Investigating Age-related Macular Degeneration in the Amish

Abstract

Purpose: Age-related macular degeneration (AMD) is the leading cause of blindness among the adult population in the developed world. To further the understanding of this disease, we have studied the genetically isolated Amish population of Ohio and Indiana. The Amish are more genetically homogeneous than outbred groups and live a stricter lifestyle, thus reducing the variability of environmental effects on AMD in this population. For this analysis we set out to characterize how known AMD associated loci contribute to disease risk in the Amish.

Methods: We performed genotyping using the Sequenom MassARRAY platform for pools of SNPs previously shown to be associated with AMD in the outbred population. In total we genotyped 84 SNPs in 1022 Amish individuals (96 with self-reported AMD). A previous study of 73 self-reported cases and controls was conducted to compare self-report AMD status to clinical diagnosis. The PPV and NPV, 89% and 90% respectively, provide evidence that self-report status is a reliable phenotype. Case-control association analysis with adjustment for relatedness based on the complete 13-generation pedigree was carried out using MQLS (Thornton & McPeek 2007). Parametric heterogeneity LOD (HLOD) scores were computed for affecteds-only parametric and nonparametric 2-point linkage using Merlin. A disease allele frequency of 10% was used. Mean cumulative genetic risk scores were calculated using a previously described weighting scheme and compared between cases and controls.

Results: Our most significant uncorrected MQLS p-value observed is 0.0013 for SNP rs10490924 on chromosome 10 in the gene encoding ARMS2. Additional signals are observed at rs2230199 (p-value = 0.0022) on chromosome 19, and rs3753394 (p-value = 0.0061) on chromosome 1. In our cumulative genetic risk score analysis we observe a mean risk score of 1.041 (95% CI [1.026, 1.055]) in our controls and 1.099 (95% CI [1.053, 1.145]) in our cases. This mean difference in risk scores is statistically significant at a p-value of 0.006.

Conclusions: In this analysis a subset of loci previously identified in the general outbred population associate with AMD risk in the Amish. We also observe a statistically significant increase in cumulative genetic risk in our cases versus controls. As of this study, only 96 self-reported cases of AMD had been ascertained within the larger Amish study. We plan to ascertain additional cases to increase power to detect associations.

Keywords: 412 age-related macular degeneration • 539 genetics • 459 clinical (human) or epidemiologic studies: biostatistics/epidemiology methodology