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Genome-Wide Association Study of Alcohol Dependence

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Genome-Wide Association Study of Alcohol Dependence ORIGINAL ARTICLE 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* Context: Alcohol dependence is a serious and com- 996 age-matched male controls. All the participants mon public health problem. It is well established that ge- were of German descent. netic factors play a major role in the development of this disorder. Identification of genes that contribute to alco- Main Outcome Measures: Significant association find- hol dependence will improve our understanding of the ings in the GWAS and follow-up study with the same mechanisms that underlie this disorder. alleles. Objective: To identify susceptibility genes for alcohol Results: The GWAS produced 121 SNPs with nominal dependence through a genome-wide association study PϽ10−4. These, together with 19 additional SNPs from (GWAS) and a follow-up study in a population of Ger- homologues of rat genes showing differential expres- man male inpatients with an early age at onset. sion, were genotyped in the follow-up sample. Fifteen SNPs showed significant association with the same al- Design: The GWAS tested 524 396 single-nucleotide lele as in the GWAS. In the combined analysis, 2 closely polymorphisms (SNPs). All SNPs with PϽ10−4 were sub- linked intergenic SNPs met genome-wide significance jected to the follow-up study. In addition, nominally sig- (rs7590720, P=9.72ϫ10−9; rs1344694, P=1.69ϫ10−8). nificant SNPs from genes that had also shown expres- They are located on chromosome region 2q35, which has sion changes in rat brains after long-term alcohol been implicated in linkage studies for alcohol pheno- consumption were selected for the follow-up step. types. Nine SNPs were located in genes, including the CDH13 and ADH1C genes, that have been reported to be Setting: Five university hospitals in southern and cen- associated with alcohol dependence. tral Germany. Conclusions: This is the first GWAS and follow-up study Participants: The GWAS included 487 male inpa- to identify a genome-wide significant association in al- tients with alcohol dependence as defined by the cohol dependence. Further independent studies are re- DSM-IV and an age at onset younger than 28 years and quired to confirm these findings. 1358 population-based control individuals. The follow-up study included 1024 male inpatients and Arch Gen Psychiatry. 2009;66(7):773-784 LCOHOL DEPENDENCE IS death and disability attributable to to- characterized by a cluster bacco use and hypertension.1,2 of cognitive, behavioral, Alcohol dependence is a phenotypi- and physiologic symp- cally heterogeneous disorder that runs in toms, with an affected in- families and has high genetic loading. Twin Adividual continuing to drink despite sig- and adoption studies3-5 have shown that nificant alcohol-induced impairment or 40% to 60% of the interindividual pheno- distress. Because alcohol affects most hu- typic variance is accounted for by genetic man organs, its abuse is associated with a factors. In congruence with the observed wide range of types of physical, mental, and phenotypic heterogeneity of alcohol de- social harm. According to the World pendence, vulnerability to alcohol depen- 1 Author Affiliations are listed at Health Organization, alcohol abuse con- dence on the molecular level is thought to the end of this article. stitutes a serious public health problem be mediated by many genetic loci of small * Indicates co-primary worldwide, accounting for 4% of the global to modest effects in Europeans.6-14 De- authorship. burden, a burden comparable with the spite strenuous efforts and numerous link- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 66 (NO. 7), JULY 2009 WWW.ARCHGENPSYCHIATRY.COM 773 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 age and candidate gene studies, identification of the un- has higher heritability in males.32,33 Patients included in the derlying susceptibility genes has proved to be difficult. GWAS (Mannheim, n=98; Bonn/Essen/Dusseldorf/ Genome-wide association studies (GWASs) conducted Homburg, n=30; Mainz, n=30; Munich, n=53; and Regens- in other complex disorders have been shown to be a suc- burg, n=276) had an age at onset younger than 28 years cessful tool in identifying underlying susceptibility genes (median, 20 years; mean [SD], 21 [4.1] years), defined as the age at which DSM-IV criteria for alcohol dependence (for all published GWASs, see