Baik I, Cho NH, Kim SH, Han B-G, Shin C. Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men. Am J Clin Nutr 2011;93:809–816.
Accompanying Editorial: Agrawal A, Freedman ND, Bierut LJ. Genome-wide association studies of alcohol intake—a promising cocktail? Am J Clin Nutr 2011;93:681–683.
Background: Genome-wide association (GWA) studies regarding the quantitative trait of alcohol consumption are limited. Objective: The objective of the study was to explore genetic loci associated with the amount of alcohol consumed.
Design: We conducted a GWA study with discovery data on single nucleotide polymorphisms (SNPs) for 1721 Korean male drinkers aged 40–69 y who were included in an urban population–based cohort. Another sample that comprised 1113 male drinkers who were from an independent cohort enrolled in a rural area served as a resource for replication. At baseline (18 June 2001 through 29 January 2003), members of both cohorts provided information on average daily alcohol consumptions, and their DNA samples were collected for genotyping.
Results: We tested 315,914 SNPs of discovery data by using multivariate linear regression analysis adjusted for age and smoking, and 12 SNPs on chromosome 12q24 had genome-wide significant associations with alcohol consumption; adjusted P values by using Bonferroni correction were 1.6 · 1025 through 5.8 · 10246. We observed most SNPs in intronic regions and showed that the genes that harbor SNPs were C12orf51, CCDC63, MYL2, OAS3, CUX2, and RPH3A. In particular, signals in or near C12orf51, CCDC63, and MYL2 were successfully replicated in the test for 317,951 SNPs; rs2074356 in C12orf51 was in high linkage disequilibrium with SNPs in ALDH2, but other SNPs were not.
Conclusions: In a GWA study, we identified loci and alleles highly associated with alcohol consumption. The findings suggest the need for further investigations on the genetic propensity for drinking excessive amounts of alcohol.
While twin studies indicate that a large proportion of alcoholism may be genetically determined, there is no question that environmental factors also play an important role. The present paper related a genome-wide association (GWA) study to the amounts of alcohol reported by Korean made drinkers. The investigators found that there was evidence of several genes, especially those related to levels of the aldehyde dehydrogenase, that were associated with larger amounts of alcohol.
The authors did not report on the pattern of drinking, only on the amount. Hence, there are no data indicating whether or not the subjects were regular moderate or binge drinkers. Further, the authors’ adjusted for smoking, which is very highly correlated with alcohol use, which may have modified the strength of the associations reported. They say that the results without such adjustment were similar, but do not present the results.
The GWA study was based on a rather small sample size, but strong associations with alcohol intake were found for genes closely associated with ALDH, probably because it was done in Asians who have a high frequency of ALDH deficiency.
The accompanying editorial points out that non-Asians are much more likely to have low levels of ALDH enzymes, which can cause flushing after very small amounts of alcohol intake. Since such deficiency is much less common among westerners, you would not expect similar strong relations with these genetic factors in westerners. However, the paper supports the importance of ALDH2 in determining alcohol intake.
A reviewer was a “little taken aback by what seemed to be acceptance of the thesis that alcohol problems are preponderantly genetically determined.” We currently have incomplete knowledge on the determinants of alcohol abuse; this makes it difficult to be very specific about genetic, environmental, and gene/environment interaction factors that are the key causes of abuse.
The paper and editorial do, however, make an important observation that genes affect drinking, and drinking affects genes, since they state that alcohol intake is an environmental factor in gene-environmental interactions for a number of diseases, such as esophageal cancer.
Forum Summary: A genome-wide association (GWA) study of reported levels of alcohol consumption by Korean men identified associations with several single nucleotide polymorphisms (SNPs) with alcohol intake. Most SNPs associated with alcohol were in the region of genes associated with levels of aldehyde dehydrogenase, low levels of which relate to flushing after even small amounts of alcohol. Such enzymes are much more common among Asians than among westerners. Associations were tested only with the weekly amount of alcohol consumed, not the pattern of drinking; hence, these findings are not direct measures of alcoholism.
The editorial by Freedman et al states “epidemiologic literature suggests that those who begin drinking at an early age may be at greater risk for a maladaptive and more genetically pronounced form of alcohol consumption, and other environmental milieus affect the risk of alcoholism.” It will be important to investigate the interplay of genes and environmental factors when seeking the determinants of alcohol abuse. Despite the findings of this study, our understanding of factors associated with alcoholism remains very limited.
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Contributions to this critique by the International Scientific Forum on Alcohol Research were made by the following members:
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA