Genome-Wide Study for Age-related Macular Degeneration in the Amish

Abstract

Purpose: : Age-related macular degeneration (AMD) is the leading cause of permanent visual loss among the adult population in the developed world. Previous genetic studies have identified variants in CFH, ARMS2/HTRA1, C2/CFB and C3 that strongly influence susceptibility to AMD. To further the understanding of this disease, we have studied the genetically isolated Amish population of Ohio and Indiana to identify additional genetic variants that contribute to disease risk.

Methods: : Through the use of the Anabaptist Genealogy Database, we have accurately defined the kinship coefficients and the family structure among our collected individuals. We performed a genome-wide association study (Affymetrix Human SNP Array 6.0) and successfully genotyped 929 Amish individuals (96 with self-reported AMD). In the Amish, we have demonstrated that self report of AMD can be used as a reliable proxy for actual AMD affection status. Case-control analysis was carried out using MQLS, adjusting for relatedness using previously calculated kinship coefficients. We performed parametric and nonparametric 2-point and parametric multipoint linkage analysis (Merlin, MINX) after using PedCut to divide our large pedigree into smaller, more computationally tractable sub-pedigrees. We conducted parametric multipoint linkage analysis in regions in which a 2-point LOD score ≥3 was calculated.

Results: : The most significant p-value for the MQLS test is 8.36 x 10^-8 for rs16988305 on chromosome 20 in UBOX5. 10 additional SNPs have p-values less than 1 x 10^-6. Under the dominant model for 2-point linkage assuming a disease allele frequency of 0.05, no LOD scores ≥ 3 are found for any locus. The maximum LOD score calculated for SNPs surrounding the major risk loci is for CFH (max LOD = 1.86).

Conclusions: : Loci previously known to contribute to AMD risk are not significant contributors in the Amish population based on these preliminary studies. However, these association results suggest that other genetic loci may influence risk of AMD. We can take advantage of the power of the relatedness in the Amish to further dissect the genetics of AMD.

Keywords: genetics • age-related macular degeneration • macula/fovea