Family-based association analyses of alcohol dependence phenotypes across DRD2 and neighboring gene ANKK1

Danielle M. Dick, Jen C. Wang, Jevon Plunkett, Fazil Aliev, Anthony Hinrichs, Sarah Bertelsen, John P. Budde, Elianna L. Goldstein, Daniel Kaplan, Howard J. Edenberg, John Nurnberger, Victor Hesselbrock, Marc Schuckit, Sam Kuperman, Jay Tischfield, Bernice Porjesz, Henri Begleiter, Laura Jean Bierut, Alison Goate

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105 Scopus citations

Abstract

Background: There is an extensive and inconsistent literature on the association of the dopamine D2 receptor gene (DRD2) with alcohol dependence. Conflicting results have been attributed to differences in the severity of the alcohol dependence phenotype across studies, failure to exclude related disorders from comparison groups, and artifacts of population-stratification. Recently the genetic polymorphism most widely analyzed in DRD2, Taq1A, has been discovered to reside in a neighboring gene, ankyrin repeat and kinase domain containing 1 (ANKK1), located 10 kb downstream from DRD2. Methods: To more carefully characterize evidence for association across this region, we genotyped 26 single nucleotide polymorphisms (SNPs) spanning DRD2 and ANKK1 in a sample of 219 Caucasian families (n = 1,923) from the Collaborative Study on the Genetics of Alcoholism (COGA), making this the most extensive analysis to date of association between this region and alcohol dependence. We used family-based analyses robust to population-stratification, and we made use of rich phenotypic data to analyze alcohol dependence and subtypes hypothesized in the literature to be more directly influenced by DRD2. Results: We found that the evidence for association is strongest in the 5′ linkage disequilibrium block of ANKK1 (that does not contain Taq1A), with weak evidence of association with a small number of SNPs in DRD2. The association in ANKK1 is strongest among the subsets of alcoholics with medical complications and with antisocial personality disorder. Conclusions: More extensive genotyping across DRD2 and ANKK1 suggests that the association with alcohol dependence observed in this region may be due to genetic variants in the ANKK1 gene. ANKK1 is involved in signal transduction pathways and is a plausible biological candidate for involvement in addictive disorders.

Original languageEnglish (US)
Pages (from-to)1645-1653
Number of pages9
JournalAlcoholism: Clinical and Experimental Research
Volume31
Issue number10
DOIs
StatePublished - Oct 1 2007

Keywords

  • Alcohol Dependence
  • ANKK1
  • Association Analyses
  • DRD2
  • Genetics

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology

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    Dick, D. M., Wang, J. C., Plunkett, J., Aliev, F., Hinrichs, A., Bertelsen, S., Budde, J. P., Goldstein, E. L., Kaplan, D., Edenberg, H. J., Nurnberger, J., Hesselbrock, V., Schuckit, M., Kuperman, S., Tischfield, J., Porjesz, B., Begleiter, H., Bierut, L. J., & Goate, A. (2007). Family-based association analyses of alcohol dependence phenotypes across DRD2 and neighboring gene ANKK1. Alcoholism: Clinical and Experimental Research, 31(10), 1645-1653. https://doi.org/10.1111/j.1530-0277.2007.00470.x