Genetics of Alcohol Drinking Behaviors for Koreans: a Population with one third of Slow Metabolizers

Abstract

Backgrounds: It is well documented that individuals with Lys mutation (Glu504Lys) (=rs671 G>A) of Aldehyde Dehydrogenase 2 (ALDH2) gene are so-called slow metabolizers and less prone to alcohol abuse. In Korea and East Asian countries, about one third of population has one or two copies of the slow allele. Many of slow metabolizers, however, drink as much and as frequently in Korea, and it remains unclear whether other differences in genetic constitutions explain drinking behaviors between slow and fast metabolizers. To identify genetic architecture of alcohol drinking behaviors, we performed genome wide association studies for a range of alcohol-related traits in general Korean population. Methods: 3,479 subjects from a family-based cohort were measured for details of drinking habits and genetic markers with 3.7 million SNP markers. After excluding 735 abstinent participants for religious reasons, we performed GWAs for self-reported facial flushing reaction with alcohol use, and three domains (hazardous alcohol use, harmful alcohol use, and dependence symptoms) of the Alcohol Use Disorders Identification Test (AUDIT), frequency and amount of drinking as phenotypes. All the analyses were repeated by stratifying the rs671 alleles, and SNPs interacting with the rs671 alleles on alcohol consumption behaviors were examined genome-widely. Results: Only ALDH2 rs671 explained facial flushing (P=1.4×10-74). For various aspects of alcohol drinking habits, some other SNPs within the LD block of rs671 showed stronger associations, but adjusting for rs671 attenuated the significance (from P=10-74 to P=10-6), which makes it inconclusive whether some other variants are exerting their effects independently. When we performed stratified analysis by fast/slow metabolizers, novel loci on the 3p14.1 region (P=6.4×10-9) and 10p14 (P=1.4×10-7) showed associations with hazardous and harmful drinking domains for fast metabolizers

also a novel locus on the 20p12.1 region (P=2.2×10-7) was associated with dependence domain of AUDIT for slow metabolizers. The same 20p12.1 region also showed probable interaction with rs671 (P=2.0×10-6) for dependence domain. Conclusion: ALDH2 gene has a large LD block (287 kb), and it is not clear whether some other loci near rs671 also participate in the susceptibility of certain drinking habits, particularly binge drinking habits. Our findings suggest genetic susceptibility for problematic drinking behaviors might differ between fast and slow metabolizers.