Rare CFH Coding Variant in Amish AMD

Abstract

Purpose: The Amish are a genetically and culturally isolated founder population descended from Swiss and German Anabaptists who emigrated from Western Europe to North America in the 1700 and 1800s. The Amish also live a more homogeneous lifestyle than the general European American population, thus reducing the variability of influence from environmental factors typically seen in complex diseases. Previous work demonstrated that the cumulative genetic risk across known age-related macular degeneration (AMD) loci is significantly lower in Amish AMD cases of Ohio and Indiana compared to non-Amish European American cases, despite that the prevalence of AMD is similar. Exome sequencing in five members of a small nuclear Amish family with AMD who lack the common risk alleles at the major AMD risk loci identified a variant (P503A) in CFH that is not present in dbSNP or 1000Genomes and is associated with AMD in the Ohio and Indiana cohort (P<9.27x10^-13). Follow-up genotyping in a European American cohort of 791 elderly non-Amish controls, and 1456 non-Amish cases indicated that the P503A variant was absent in the population sample.

Methods: In this analysis we examine the presence of the P503A variant in an Amish community in Pennsylvania. The P503A variant was genotyped using Taqman in a Pennsylvania Amish cohort consisting of 546 AMD cases and controls.

Results: We do not observe the P503A risk allele in the Pennsylvania Amish cohort.

Conclusions: Previous Exome sequencing of a nuclear Amish family revealed a rare CFH variant that suggested a minor contribution to AMD risk in the Amish of Ohio and Indiana. This variant is absent in both a non-Amish population sample and an Amish population sample ascertained from the Pennsylvania community. Further investigation into understand the potential role that founder effects are playing on AMD risk within the different Amish communities is necessary.