Recessive genetic mode of an ADH4 variant in substance dependence in African-Americans: A model of utility of the HWD test

Luo, Xingguang; Zuo, Lingjun; Kranzler, Henry; Wang, Shuang; Anton, Raymond; Gelernter, Joel

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.



Also Published In

Behavioral and Brain Functions

More About This Work

Academic Units
BioMed Central
Published Here
September 8, 2014