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Comparative Study
. 2002 Jul;71(1):84-99.
doi: 10.1086/341290. Epub 2002 Jun 5.

A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity

Michael V Osier  1 , Andrew J Pakstis, Himla Soodyall, David Comas, David Goldman, Adekunle Odunsi, Friday Okonofua, Josef Parnas, Leslie O Schulz, Jaume Bertranpetit, Batsheva Bonne-Tamir, Ru-Band Lu, Judith R Kidd, Kenneth K Kidd
Affiliations
Comparative Study

A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity

Michael V Osier et al. Am J Hum Genet. 2002 Jul.

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.

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Figures

Figure 1
Figure 1
Relative map of SNP sites studied. A detailed map of the Class I cluster is expanded above the map of the gene cluster as a whole. In the map of the whole gene cluster, the names of the Class I ADH genes are abbreviated to “1A,” “1B,” and “1C,” for “ADH1A,” “ADH1B,” and “ADH1C,” respectively.
Figure 2
Figure 2
ADH SNP allele frequencies. In each panel, the populations are in the same order, from left to right (as in tables 4, 6, and 7 and from top to bottom). Geographic regions are indicated, across the top of each panel, by the abbreviations “sS Africa,” for “sub-Saharan Africa”; “N Africa,” for “northern Africa”; “SW Asia,” for “southwestern Asia”; “E Asia,” for “eastern Asia”; “P,” for “Pacific” (Micronesians and Nasioi); “S,” for “Siberia” (Yakut); “N Am,” for “North America”; and “S Am,” for “South America.” The allele graphed for each SNP is indicated. A, Allele frequencies at the three ADH1B SNPs. B, Allele frequencies at the three ADH1C SNPs and the ADH7 SNP.
Figure 3
Figure 3
Class I ADH–haplotype evolutionary tree. Haplotype names are listed in table 4. All haplotypes in the figure are observed at frequencies >5% in one or more African samples. Each solid arrow represents a single base mutation. The two dashed arrows cannot both be single mutations if recurrent mutation to ADH1B*47His is excluded; one of the two presumably arose by recombination. The 221221 haplotype is the one most common in eastern Asia and associated with the protective effect against alcoholism. The 221112 haplotype is the only one with the African-specific ADH1B*369Cys allele.
See this image and copyright information in PMC

References

Electronic-Database Information

    1. ALFRED, http://alfred.med.yale.edu/alfred/
    1. dbSNP, http://www.ncbi.nlm.nih.gov/SNP/
    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for 4q21-23 [accession numbers AP002026, AP002027, AP002028, and AC097530])
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for ADH1A [MIM 103700], ADH1B [MIM 103720], ADH1C [MIM 103730], ADH7 [MIM 600086], ADH6 [MIM 103735], ADH4 [MIM 103740], and ADH5 [MIM 103710])

References

    1. Bosch E, Calafell F, Comas D, Oefner PJ, Underhill PA, Bertranpetit J (2001) High-resolution analysis of human Y-chromosome variation shows a sharp discontinuity and limited gene flow between northwestern African and the Iberian Peninsula. Am J Hum Genet 68:1019–1029 - PMC - PubMed
    1. Bosron WF, Li TK, Vallee BL (1979) Heterogeneity and new molecular forms of human liver alcohol dehydrogenase. Biochem Biophys Res Commun 91:1549–1555 - PubMed
    1. Bosron WF, Magnes LJ, Li T-K (1983) Human liver alcohol dehydrogenase: ADHIndianapolis results from genetic polymorphism at the ADH2 gene locus. Biochem Genet 21:735–744 - PubMed
    1. Carr LG, Xu Y, Ho W-H, Edenberg HJ (1989) Nucleotide sequence of the ADH23 gene encoding the human alcohol dehydrogenase β3 subunit. Alcohol Clin Exp Res 13:594–586 - PubMed
    1. Chen WJ, Loh EW, Hsu YP, Chen CC, Yu JM, Cheng AT (1996) Alcohol-metabolizing genes and alcoholism among Taiwanese Han men: independent effect of ADH2, ADH3, and ALDH2. Br J Psychiatry 168:762–767 - PubMed

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