title: A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity.
abstract: Variants of different Class I alcohol dehydrogenase (ADH) genes have been shown to be associated with an effect that is protective against alcoholism. 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 as causative, with the ADH1C Ile349Val site showing association only because of the disequilibrium. Here, we describe an initial study of the nature of linkage 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 I ADH genes and ADH7). Linkage disequilibrium across approximately 40 kb of the Class I ADH cluster is moderate to strong in all population samples that we studied. We observed nominally significant pairwise linkage disequilibrium, in some populations, between the ADH7 site and some Class I ADH sites, at moderate values and at a molecular distance as great as 100 kb. Our data indicate (1) that most ADH-alcoholism association studies have failed to consider many sites in the ADH cluster that may harbor etiologically significant alleles and (2) that the relevance of the various ADH sites will be population dependent. Some individual sites in the Class I ADH cluster show Fst values that are among the highest seen among several dozen unlinked sites that were studied in the same subset of populations. The high Fst values can be attributed to the discrepant frequencies of specific alleles in eastern Asia relative to those in other regions of 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.
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Osier
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pakstis
authors.forename: Himla
authors.initials: H
authors.lastname: Soodyall
authors.forename: David
authors.initials: D
authors.lastname: Comas
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: Adekunle
authors.initials: A
authors.lastname: Odunsi
authors.forename: Friday
authors.initials: F
authors.lastname: Okonofua
authors.forename: Josef
authors.initials: J
authors.lastname: Parnas
authors.forename: Leslie O
authors.initials: LO
authors.lastname: Schulz
authors.forename: Jaume
authors.initials: J
authors.lastname: Bertranpetit
authors.forename: Batsheva
authors.initials: B
authors.lastname: Bonne-Tamir
authors.forename: Ru-Band
authors.initials: RB
authors.lastname: Lu
authors.forename: Judith R
authors.initials: JR
authors.lastname: Kidd
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Kidd
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D019143:Evolution, Molecular; D005787:Gene Frequency; D014644:Genetic Variation; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D005810:Multigene Family; D020641:Polymorphism, Single Nucleotide; D011323:Primates / Q000235:genetics
chemical_list: D004247:DNA; D000426:Alcohol Dehydrogenase