Association of ADH and ALDH Genes With Alcohol Dependence in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) Sample

Authors

  • Po-Hsiu Kuo,

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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  • Gursharan Kalsi,

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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  • Carol A. Prescott,

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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  • Colin A. Hodgkinson,

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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  • David Goldman,

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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  • Edwin J. Van Den Oord,

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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  • Jeffry Alexander,

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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  • Cizhong Jiang,

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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  • Patrick F. Sullivan,

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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  • Diana G. Patterson,

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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  • Dermot Walsh,

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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  • Kenneth S. Kendler,

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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  • Brien P. Riley

    1. From the Institute of Clinical Medicine, College of Medicine (P-HK), National Cheng Kung University, Taiwan; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics (P-HK, GK, JA, KSK, BPR), Virginia Commonwealth University, Richmond, Virginia; Department of Psychology (CAP), University of Southern California, Los Angeles, California; Laboratory of Neurogenetics (CAH, DG), DICBR, NIAAA, Rockville, Maryland; Center for Biomarker Research and Personalized Medicine (EJO), Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology (CJ), Pennsylvania State University, University Park, Pennsylvania; Departments of Genetics & Psychiatry (PFS), Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; Shaftsbury Square Hospital (DGP), Belfast, Northern Ireland; and Health Research Board (DW), Dublin, Ireland.
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Reprint requests: Po-Hsiu Kuo, PhD, Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Hospital 138, National Cheng Kung University, Sheng-Li Road, Tainan 704, Taiwan; Fax: +886-6-3028162; E-mail: pkuo@mail.ncku.edu.tw

Abstract

Background:  The genes coding for ethanol metabolism enzymes [alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)] have been widely studied for their influence on the risk to develop alcohol dependence (AD). However, the relation between polymorphisms of these metabolism genes and AD in Caucasian subjects has not been clearly established. The present study examined evidence for the association of alcohol metabolism genes with AD in the Irish Affected Sib Pair Study of alcohol dependence.

Methods:  We conducted a case–control association study with 575 independent subjects who met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, AD diagnosis and 530 controls. A total of 77 single nucleotide polymorphisms (SNPs) in the seven ADH (ADH1-7) and two ALDH genes (ALDH1A1 and ALDH2) were genotyped using the Illumina GoldenGate protocols. Several statistical procedures were implemented to control for false discoveries.

Results:  All markers with minor allele frequency greater than 0.01 were in Hardy–Weinberg equilibrium. Numerous SNPs in ADH genes showed association with AD, including one marker in the coding region of ADH1C (rs1693482 in exon6, Ile271Gln). Haplotypic association was observed in the ADH5 and ADH1C genes, and in a long haplotype block formed by the ADH1A and ADH1B loci. We detected two significant interactions between pairs of markers in intron 6 of ADH6 and intron 12 of ALDH2 (= 5 × 10−5), and 5′ of both ADH4 and ADH1A (= 2 × 10−4).

Conclusion:  We found evidence for the association of several ADH genes with AD in a sample of Western European origin. The significant interaction effects between markers in ADH and ALDH genes suggest possible epistatic roles between alcohol metabolic enzymes in the risk for AD.

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