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.

Download full-text


Available from: Braxton D Mitchell,

Click to see the full-text of:

Article: Extent and Distribution of Linkage Disequilibrium in the Old Order Amish

89.15 KB

See full-text
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome mapping in animals is now one of the leading disciplines in animal sciences. It is employed for all facets in genome analysis in animals and their improvement for benefit of human beings. Mapping of genomes in farm animals, companion animals, laboratory animals, aquatic animals, insects, and primates, including humans have generated stupendous data bases to elucidate origin, evolution, phylogenetic relationship; position of genes; function, expression, regulation and sequence of genes. This information has tremendous applied value in agriculture, medicine, and environmental sciences. Paradoxically the information is mainly scattered only on the pages of journals, review papers and project/institutional reports. It is imperative now to have a comprehensive compilation of all these research findings in a single series for easy access to all levels of end users. The series Genome Mapping in Animals will fill this gap. It will provide comprehensive and up to date reviews on a large variety of selected animals systems contributed by teams of leading scientists from around the world.
    Volume 5 edited by R. Duggirala, L. Almasy, S. Williams-Blangero, S.F.D. Paul, C. Kole, 01/2015; Springer-Verlag GmbH Berlin Heidelberg., ISBN: Genome Mapping and Genomics in Animals ISBN 978-3-662-46305-5 ISBN 978-3-662-46306-2 (eBook)
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Because they are a closed founder population, the Old Order Amish (OOA) of Lancaster County have been the subject of many medical genetics studies. We constructed four versions of Anabaptist Genealogy Database (AGDB) using three sources of genealogies and multiple updates. In addition, we developed PedHunter, a suite of query software that can solve pedigree-related problems automatically and systematically. We report on how we have used new features in PedHunter to quantify the number and expected genetic contribution of founders to the OOA. The queries and utility of PedHunter programs are illustrated by examples using AGDB in this paper. For example, we calculated the number of founders expected to be contributing genetic material to the present-day living OOA and estimated the mean relative founder representation for each founder. New features in PedHunter also include pedigree trimming and pedigree renumbering, which should prove useful for studying large pedigrees. With PedHunter version 2.0 querying AGDB version 4.0, we identified 34,160 presumed living OOA individuals and connected them into a 14-generation pedigree descending from 554 founders (332 females and 222 males) after trimming. From the analysis of cumulative mean relative founder representation, 128 founders (78 females and 50 males) accounted for over 95% of the mean relative founder contribution among living OOA descendants. The OOA are a closed founder population in which a modest number of founders account for the genetic variation present in the current OOA population. Improvements to the PedHunter software will be useful in future studies of both the OOA and other populations with large and computerized genealogies.
    BMC Medical Genetics 05/2010; 11(1):68. DOI:10.1186/1471-2350-11-68 · 2.08 Impact Factor
  • Source
    • "We can extrapolate that the trends we observe for genotyped loci will remain for untyped loci, and therefore conclude that genotyping arrays should perform equally well in our isolate than in outbred European populations for disease mapping studies. Furthermore, and as highlighted as well by Thompson et al. [2009] and Van Hout et al. [2009], susceptibility alleles should be the same in the isolates as in outbred European populations, so any findings made in those more homogeneous (in terms of environment) and well-characterized populations should be valid in the general European population from which they descend. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human isolates have been postulated as a good resource for the identification of QTL due to reduced genetic diversity and a more homogeneous environment. Isolates may also have increased linkage disequilibrium (LD) due to small effective population size and, either loss or increase in frequency of alleles that are rare in the general population from which they originate. Here we investigate the difference in allele and genotype frequencies, LD and homozygous tracts between an isolate-several villages from the island of Vis in Croatia-and an outbred population of European origin: the Hapmap CEPH founders. Using the HumanHap300 v1 Genotyping BeadChip, we show that our population does not differ greatly from the reference CEU outbred population despite having a slightly higher proportion of monomorphic loci, a slightly higher long-range LD, and a greater proportion of individuals with long homozygous tracts. We conclude that genotyping arrays should perform equally well in our isolate as in outbred European populations for disease mapping studies and that SNP-trait associations discovered in our well-characterized Croatian isolate should be valid in the general European population from which they descend.
    Genetic Epidemiology 02/2010; 34(2):140-5. DOI:10.1002/gepi.20443 · 2.60 Impact Factor
Show more