Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: an integrated analysis

Abstract

Alcohol dependence (AD) is a complex disorder with environmental and genetic origins. The role of two genetic variants in ALDH2 and ADH1B in AD risk has been extensively investigated. This study tested for associations between nine polymorphisms in ALDH2 and 41 in the seven ADH genes, and alcohol-related flushing, alcohol use and dependence symptom scores in 4597 Australian twins. The vast majority (4296) had consumed alcohol in the previous year, with 547 meeting DSM-IIIR criteria for AD. There were study-wide significant associations (P<2.3 x 10(-4)) between ADH1B-Arg48His (rs1229984) and flushing and consumption, but only nominally significant associations (P<0.01) with dependence. Individuals carrying the rs1229984 G-allele (48Arg) reported a lower prevalence of flushing after alcohol (P=8.2 x 10(-7)), consumed alcohol on more occasions (P=2.7 x 10(-6)), had a higher maximum number of alcoholic drinks in a single day (P=2.7 x 10(-6)) and a higher overall alcohol consumption (P=8.9 x 10(-8)) in the previous year than those with the less common A-allele (48His). After controlling for rs1229984, an independent association was observed between rs1042026 (ADH1B) and alcohol intake (P=4.7 x 10(-5)) and suggestive associations (P<0.001) between alcohol consumption phenotypes and rs1693482 (ADH1C), rs1230165 (ADH5) and rs3762894 (ADH4). ALDH2 variation was not associated with flushing or alcohol consumption, but was weakly associated with AD measures. These results bridge the gap between DNA sequence variation and alcohol-related behavior, confirming that the ADH1B-Arg48His polymorphism affects both alcohol-related flushing in Europeans and alcohol intake. The absence of study-wide significant effects on AD results from the low P-value required when testing multiple single nucleotide polymorphisms and phenotypes.

Figure 1.

LD between the SNPs genotyped in ALDH2 and seven ADH genes: (A) the gene structure of ALDH2 is shown with exons numbered (1–13) and relative exon size denoted by the width of the vertical bars. Pairwise marker–marker LD (shown below the gene structure) was generated using Haploview 4.0 (75). Regions of low to high LD (D′) are represented by white to red shading, respectively; (B) gene location, structure and LD (D′) between the SNPs genotyped in the ADH cluster.

Figure 2.

Total association of SNPs across the ADH gene cluster with quantitative AD variables, alcohol consumption variables and self-reported alcohol reactions. The location of the seven ADH genes is shown at the top of the figure. Results are plotted as –log₁₀(P-value) against the physical location of each SNP on chromosome 4. See Table 1 for further description of the variables.

Figure 3.

Cumulative frequency distribution plots for number of drinks in the previous 12 months (estimated from self-reported frequency and quantity) by rs1229984 (ADH1B Arg48His) genotypes, in (A) men and (B) women (GG = 48Arg homozygotes, AG = heterozygotes, AA = 48His homozygotes).