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Common Variants in HLA-DRA Gene are Associated with Alcohol Dependence in Two Caucasian Samples

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Abstract

HLA-DRA gene polymorphisms might play an important role in alcohol dependence (AD). We examined genetic associations of 29 single-nucleotide polymorphisms (SNPs) within the HLA-DRA gene with AD using two Caucasian samples—the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls) and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). Logistic regression analysis using PLINK showed that 16 SNPs were associated with AD in the COGA sample and 13 SNPs were associated with AD in the SAGE sample (p < 0.05). The best novel signal was SNP rs2239803 associated with AD in both samples (p = 0.000817 for the COGA sample and p = 0.0026 for the SAGE sample, respectively) while one flanking SNP rs4935356 also showed strong association in both samples (p = 0.00219 and 0.0026 for the COGA and SAGE samples, respectively). Furthermore, these two SNPs revealed stronger associations in meta-analysis of these two samples (p = 8.97 × 10−6 and 2.02 × 10−5 for rs2239803 and rs4935356, respectively). In addition, the G-A haplotype from these two SNPs revealed a significant association with AD in both the COGA and SAGE samples (p = 0.0007 and 0.0019, respectively). These findings highlight the novel associations with HLA-DRA that may play an important role in the etiology of AD.

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Acknowledgments

Funding support for the (CIDR-COGA Study) was provided through the Center for Inherited Disease Research (CIDR) and the Collaborative Study on the Genetics of Alcoholism (COGA). The CIDR-COGA Study is a genome-wide association studies funded as part of the COGA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the COGA. Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples were provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease" (HHSN268200782096C). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gap through dbGaP accession number: phs000125.v1.p1. Funding support for the SAGE was provided through the National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) Grant U01 HG004422. SAGE is one of the GWAS funded as part of the GENEVA under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (Grant U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples were provided by COGA (Grant U10 AA008401), COGEND (Grant P01 CA089392), and FSCD (Grant R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by NIH GEI Grant U01HG004438, the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract “High throughput genotyping for studying the genetic contributions to human disease” (HHSN268200782096C). This study was approved by Internal Review Board (IRB), East Tennessee State University.

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Authors and Affiliations

  1. Department of Epidemiology and Public Health, Miller School of Medicine, University of Miami, Miami, FL, 33101, USA

    Yue Pan

  2. Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, PO Box 70259, Lamb Hall, Johnson City, TN, 37614-1700, USA

    Ke-Sheng Wang & Liang Wang

  3. Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, ON, Canada

    Long-Yang Wu

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  1. Yue Pan
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Correspondence to Ke-Sheng Wang.

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Pan, Y., Wang, KS., Wang, L. et al. Common Variants in HLA-DRA Gene are Associated with Alcohol Dependence in Two Caucasian Samples. J Mol Neurosci 49, 574–581 (2013). https://doi.org/10.1007/s12031-012-9869-3

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