http://www.genome.gov were fulfilled for the first time. /26525384) and have already resulted in the identifica- The follow-up sample consisted of 1024 German males re- tion of genetic susceptibility variants for psychiatric dis- cruited at the same sites and under the same protocol as the orders such as nicotine addiction, schizophrenia, and patients in the GWAS (Mannheim, n=256; Bonn/Essen/ bipolar disorder,15-24 which were mostly not detected using Dusseldorf/Homburg, n=149; Mainz, n=63; Munich, n=136; other diagnosis-based discovery approaches. For alco- and Regensburg, n=420). Because most of the patients with an hol dependence, only one GWAS using pooled DNA earlier age at onset had already been included in the GWAS, samples has been published to date, and it has proposed age at onset for the follow-up study was necessarily less strin- several new susceptibility loci for alcohol dependence. gent and was defined as younger than 45 years (median, 30 years; Their products are implicated in cellular signaling, gene mean [SD], 29.3 [7] years). Phenotypes and genotypes result- 25 ing from the GWAS are stored in a comprehensive database at regulation, development, and cell adhesion. Conver- the Institute for Medical Biometry, Informatics, and Epidemi- gent translational approaches integrate genetic findings ology in Bonn. from animal models with a candidate gene or GWAS ap- proach in humans and have proved to be very success- ful.26,27 The goal of the present study is to conduct a GWAS Control Subjects and a follow-up study for alcohol dependence using in- dividual genotyping in samples stratified for homogene- A total of 1358 control subjects were included in the GWAS. ity with respect to sex, ethnicity, age at onset, and re- Controls were taken from 3 population-based epidemiologic cruitment procedures. To increase the explanatory power studies: 487 from PopGen,34 488 from KORA-gen,35 and 383 from the Heinz Nixdorf Risk Factors, Evaluation of Coro- of the findings, we applied a convergent functional ge- 36 nomics28 approach to integrate findings from gene ex- nary Calcium, and Lifestyle (RECALL) Study. These 3 pression data in alcohol-dependent rats with the GWAS recruitment areas are located in Schleswig-Holstein (north- ern Germany), Augsburg (southern Germany), and Essen/ findings. Bochum/Mulheim (Ruhr Area, western Germany). The Population-Based Recruitment of Patients and Controls for METHODS the Analysis of Complex Genotype-Phenotype Relationships (PopGen) project (http://www.science.ngfn.de/10_233.htm; http: //www.popgen.de) was initiated to provide all locally preva- HUMAN STUDIES lent cases with the diseases in question for the disease- oriented projects from the National Genome Research Project Patients (NGFN) and population-based control samples that will ulti- mately be comprised of 7200 persons. The Cooperative Health Patients were recruited from consecutive admissions to the Research in the Region of Augsburg (KORA-gen) project (http: psychiatric and addiction medicine departments of 5 different //www.science.ngfn.de/10_234.htm; http://www.gsf.de study centers at university hospitals across southern and cen- /KORA), which has evolved from the World Health Organiza- tral Germany: Regensburg, Mannheim, Munich, Bonn/Essen/ tion MONICA (Monitoring of Trends and Determinants of Dusseldorf/Homburg, and Mainz. These centers are members Cardiovascular Disease) study, contains the biosamples, phe- of the German Addiction Research Network (GARN; http://www notypic characteristics, and environmental parameters of 18 000 .bw-suchtweb.de), for which one of us (K.M.) is the spokesper- adults from Augsburg and the surrounding regions. The bio- son. All the patients included in the study had alcohol depen- logical specimen bank was established to enable researchers to dence of such severity that hospitalization for the treatment or perform epidemiologic research regarding molecular and ge- prevention of severe withdrawal symptoms was warranted. All netic factors. The Heinz Nixdorf RECALL Study (http://www the patients received a diagnosis of alcohol dependence (per .recall-studie.uni-essen.de) was started in the year 2000 as a DSM-IV criteria) by the consensus of 2 clinical psychiatrists. In prospective cohort study to determine predictors of coronary the German Addiction Research Network study, DSM-IV crite- heart disease. It includes the biosamples, phenotypic charac- ria were ascertained systematically through the use of semistruc- teristics, and environmental
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