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

Luo X, Zuo L, Kranzler HR, Wang S, Anton RF, Gelernter J - Behav Brain Funct (2008)

Bottom Line: 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.The best-fit genetic disease model for this marker is a recessive genetic model.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. joel.gelernter@yale.edu.

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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

Pairwise LD between the candidate marker SNP8 and other seven flanking markers in unrelated African-American subjects. [D' = 1.00 in the blank squares; the numbers inside the red squares are D' × 100%; the blue squares represent low r2 values; the white squares represent low D' and low r2 values. SNPs 1–7 were reported previously in Luo et al. (2006) and span from 3' to 5'.].
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Figure 1: Pairwise LD between the candidate marker SNP8 and other seven flanking markers in unrelated African-American subjects. [D' = 1.00 in the blank squares; the numbers inside the red squares are D' × 100%; the blue squares represent low r2 values; the white squares represent low D' and low r2 values. SNPs 1–7 were reported previously in Luo et al. (2006) and span from 3' to 5'.].

Mentions: 1. SNP8 was in LD with the seven flanking markers in EAs (D' > 0.9 in each case), but provided information independent of these markers in AAs (D' < 0.10 in each case) (Figure 1). TDT in Sample 3 and FBAT in Sample 4 showed no significant association between the ADH4 SNP8 and AD or DD, whether analysis is conducted by combining or separating the different ethnicities (all p > 0.05) (Sample 3: see additional file 2; Sample 4: data not shown). The genotype frequency distributions in Sample 4 were shown in Table 3, not for the association analysis, but for providing a replication of the rare genotype frequencies to those in the unrelated Samples 1 and 2 (see additional file 1).


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

Luo X, Zuo L, Kranzler HR, Wang S, Anton RF, Gelernter J - Behav Brain Funct (2008)

Pairwise LD between the candidate marker SNP8 and other seven flanking markers in unrelated African-American subjects. [D' = 1.00 in the blank squares; the numbers inside the red squares are D' × 100%; the blue squares represent low r2 values; the white squares represent low D' and low r2 values. SNPs 1–7 were reported previously in Luo et al. (2006) and span from 3' to 5'.].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2563013&req=5

Figure 1: Pairwise LD between the candidate marker SNP8 and other seven flanking markers in unrelated African-American subjects. [D' = 1.00 in the blank squares; the numbers inside the red squares are D' × 100%; the blue squares represent low r2 values; the white squares represent low D' and low r2 values. SNPs 1–7 were reported previously in Luo et al. (2006) and span from 3' to 5'.].
Mentions: 1. SNP8 was in LD with the seven flanking markers in EAs (D' > 0.9 in each case), but provided information independent of these markers in AAs (D' < 0.10 in each case) (Figure 1). TDT in Sample 3 and FBAT in Sample 4 showed no significant association between the ADH4 SNP8 and AD or DD, whether analysis is conducted by combining or separating the different ethnicities (all p > 0.05) (Sample 3: see additional file 2; Sample 4: data not shown). The genotype frequency distributions in Sample 4 were shown in Table 3, not for the association analysis, but for providing a replication of the rare genotype frequencies to those in the unrelated Samples 1 and 2 (see additional file 1).

Bottom Line: 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.The best-fit genetic disease model for this marker is a recessive genetic model.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. joel.gelernter@yale.edu.

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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus