidate Gene on 1p36

Abstract

Purpose: : Converging evidence from a coarse association scan in the Beaver Dam Eye Study (BDES) and a novel knockout mouse with progressive age-related cataract (ARC) was used to focus on a candidate gene on 1p36 to perform deeper association analysis.

Methods: : Twenty-one SNPs in the candidate gene were selected and genotyped in a discovery (BDES; N = 1501) and two replication samples [United Kingdom Twin Study (UKTS; N = 196) and Blue Mountains Eye Study (BMES; N = 1618)]. Association was tested using ARC traits including cortical (CC), nuclear (NC), posterior subcapsular (PSC), and any (ANYCAT) cataract. A moving window haplotype test was performed in BDES and BMES. Exons, including intron-exon junctions, were scanned for mutations using re-sequencing (N=34).

Results: : Multiple SNPs in BDES and UKTS met genome-wide significance, but weaker association was found in BMES. The most significant combined P values were identified with ANYCAT (SNP7: P = 1 x 10^-7), with severe CC (affected area ≥ 25% of the lens; SNP6: P = 6 x 10^-8), and with NC (SNP8: P = 2 x 10^-4). Haplotype analysis showed a common shared risk haplotype in BDES and BMES for multiple ARC traits. An additional common risk haplotype was found in BMES. Re-sequencing identified two potentially causal non-synonymous variants. The variants reside in conserved genomic regions and may play a role in alternative splicing and transcriptional regulation.

Conclusions: : We have identified a novel gene that causes age-related cataract with support from both human epidemiologic data and mouse models.

Keywords: cataract • gene mapping • aging