title: Recessive genetic mode of an ADH4 variant in substance dependence in African-Americans: A model of utility of the HWD test.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. joel.gelernter@yale.edu.
authors.forename: Xingguang
authors.initials: X
authors.lastname: Luo
authors.forename: Lingjun
authors.initials: L
authors.lastname: Zuo
authors.forename: Henry R
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authors.forename: Shuang
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authors.lastname: Wang
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Anton
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
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