Family-Based Association Analyses of Alcohol Dependence Phenotypes Across DRD2 and Neighboring Gene ANKK1

Authors

  • Danielle M. Dick,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Jen C. Wang,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Jevon Plunkett,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Fazil Aliev,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Anthony Hinrichs,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Sarah Bertelsen,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • John P. Budde,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Elianna L. Goldstein,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Daniel Kaplan,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Howard J. Edenberg,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • John Nurnberger Jr.,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Victor Hesselbrock,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Marc Schuckit,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Sam Kuperman,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Jay Tischfield,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Bernice Porjesz,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Henri Begleiter,

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    • Deceased.

  • Laura Jean Bierut,

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • Alison Goate

    1. From Washington University in St Louis, St Louis, Missouri (DMD, JCW, JP, FA, AH, SB, JPB, ELG, DK, LJB, AG); Indiana University School of Medicine, Indianapolis, Indiana (HJE, JN); University of Connecticut Health Center, Farmington, Connecticut (VH); San Diego VA Medical Center, University of California, San Diego, California (MS); University of Iowa College of Medicine, Iowa City, Iowa (SK); Rutgers University, Piscataway, New Jersey (JT); and SUNY Health Science Center at Brooklyn, Brooklyn, New York (BP, HB).
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  • This national collaborative study is supported by NIH Grant U10AA08401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA).

Reprint requests: Danielle M. Dick, PhD, Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, P.O. Box 980126, Richmond, VA 23298-0126; E-mail: ddick@vcu.edu

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.

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