ALDH2 is associated to alcohol dependence and is the major genetic determinant of "daily maximum drinks" in a GWAS study of an isolated rural Chinese sample

Abstract

Alcohol dependence (AD) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 595 members of documented, extended pedigrees in which AD segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome-wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the ALDH2 region for AD (minimum P = 4.73 × 10(-8)) and two AD-related phenotypes: flushing response (minimum P = 4.75 × 10(-26)) and maximum drinks in a 24-hr period (minimum P = 1.54 × 10(-16)). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with ALDH2. ALDH2 is strongly associated with flushing response, AD, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9%, and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in flushing response, but alcohol consumption rates were too low among females-despite familial enrichment for AD-for an adequate test of association for either AD or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor.

Keywords: alcohol dependence; aldehyde dehydrogenase; flushing response; genome-wide association; maximum drinks.

Figure 1. Manhattan plots of GWA results

Horizontal lines represent the genome-wide significant (p < 5e-8) and suggestive (p < 5e-7) association thresholds and are held constant across the differing y-axes.

Figure 2. Distribution of maximum drinks in 24 hours by flushing status

Individuals who self-report flushing following consumption of alcohol and those who do not comprise overlapping distributions of maximum drinks with significantly different means. Percentage of total represents the proportion of individuals within the flushing status (yes/no) who report a given maximum drinks value.