Diplotype trend regression analysis of the ADH gene cluster and the ALDH2 gene: multiple significant associations with alcohol dependence - PubMed (original) (raw)

Diplotype trend regression analysis of the ADH gene cluster and the ALDH2 gene: multiple significant associations with alcohol dependence

Xingguang Luo et al. Am J Hum Genet. 2006 Jun.

Abstract

The set of alcohol-metabolizing enzymes has considerable genetic and functional complexity. The relationships between some alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes and alcohol dependence (AD) have long been studied in many populations, but not comprehensively. In the present study, we genotyped 16 markers within the ADH gene cluster (including the ADH1A, ADH1B, ADH1C, ADH5, ADH6, and ADH7 genes), 4 markers within the ALDH2 gene, and 38 unlinked ancestry-informative markers in a case-control sample of 801 individuals. Associations between markers and disease were analyzed by a Hardy-Weinberg equilibrium (HWE) test, a conventional case-control comparison, a structured association analysis, and a novel diplotype trend regression (DTR) analysis. Finally, the disease alleles were fine mapped by a Hardy-Weinberg disequilibrium (HWD) measure (J). All markers were found to be in HWE in controls, but some markers showed HWD in cases. Genotypes of many markers were associated with AD. DTR analysis showed that ADH5 genotypes and diplotypes of ADH1A, ADH1B, ADH7, and ALDH2 were associated with AD in European Americans and/or African Americans. The risk-influencing alleles were fine mapped from among the markers studied and were found to coincide with some well-known functional variants. We demonstrated that DTR was more powerful than many other conventional association methods. We also found that several ADH genes and the ALDH2 gene were susceptibility loci for AD, and the associations were best explained by several independent risk genes.

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Figures

Figure 1

Figure 1

ADH gene cluster

Figure 2

Figure 2

LD analysis for ADH and ALDH2 markers in EAs and AAs. a, ADH genes in EAs. b, ADH genes in AAs. c, ALDH2 gene in EAs or AAs.

Figure 3

Figure 3

Fine mapping the risk alleles at the ADH gene cluster in EA cases on the basis of J values. The _X_-axis represents the marker names; the _Y_-axis represents the J values. Marker numbers (which do not include markers mapped to the ADH4 gene) correspond to the order presented in table 2. The marker ADH1B ∧ SNP16 (i.e., ADH2*Arg/His, with the highest J value) is included in the left figure but excluded in the right figure (to enlarge the scale of the _Y_-axis).

Figure 4

Figure 4

Pairwise correlations between different genotypes (at the ADH5 and ADH6 genes), diplotypes (at other genes) in EAs (a) and AAs (b). The gene names corresponding to the genotypes and diplotypes are shown on the axes, but the detailed names of genotypes and diplotypes are not shown (the names of parts of the risk genotypes and diplotypes can be found in table 6). The colored scale denotes the correlation coefficient (r). This figure was generated using the program GOLD.

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References

Web Resources

    1. Applied Biosystems (ABI), http://www.appliedbiosystems.com/
    1. dbSNP, http://www.ncbi.nlm.nih.gov/SNP/
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for AD, ADH1B, ADH1C, ADH5, ADH4, ADH7, ALDH2, ADH6, and ADH1A)
    1. PowerMarker, http://www.powermarker.net/ (for genetic data analysis software)

References

    1. Reich T, Edenberg HJ, Goate A, Williams JT, Rice JP, Van Eerdewegh P, Foroud T, Hesselbrock V, Schuckit MA, Bucholz K, Porjesz B, Li TK, Conneally PM, Nurnberger JI Jr, Tischfield JA, Crowe RR, Cloninger CR, Wu W, Shears S, Carr K, Crose C, Willig C, Begleiter H (1998) Genome-wide search for genes affecting the risk for alcohol dependence. Am J Med Genet 81:207–22110.1002/(SICI)1096-8628(19980508)81:3<207::AID-AJMG1>3.0.CO;2-T - DOI - PubMed
    1. Zinn-Justin A, Abel L (1999) Genome search for alcohol dependence using the weighted pairwise correlation linkage method: interesting findings on chromosome 4. Genet Epidemiol Suppl 1 17:S421–S426 - PubMed
    1. Williams JT, Begleiter H, Porjesz B, Edenberg HJ, Foroud T, Reich T, Goate A, Van Eerdewegh P, Almasy L, Blangero J (1999) Joint multipoint linkage analysis of multivariate qualitative and quantitative traits. II. Alcoholism and event-related potentials. Am J Hum Genet 65:1148–1160 - PMC - PubMed
    1. Saccone NL, Kwon JM, Corbett J, Goate A, Rochberg N, Edenberg HJ, Foroud T, Li TK, Begleiter H, Reich T, Rice JP (2000) A genome screen of maximum number of drinks as an alcoholism phenotype. Am J Med Genet 96:632–63710.1002/1096-8628(20001009)96:5<632::AID-AJMG8>3.0.CO;2-# - DOI - PubMed
    1. Long JC, Knowler WC, Hanson RL, Robin RW, Urbanek M, Moore E, Bennett PH, Goldman D (1998) Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population. Am J Med Genet 81:216–22110.1002/(SICI)1096-8628(19980508)81:3<216::AID-AJMG2>3.0.CO;2-U - DOI - PubMed

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