Mapping genes in isolated populations: Lessons from the old order Amish

Abstract

The Amish, a socially and religiously isolated population with large communities in Pennsylvania, Ohio, and Indiana, have been frequent participants in genetic studies since the 1960s. Although initial studies focused on rare, recessive diseases, others since the 1990s, largely ours, have focused on common disorders and the genetic underpinnings of their risk factors. We have shown both by simulation and practical case studies that the genetic architecture of the Old Order Amish (OOA) includes rare variants having strong phenotypic effects, some of which have reached non-negligible frequencies due to a founder effect and genetic drift. In this chapter, we review our case studies on variants in four genes: ABCG8, APOB, APOC3, and COL1A2. While traditionally medical genetics studies carried out in isolated populations have focused on individuals who are homozygous for some mutation; the four case studies that we present focus on individuals who are heterozygous carriers of a single mutation. This genetic homogeneity of the Amish and the enrichment of these variants allow us adequate statistical power to characterize the phenotypic variation resulting from a single mutation. These case studies have provided biologic insights into the relevance of these genes to human health and disease reaching beyond the OOA population.