Genome Wide Association Study (GWAS) of Age-Related Macular Degeneration (AMD)

Abstract

Purpose: : AMD is the leading cause of untreatable blindness in the elderly. The goal of this project is to evaluate the contribution of common genetic variants to disease susceptibility by a genome-wide association study (GWAS).

Methods: : We genotyped 370,404 SNPs in 2,136 unrelated Caucasian AMD cases and 1138 unrelated age-matched Caucasian controls using the Illumina Human CNV370-Duo BeadChip. We used information generated by the HapMap consortium to impute genotypes at ~2 million additional common SNPs. Using logistic regression, and covariates to account for minor differences in genetic background between the samples, we tested for association between genotyped and imputed SNPs and AMD.

Results: : We identified several genetic variations already reported to be associated with AMD. In particular, we observe strong evidence of association with SNPs at CFH (p < 10-74), C2/BF (p < 10-21), C3 (p < 10-9) and CFI (p < 10-7), emphasizing the role of the complement pathway on disease susceptibility. We also confirm the strong contribution of ARMS2 (p < 10-57), suggesting a potential role of mitochondrial dysfunction in AMD pathogenesis. A number of additional positive association signals are being replicated in independent case-control subject groups.

Conclusions: : We describe the first highly powered GWAS for AMD with dense coverage across the human genome. We have established the association of three major genes with large effect size and two genes with modest effect size. Novel candidate genes were identified but require further study and evaluation. Our GWAS data should yield a majority of susceptibility variants and assist in pathway analysis and disease management of AMD.

Keywords: genetics • age-related macular degeneration