Abstract
Human alcohol-consumption behavior is partly genetically encoded. The alcohol consumption of 987 residents in Keelung, Taiwan, was evaluated by using the Alcohol Use Disorder Identification Test (AUDIT). We assessed ~750,000 genomic variants of 71 residents who drank hazardously (AUDIT score ≥ 8) and 126 residents who did not drink in their daily lives (AUDIT score = 0), using high-density single nucleotide polymorphism (SNP) arrays. The rs671 G > A manifests the highest significance of the association with drinking behavior (Fisher’s exact P = 8.75 × 10−9). It is a pleiotropic, non-synonymous variant in the aldehyde dehydrogenase 2 (ALDH2) gene. The minor allele “A”, commonly known as ALDH2*2, is associated with non-drinkers. Intriguingly, identity-by-descent haplotypes encompassing genomic regions with a median length of 1.6 (0.6–2.0) million nucleotide bases were found in all study participants with either heterozygous or homozygous ALDH2*2 (n = 81 and 13, respectively). We also analyzed a public-domain dataset with genome-wide genotypes of 2000 participants in Guangzhou, a coastal city in Southern China. Among them, 175 participants have homozygous ALDH2*2 genotype, and again, long ALDH2*2-carrying haplotypes were found in all 175 participants without exceptions. The median length of the ALDH2*2-carrying haplotype is 1.7 (0.5–2.8) million nucleotide bases. The haplotype lengths in the Keelung and Guangzhou cohorts combined indicate that the origin of the ALDH2*2 allele dates back to 7935 (7014–9381) years ago. In conclusion, the rs671 G > A is the leading genomic variant associated with the long-term drinking behavior among residents of Keelung, Taiwan. The ALDH2*2 allele has been in Asian populations since prehistoric times.
Highlights
Inventions of alcoholic beverages predate written history
To pinpoint genetic variants associated with habitual drinking behaviors, many candidate-gene and genome-wide association studies (GWAS) have been conducted [11,12,13,14,15,16,17]
A recent pan-ethnic group study in conjunction with a meta-analysis showed that the single nucleotide polymorphism (SNP) rs671, located at exon 12 of the aldehyde dehydrogenase 2 (ALDH2) gene, has the strongest association in East Asians [11]
Summary
Inventions of alcoholic beverages predate written history. Evidence of the earliest manmade alcoholic beverages, which date back to 9000 years ago, was found in the Henan province of China [1]. Alcohol-use disorder is developed in some persons, causing burdens to families and societies This disorder is influenced by genetics, with 60% heritability estimated in a twin study [10]. Genomic variants of metabolic genes, such as alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs), have been reported frequently [11,14,15], suggesting the intimate connections between alcohol metabolisms and drinking behaviors. These genomic variants dictate personal metabolic rates of ethanol and aldehydes, including acetaldehyde [18] and 4HNE [19]. A recent pan-ethnic group study in conjunction with a meta-analysis showed that the single nucleotide polymorphism (SNP) rs671, located at exon 12 of the ALDH2 gene, has the strongest association in East Asians [11]
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