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Genome-wide Association Study of Alcohol Dependence
Jens Treutlein, PhD*;
Sven Cichon, PhD*;
Monika Ridinger, MD*;
Norbert Wodarz, MD;
Michael Soyka, MD;
Peter Zill, PhD;
Wolfgang Maier, MD;
Rainald Moessner, MD;
Wolfgang Gaebel, MD;
Norbert Dahmen, MD;
Christoph Fehr, MD;
Norbert Scherbaum, MD;
Michael Steffens, MD;
Kerstin U. Ludwig, MSc;
Josef Frank, MA;
H. Erich Wichmann, MD, PhD;
Stefan Schreiber, MD;
Nico Dragano, PhD;
Wolfgang H. Sommer, MD, PhD;
Fernando Leonardi-Essmann, MA;
Anbarasu Lourdusamy, PhD;
Peter Gebicke-Haerter, PhD;
Thomas F. Wienker, MD;
Patrick F. Sullivan, MD;
Markus M. Nöthen, MD;
Falk Kiefer, MD;
Rainer Spanagel, PhD*;
Karl Mann, MD*;
Marcella Rietschel, MD*
Arch Gen Psychiatry. 2009;66(7):773-784.
Context Alcohol dependence is a serious and common public health problem. It is well established that genetic factors play a major role in the development of this disorder. Identification of genes that contribute to alcohol dependence will improve our understanding of the mechanisms that underlie this disorder.
Objective To identify susceptibility genes for alcohol dependence through a genome-wide association study (GWAS) and a follow-up study in a population of German male inpatients with an early age at onset.
Design The GWAS tested 524 396 single-nucleotide polymorphisms (SNPs). All SNPs with P < 10–4 were subjected to the follow-up study. In addition, nominally significant SNPs from genes that had also shown expression changes in rat brains after long-term alcohol consumption were selected for the follow-up step.
Setting Five university hospitals in southern and central Germany.
Participants The GWAS included 487 male inpatients with alcohol dependence as defined by the DSM-IV and an age at onset younger than 28 years and 1358 population-based control individuals. The follow-up study included 1024 male inpatients and 996 age-matched male controls. All the participants were of German descent.
Main Outcome Measures Significant association findings in the GWAS and follow-up study with the same alleles.
Results The GWAS produced 121 SNPs with nominal P < 10–4. These, together with 19 additional SNPs from homologues of rat genes showing differential expression, were genotyped in the follow-up sample. Fifteen SNPs showed significant association with the same allele as in the GWAS. In the combined analysis, 2 closely linked intergenic SNPs met genome-wide significance (rs7590720, P = 9.72 x 10–9; rs1344694, P = 1.69 x 10–8). They are located on chromosome region 2q35, which has been implicated in linkage studies for alcohol phenotypes. Nine SNPs were located in genes, including the CDH13 and ADH1C genes, that have been reported to be associated with alcohol dependence.
Conclusions This is the first GWAS and follow-up study to identify a genome-wide significant association in alcohol dependence. Further independent studies are required to confirm these findings.
Author Affiliations: Departments of Genetic Epidemiology in Psychiatry (Drs Treutlein and Rietschel and Mr Frank), Psychopharmacology (Drs Sommer, Gebicke-Haerter, and Spanagel and Mr Leonardi-Essmann), and Addictive Behavior and Addiction Medicine (Drs Treutlein, Kiefer, and Mann), Central Institute of Mental Health, Mannheim, Germany; Department of Genomics, Life and Brain Center (Drs Cichon and Nöthen and Ms Ludwig), Institute of Human Genetics (Drs Cichon and Nöthen), Department of Psychiatry (Drs Maier and Moessner), and Institute for Medical Biometry, Informatics and Epidemiology (Drs Steffens and Wienker), University of Bonn, Bonn, Germany; Department of Psychiatry, Mental State Hospital, University of Regensburg, Regensburg, Germany (Drs Ridinger and Wodarz); Private Hospital Meiringen, Meiringen, Switzerland (Dr Soyka); Department of Psychiatry, University of Munich, Munich, Germany (Drs Soyka and Zill); Department of Psychiatry and Psychotherapy, University of Dusseldorf, Dusseldorf, Germany (Dr Gaebel); Department of Psychiatry, University of Mainz, Mainz, Germany (Drs Dahmen and Fehr); Addiction Research Group at the Department of Psychiatry and Psychotherapy, Rhine State Hospital Essen, University of Duisburg-Essen, Essen, Germany (Dr Scherbaum); Institute of Epidemiology, Helmholtz Center, Munich (Dr Wichmann); Institute of Medical Data Management, Biometrics, and Epidemiology, Chair of Epidemiology, Ludwig Maximilians University, Munich (Dr Wichmann); Institute for Clinical Molecular Biology and Department of General Internal Medicine, University of Kiel, Kiel, Germany (Dr Schreiber); Department of Medical Sociology, University of Dusseldorf for the Heinz Nixdorf Risk Factors, Evaluation of Coronary Calcium, and Lifestyle (RECALL) Study Group, Dusseldorf (Dr Dragano); National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (Dr Sommer); Dipartimento di Medicina Sperimentale e Sanità Pubblica, Università di Camerino, Camerino, Italy (Dr Lourdusamy); and Department of Genetics, University of North Carolina at Chapel Hill (Dr Sullivan).
*Indicates co-primary authorship.
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