ALDH2 is associated to alcohol dependence and is the major genetic determinant of “daily maximum drinks” in a GWAS study of an isolated rural chinese sample

Authors

  • Ellen E. Quillen,

    1. Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas
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  • Xiang-Ding Chen,

    1. Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Institute of Biology, Hunan Normal University, Changsha, Hunan, China
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  • Laura Almasy,

    1. Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas
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  • Fang Yang,

    1. Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Institute of Biology, Hunan Normal University, Changsha, Hunan, China
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  • Hao He,

    1. Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Institute of Biology, Hunan Normal University, Changsha, Hunan, China
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  • Xi Li,

    1. Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Institute of Biology, Hunan Normal University, Changsha, Hunan, China
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  • Xu-Yi Wang,

    1. Mental Health Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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  • Tie-Qiao Liu,

    1. Mental Health Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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  • Wei Hao,

    1. Mental Health Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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  • Hong-Wen Deng,

    1. School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana
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  • Henry R. Kranzler,

    1. Department of Psychiatry, Philadelphia VA Medical Center, Philadelphia, Pennsylvania
    2. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
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  • Joel Gelernter

    Corresponding author
    1. Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, West Haven, Connecticut
    2. Department of Genetics, Yale University School of Medicine, West Haven, Connecticut
    3. Department of Neurobiology, Yale University School of Medicine, West Haven, Connecticut
    4. Department of Psychiatry, VA CT Healthcare Center, West Haven, Connecticut
    • Correspondence to:

      Joel Gelernter, M.D., Department of Psychiatry, VA CT Healthcare Center S116A2, Yale University School of Medicine, 950 Campbell Avenue, West Haven, CT 06516. E-mail: joel.gelernter@yale.edu

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  • Ellen E. Quillen and Xiang-Ding Chen contributed equally to this work.
  • Conflict of Interest: Dr. Kranzler has been a paid consultant or advisory board member for Alkermes, Lilly, Lundbeck, Pfizer, and Roche and has received honoraria from the Alcohol Clinical Trials Initiative (ACTIVE) of the American Society of Clinical Psychopharmacology, which is supported by Lilly, Lundbeck, Abbott, and Pfizer.

Abstract

Alcohol dependence (AD) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 595 members of documented, extended pedigrees in which AD segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome-wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the ALDH2 region for AD (minimum P = 4.73 × 10−8) and two AD-related phenotypes: flushing response (minimum P = 4.75 × 10−26) and maximum drinks in a 24-hr period (minimum P = 1.54 × 10−16). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with ALDH2. ALDH2 is strongly associated with flushing response, AD, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9%, and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in flushing response, but alcohol consumption rates were too low among females—despite familial enrichment for AD—for an adequate test of association for either AD or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor. © 2013 Wiley Periodicals, Inc.

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