Recessive genetic mode of an ADH4 variant in substance dependence in African-Americans: A model of utility of the HWD test
1 Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
2 VA Connecticut Healthcare System, West Haven Campus, CT, USA
3 Alcohol Research Center, Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA
4 Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA
5 Alcohol Research Center, Institute of Psychiatry, Medical University of South Carolina, Charleston, SC, USA
Behavioral and Brain Functions 2008, 4:42 doi:10.1186/1744-9081-4-42Published: 18 September 2008
In our previous studies, we reported positive associations between seven ADH4 polymorphisms and substance dependence [i.e., alcohol dependence (AD) and/or drug dependence (DD)] in European-Americans (EAs). In the present study, we address the relationship between ADH4 variation and substance dependence in an African-American (AA) population, and report evidence that supports an association between a different ADH4 polymorphism (rs2226896) and these phenotypes in AAs.
Two family-based association study methods, i.e., TDT and FBAT, were applied to test the relationship between ADH4 variation and substance dependence in Sample 3 (112 small nuclear families) and in Sample 4 (632 pedigrees), respectively. A population-based case-control association study method was also applied to test this relationship in 1303 unrelated subjects, with and without controlling for admixture effects. Finally, a Hardy-Weinberg Disequilibrium (HWD) test was applied to examine the association in the case-only sample, infer the genetic disease models, and distinguish the disease and non-disease factors contributing to HWD.
The marker examined was found to be in significant HWD in AA alcoholics (p = 0.0071) and drug dependent subjects (p = 0.0341), but in Hardy-Weinberg Equilibrium (HWE) in all other subgroups. Other association methods failed to detect any association between this variation and phenotypes. The best-fit genetic disease model for this marker is a recessive genetic model.
ADH4 variation might play a role in risk for substance dependence in AAs, potentially via a recessive mechanism. Under certain conditions, the HWD test could be a more powerful association method than conventional family-based and population-based case-control association analyses, for which, the present study provides an extreme example.