Limited Associations of Dopamine System Genes With Alcohol Dependence and Related Traits in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD)

Authors

  • Laura M. Hack,

    1. From the Department of Human and Molecular Genetics (LMH, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Department of Psychiatry (GK, FA, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Ankara University (FA), Ankara, Turkey; Department of Public Health (P-HK), National Taiwan University, Taipei, Taiwan; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Shaftesbury Square Hospital (DGP), Belfast, Northern Ireland, United Kingdom; and Health Research Board (DW), Dublin, Ireland.
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  • Gursharan Kalsi,

    1. From the Department of Human and Molecular Genetics (LMH, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Department of Psychiatry (GK, FA, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Ankara University (FA), Ankara, Turkey; Department of Public Health (P-HK), National Taiwan University, Taipei, Taiwan; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Shaftesbury Square Hospital (DGP), Belfast, Northern Ireland, United Kingdom; and Health Research Board (DW), Dublin, Ireland.
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  • Fazil Aliev,

    1. From the Department of Human and Molecular Genetics (LMH, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Department of Psychiatry (GK, FA, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Ankara University (FA), Ankara, Turkey; Department of Public Health (P-HK), National Taiwan University, Taipei, Taiwan; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Shaftesbury Square Hospital (DGP), Belfast, Northern Ireland, United Kingdom; and Health Research Board (DW), Dublin, Ireland.
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  • Po-Hsiu Kuo,

    1. From the Department of Human and Molecular Genetics (LMH, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Department of Psychiatry (GK, FA, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Ankara University (FA), Ankara, Turkey; Department of Public Health (P-HK), National Taiwan University, Taipei, Taiwan; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Shaftesbury Square Hospital (DGP), Belfast, Northern Ireland, United Kingdom; and Health Research Board (DW), Dublin, Ireland.
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  • Carol A. Prescott,

    1. From the Department of Human and Molecular Genetics (LMH, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Department of Psychiatry (GK, FA, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Ankara University (FA), Ankara, Turkey; Department of Public Health (P-HK), National Taiwan University, Taipei, Taiwan; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Shaftesbury Square Hospital (DGP), Belfast, Northern Ireland, United Kingdom; and Health Research Board (DW), Dublin, Ireland.
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  • Diana G. Patterson,

    1. From the Department of Human and Molecular Genetics (LMH, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Department of Psychiatry (GK, FA, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Ankara University (FA), Ankara, Turkey; Department of Public Health (P-HK), National Taiwan University, Taipei, Taiwan; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Shaftesbury Square Hospital (DGP), Belfast, Northern Ireland, United Kingdom; and Health Research Board (DW), Dublin, Ireland.
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  • Dermot Walsh,

    1. From the Department of Human and Molecular Genetics (LMH, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Department of Psychiatry (GK, FA, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Ankara University (FA), Ankara, Turkey; Department of Public Health (P-HK), National Taiwan University, Taipei, Taiwan; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Shaftesbury Square Hospital (DGP), Belfast, Northern Ireland, United Kingdom; and Health Research Board (DW), Dublin, Ireland.
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  • Danielle M. Dick,

    1. From the Department of Human and Molecular Genetics (LMH, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Department of Psychiatry (GK, FA, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Ankara University (FA), Ankara, Turkey; Department of Public Health (P-HK), National Taiwan University, Taipei, Taiwan; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Shaftesbury Square Hospital (DGP), Belfast, Northern Ireland, United Kingdom; and Health Research Board (DW), Dublin, Ireland.
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  • Brien P. Riley,

    1. From the Department of Human and Molecular Genetics (LMH, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Department of Psychiatry (GK, FA, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Ankara University (FA), Ankara, Turkey; Department of Public Health (P-HK), National Taiwan University, Taipei, Taiwan; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Shaftesbury Square Hospital (DGP), Belfast, Northern Ireland, United Kingdom; and Health Research Board (DW), Dublin, Ireland.
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  • Kenneth S. Kendler

    1. From the Department of Human and Molecular Genetics (LMH, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Department of Psychiatry (GK, FA, DMD, BPR, KSK), Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia; Ankara University (FA), Ankara, Turkey; Department of Public Health (P-HK), National Taiwan University, Taipei, Taiwan; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Shaftesbury Square Hospital (DGP), Belfast, Northern Ireland, United Kingdom; and Health Research Board (DW), Dublin, Ireland.
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Reprint requests: Laura M. Hack, BS, Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, P.O. Box 980424, Virginia Commonwealth University, Richmond, VA 23298-0424; Tel: +1-804-828-4120; Fax: +1-804-828-1471; E-mail: hacklm@vcu.edu

Abstract

Background:  Over 50 years of evidence from research has established that the central dopaminergic reward pathway is likely involved in alcohol dependence (AD). Additional evidence supports a role for dopamine (DA) in other disinhibitory psychopathology, which is often comorbid with AD. Family and twin studies demonstrate that a common genetic component accounts for most of the genetic variance in these traits. Thus, DA-related genes represent putative candidates for the genetic risk that underlies not only AD but also behavioral disinhibition. Many linkage and association studies have examined these relationships with inconsistent results, possibly because of low power, poor marker coverage, and/or an inappropriate correction for multiple testing.

Methods:  We conducted an association study on the products encoded by 10 DA-related genes (DRD1-D5, SLC18A2, SLC6A3, DDC, TH, COMT) using a large, ethnically homogeneous sample with severe AD (n = 545) and screened controls (n = 509). We collected genotypes from linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) and employed a gene-based method of correction. We tested for association with AD diagnosis in cases and controls and with a variety of alcohol-related traits (including age-at-onset, initial sensitivity, tolerance, maximum daily drinks, and a withdrawal factor score), disinhibitory symptoms, and a disinhibitory factor score in cases only. A total of 135 SNPs were genotyped using the Illumina GoldenGate and Taqman Assays-on-Demand protocols.

Results:  Of the 101 SNPs entered into standard analysis, 6 independent SNPs from 5 DA genes were associated with AD or a quantitative alcohol-related trait. Two SNPs across 2 genes were associated with a disinhibitory symptom count, while 1 SNP in DRD5 was positive for association with the general disinhibitory factor score.

Conclusions:  Our study provides evidence of modest associations between a small number of DA-related genes and AD as well as a range of alcohol-related traits and measures of behavioral disinhibition. While we did conduct gene-based correction for multiple testing, we did not correct for multiple traits because the traits are correlated. However, false-positive findings remain possible, so our results must be interpreted with caution.

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