The frequency of alcohol dependence and comorbid nicotine and cocaine dependence is consistent with the study design and ascertainment protocols for each study (). Rs1229984 is strongly associated with alcohol dependence in each dataset (). See Supplementary Table 1
for results for the full models. In the meta-analysis across the three adult studies, which included 2298 alcohol dependent cases and 3334 non-dependent controls, the allele encoding His48 is significantly associated with reduced risk for alcohol dependence, with an odds ratio of 0.34 (95% CI 0.24, 0.48) and p value = 6.6 × 10−10
. The magnitude of effect is similar in both European American and African American populations. Analyses were repeated using principal components to ensure that the association is not an artifact of population stratification, and results are essentially unchanged (Supplementary Table 2
). The findings are robust, not only with respect to ethnicity, but also with major covariates (age, sex, nicotine and cocaine dependence), as removing or limiting covariates did not markedly affect the results (Supplementary Tables 3 and 4
). These results are consistent with the recent meta-analysis of Asian populations (47 studies, AG (Arg/His) and AA (His/His) versus GG (Arg/Arg), OR=0.24 (95% CI 0.19, 0.31), p value=2 × 10−31
Association of rs1229984 with DSM-IV alcohol dependence and maximum drinks consumed in a 24-hour period.
These results are further supported by analyses of an independent sample of adolescents and young adults (aged 12–25 years) of European descent. Using survival analysis, the His48 allele is associated with a 0.51 reduced hazard of developing alcohol dependence (N=2039; Hazard Ratio=0.51 (95% CI 0.30, 0.88) and p value = 0.015).
The His48 allele is also associated with lower alcohol consumption as measured by the subjects’ lifetime maximum alcohol consumption in a 24-hour period (β = −0.28 (95% CI −0.35, − 0.20), p value = 3.24 × 10−13
) (). A similar association is seen in both European American and African American subjects. These findings are consistent with, but exceed in magnitude, those from a prior report of association between His48 and maximum drinks consumed in a 24-hour period22
These results provide strong evidence that the His48 allele in β-ADH is strongly associated with a reduced likelihood of a lifetime diagnosis of alcohol dependence and a lower maximum number of drinks consumed in a 24-hour period in individuals of both European and African ancestry. The effect of this association is seen early in the course of illness and predicts the development of alcohol dependence in adolescents and young adults who are at the beginning of their drinking career. The direction of these effects is similar to that found in Asians, among whom the allele frequency is much higher.
Because rs1229984 is not on most GWAS arrays, is relatively uncommon (< 5% minor allele frequency) in populations of European and African descent, and the accuracy of imputation is poor, the association with alcohol dependence has not been detected in several recent genome-wide association studies11, 23–24
, including studies in which these subjects were included in this sample11, 24
. For example, this SNP was imputed from the GWAS data using BEAGLE25
. Though over 98% of the genotyped GG samples are correctly assigned, only 68% of the AG heterozygote and AA homozygote genotypes are accurately imputed. As a result, testing this association required direct genotyping of this SNP.
Although the population attributable risk of His48 differs because of the varying allele frequencies, at an individual level the effect of this ADH1B variant on amount of alcohol consumed and on the risk of developing alcohol dependence is the same regardless of ancestry. This polymorphism is an exception to the generally small effect sizes associated with other variants that affect complex traits including alcohol dependence; rs1229984 has a substantial effect on risk of developing alcohol dependency, reducing it by two-thirds.