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A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53

Molecular Psychiatry volume 18, pages 1218–1224 (2013)Cite this article

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Abstract

Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10−8, inflation-corrected P=9.4 × 10−7). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D′=1, r2⩾ 0.95), have previously been associated with risk for bipolar disorder.

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Acknowledgements

The Collaborative Study on the Genetics of Alcoholism (COGA): COGA, Principal Investigators B Porjesz, V Hesselbrock, H Edenberg, L Bierut includes ten different centers: University of Connecticut (V Hesselbrock); Indiana University (HJ Edenberg, J Nurnberger Jr, T Foroud); University of Iowa (S Kuperman, J Kramer); SUNY Downstate (B Porjesz); Washington University in Saint Louis (L Bierut, A Goate, J Rice, K Bucholz); University of California at San Diego (M Schuckit); Rutgers University (J Tischfield); Southwest Foundation (L Almasy), Howard University (R Taylor) and Virginia Commonwealth University (D Dick). A Parsian and M Reilly are the NIAAA Staff Collaborators. We continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, currently a consultant with COGA, P Michael Conneally, Raymond Crowe and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA).

The Study of Addiction: Genetics and Environment (SAGE): Funding support for SAGE was provided through the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the GWAS funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by COGA (U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423, R01 DA019963). Genotyping at the Johns Hopkins University Center for Inherited Disease Research was supported by the NIH GEI (U01HG004438) Grant, NIAAA, NIDA and the NIH contract ‘High throughput genotyping for studying the genetic contributions to human disease’

The Australian Twin-family Study of Alcohol-Use Disorder (OZALC) Sample: The OZALC study was supported by National Institutes of Health Grants AA07535, AA07728, AA13320, AA13321, AA14041, AA11998, AA17688, DA012854 and DA019951; by Grants from the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485 and 552498); by Grants from the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016 and DP0343921); and by the 5th Framework Programme (FP-5) GenomEUtwin Project (QLG2-CT-2002-01254). Genotyping at Center for Inherited Disease Research was supported by a Grant to the late Richard Todd, MD, PhD., former Principal Investigator of Grant AA13320. We acknowledge the contribution of Anjali Henders and Yi-Ling for their technical assistance.

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Author notes

  1. J-C Wang, T Foroud and A L Hinrichs: These authors contributed equally to this work.

  2. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA

  3. San Diego Department of Psychiatry, University of California, La Jolla, CA, USA

Authors and Affiliations

  1. Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA

    J-C Wang, A L Hinrichs, N X H Le, S Bertelsen, J P Budde, O Harari, A Agrawal, K Bucholz, M Kapoor, P A F Madden, J Rice, A C Heath, L J Bierut & A M Goate

  2. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    T Foroud, D L Koller, L Wetherill & H J Edenberg

  3. Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA

    L Almasy & J A Tischfield

  4. Department of Genetics, Rutgers University, Piscataway, NJ, USA

    A I Brooks

  5. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    D Dick

  6. Department of Psychiatry, University of Connecticut Health Center, Farmington, CT, USA

    V Hesselbrock

  7. Division of Health, Social and Economic Research, Research Triangle Institute International, Research Triangle Park, NC, USA

    E O Johnson

  8. Department of Psychiatry and Behavioral Sciences, Henri Begleiter Neurodynamics Laboratory, SUNY Downstate Medical Center, Brooklyn, NY, USA

    S Kang, N Manz, M Rangaswamy & B Porjesz

  9. Department of Psychiatry, University of Iowa College of Medicine, Iowa City, IA, USA

    J Kramer

  10. Division of Child Psychiatry, University of Iowa Hospitals, Iowa City, IA, USA

    S Kuperman, J N McClintick, X Xuei & H J Edenberg

  11. Queensland Institute of Medical Research, Queensland, Australia

    N G Martin, G W Montgomery, J I Nurnberger Jr & J B Whitfield

  12. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    M Schuckit

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  1. J-C Wang
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Correspondence to A M Goate.

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Competing interests

Doctors LJ Bierut, AM Goate, AJ Hinrichs, J Rice and JC Wang are listed as inventors on the patent ‘Markers for Addiction’ (US 20070258898) covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction. The remaining authors declare no conflict of interest.

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Wang, JC., Foroud, T., Hinrichs, A. et al. A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53. Mol Psychiatry 18, 1218–1224 (2013). https://doi.org/10.1038/mp.2012.143

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