Extent and Distribution of Linkage Disequilibrium in the Old Order Amish

Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, 48109-5618, USA.
Genetic Epidemiology (Impact Factor: 2.6). 02/2010; 34(2):146-50. DOI: 10.1002/gepi.20444
Source: PubMed


Knowledge of the extent and distribution of linkage disequilibrium (LD) is critical to the design and interpretation of gene mapping studies. Because the demographic history of each population varies and is often not accurately known, it is necessary to empirically evaluate LD on a population-specific basis. Here we present the first genome-wide survey of LD in the Old Order Amish (OOA) of Lancaster County Pennsylvania, a closed population derived from a modest number of founders. Specifically, we present a comparison of LD between OOA individuals and US Utah participants in the International HapMap project (abbreviated CEU) using a high-density single nucleotide polymorphism (SNP) map. Overall, the allele (and haplotype) frequency distributions and LD profiles were remarkably similar between these two populations. For example, the median absolute allele frequency difference for autosomal SNPs was 0.05, with an inter-quartile range of 0.02-0.09, and for autosomal SNPs 10-20 kb apart with common alleles (minor allele frequency > or =0.05), the LD measure r(2) was at least 0.8 for 15 and 14% of SNP pairs in the OOA and CEU, respectively. Moreover, tag SNPs selected from the HapMap CEU sample captured a substantial portion of the common variation in the OOA ( approximately 88%) at r(2) > or =0.8. These results suggest that the OOA and CEU may share similar LD profiles for other common but untyped SNPs. Thus, in the context of the common variant-common disease hypothesis, genetic variants discovered in gene mapping studies in the OOA may generalize to other populations.

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    • "Thus, low-frequency population alleles on single nucleotide polymorphism (SNP) chips that are not monomorphic in the Amish tend to track founder chromosome segments and as a consequence any rare causal variant on that segment. Precisely because rare alleles in the OOA generally represent founder alleles, there tends to be long-range linkage disequilibrium (LD) among low-frequency alleles in the OOA, although the same is not true for common alleles that have entered the population in multiple founders (Van Hout et al. 2009). The long-range LD between low-frequency alleles in the Amish has facilitated detection of both major genes for triglycerides (APOC3 R19X) and low density lipoprotein (LDL) levels (APOB R3500Q) in the Amish, where the most associated SNPs were >300 kb from the gene, respectively. "
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    • "The assumption of common alleles is important as random drift over the 14 generations spanned by AGDB will not eliminate common variation. For low frequency alleles there is longer LD in the Amish due to linkage as shown in [51] and also in some of our association studies [20,58], where the most significant signal can be more than 500 kbp from the causal allele. "
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