Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men
ABSTRACT Genome-wide association (GWA) studies regarding the quantitative trait of alcohol consumption are limited.
The objective of the study was to explore genetic loci associated with the amount of alcohol consumed.
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.
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 × 10(-5) through 5.8 × 10(-46). 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.
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.
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ABSTRACT: Blood levels of gamma-glutamyl transferase (GGT) are used as a marker for (heavy) alcohol use. The role of GGT in the anti-oxidant defense mechanism that is part of normal metabolism supposes a causal effect of alcohol intake on GGT. However, there is variability in the response of GGT to alcohol use, which may result from genetic differences between individuals. This study aimed to determine whether the epidemiological association between alcohol intake and GGT at the population level is necessarily a causal one or may also reflect effects of genetic pleiotropy (genes influencing multiple traits). Data on alcohol intake (grams alcohol/day) and GGT, originating from twins, their siblings and parents (N=6465) were analyzed with structural equation models. Bivariate genetic models tested whether genetic and environmental factors influencing alcohol intake and GGT correlated significantly. Significant genetic and environmental correlations are consistent with a causal model. If only the genetic correlation is significant, this is evidence for genetic pleiotropy. Phenotypic correlations between alcohol intake and GGT were significant in men (r=.17) and women (r=.09). The genetic factors underlying alcohol intake correlated significantly with those for GGT, whereas the environmental factors were weakly correlated (explaining 4-7% vs. 1-2% of the variance in GGT respectively). In this healthy population sample, the epidemiological association of alcohol intake with GGT is at least partly explained by genetic pleiotropy. Future longitudinal twin studies should determine whether a causal mechanism underlying this association might be confined to heavy drinking populations.Drug and alcohol dependence 09/2013; 134. DOI:10.1016/j.drugalcdep.2013.09.016 · 3.28 Impact Factor
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ABSTRACT: Alcohol dependence (AD) is a multifactorial and polygenic disorder involving complex gene-to-gene and gene-to-environment interactions. Several genome-wide association studies have reported numerous risk factors for AD, but replication results following these studies have been controversial. To identify new candidate genes, the present study used GWAS and replication studies in a Korean cohort with AD. Genome-wide association analysis revealed that two chromosome regions on Chr. 4q22-q23 (ADH gene cluster, including ADH5, ADH4, ADH6, ADH1A, ADH1B, and ADH7) and Chr. 12q24 (ALDH2) showed multiple association signals for the risk of AD. To investigate detailed genetic effects of these ADH genes on AD, a follow-up study of the ADH gene cluster on 4q22-q23 was performed. A total of 90 SNPs, including ADH1B rs1229984 (H47R), were genotyped in an additional 975 Korean subjects. In case-control analysis, ADH1B rs1229984 (H47R) showed the most significant association with the risk of AD (p = 2.63 × 10-21, OR = 2.35). Moreover, subsequent conditional analyses revealed that all positive associations of other ADH genes in the cluster disappeared, which suggested that ADH1B rs1229984 (H47R) might be the sole functional genetic marker across the ADH gene cluster. Our findings could provide additional information on the ADH gene cluster regarding the risk of AD, as well as a new and important insight into the genetic factors associated with AD.Human Genetics 03/2013; 132(6). DOI:10.1007/s00439-013-1281-8 · 4.52 Impact Factor
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ABSTRACT: Background Depressiveness and tobacco use in adolescents are linked, however, there is limited evidence about the cognitive mediators involved and how the role of mediators may differ by gender and racial/ethnic subgroups. Methods We used a racially/ethnically diverse population-based cross-sectional sample of middle and high school students (n = 24,350). Logistic regression models measured the associations of depressiveness with tobacco smoking status, and whether smoking-related knowledge and attitudes (KA) and smoking refusal self-efficacy (SE) attenuated the associations indicating preliminary evidence of mediation. Results Depressiveness was associated with intention to smoke (OR = 2.41; 95% CI = 2.22, 2.61), experimental smoking (OR = 1.93; 95% CI = 1.72, 2.17) and established smoking (OR = 1.85; 95% CI = 1.57, 2.18). The percent attenuation of these associations due to the inclusion of smoking-related KA and smoking refusal SE was 58% for intention to smoke (p < 0.001), 68% for experimental smoking (p < 0.001) and 86% for established smoking (p < 0.001). The association of depressiveness with established smoking did not remain statistically significant (OR = 1.16; CI = 0.97, 1.40) after including smoking-related KA and smoking refusal SE. Attenuation was more pronounced in males and white students. Conclusions The results suggest that smoking-related KA and smoking refusal SE attenuated the relation between depressiveness and smoking, indicating that they may serve as mediators of the link between depressiveness and smoking. Tobacco use prevention programs targeting teens with the aim of increasing anti-smoking KA and smoking refusal SE may benefit from addressing depressiveness, particularly by using gender and racially/ethnically tailored strategies. The cross-sectional nature of the data precludes causal inferences.Drug and Alcohol Dependence 07/2014; DOI:10.1016/j.drugalcdep.2014.03.022 · 3.28 Impact Factor