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Title: A Global Perspective on Genetic Variation at the ADH Genes Reveals Unusual Patterns of Linkage Disequilibrium and Diversity.
Authors: Osier, V. Michael
Pakstis, .J. Andrew
Himla, Soodyall
David, Cosmas
Goldman, David
Odunsi, Adekunle
Okonofua, Friday
Parnas, Josef
Schulz, O. Leslie
Bertranpetit, Jaume
Batsheva, Bonne-Tamir
Ru-Band, Lu
kidd, R. Judith
Kidd, K. Kenneth
Keywords: Research work
Issue Date: 2002
Publisher: Am. J. Hum. Genet.
Series/Report no.: 71;84-99
Abstract: Variants of Different Class 1 alchohol dehydrogenase (ADH) genes have been shown to be associatedwith an effectthat is protective against alchoholism. Previous work from our laboratory has shown that the two sites showing the association are in linkage disequilibrium and has identified the ADH1b Arg47His site ascausative, with the ADHIC I1e349Val site showing association only because of the disequilibrium. Here, we describe an initial studyof the nature linkge disequilibrium and genetic variation, in population samples from different regions of the world, in a larger segment of the ADH cluster (including the three class 1 ADH genes and ADH7). Linkage disequilibrium across ~40kb of the class 1 ADH cluster is moderate to strong in all populations samples that we studied. We observed nominally significant pairwise linkage disequilibrium, in some populations, between the ADH7 sites, at moderate values and at a molecular distance as great as 100kb.Our data include (1) that most ADH-alcholism association studies have failed to consider many sites in the ADH cluster that may harbor etiologically significant alleles and (2) thatthe relevance of the various ADH sites will be population dependent. Some individual sites inthe class 1 ADH cluster show Fstvalues that are among the highest seen among several dozen unlinked sites that were studied in the same subset of populations. The high Fstvalues can be attributed to the discrepant frequencies of specific alleles in eastern Asia relative to those in other regionsof the world. These alleles are part of a single haplotype that exists at high (>65%) frequency only in the eastern-Asian samples. It seems unlikely that this haplotype, which is rare or unobserved in other populations, reached such high frequency because of random genetic drift alone
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