title: Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster.
abstract: Alcohol dependence (AD) is an important contributory factor to the global burden of disease. The etiology of AD involves both environmental and genetic factors, and the disorder has a heritability of around 50%. The aim of the present study was to identify susceptibility genes for AD by performing a genome-wide association study (GWAS). The sample comprised 1333 male in-patients with severe AD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and 2168 controls. These included 487 patients and 1358 controls from a previous GWAS study by our group. All individuals were of German descent. Single-marker tests and a polygenic score-based analysis to assess the combined contribution of multiple markers with small effects were performed. The single nucleotide polymorphism (SNP) rs1789891, which is located between the ADH1B and ADH1C genes, achieved genome-wide significance [P = 1.27E-8, odds ratio (OR) = 1.46]. Other markers from this region were also associated with AD, and conditional analyses indicated that these made a partially independent contribution. The SNP rs1789891 is in complete linkage disequilibrium with the functional Arg272Gln variant (P = 1.24E-7, OR = 1.31) of the ADH1C gene, which has been reported to modify the rate of ethanol oxidation to acetaldehyde in vitro. A polygenic score-based approach produced a significant result (P = 9.66E-9). This is the first GWAS of AD to provide genome-wide significant support for the role of the ADH gene cluster and to suggest a polygenic component to the etiology of AD. The latter result may indicate that many more AD susceptibility genes still await identification.
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Germany.
authors: Josef
authors: J
authors: Frank
authors: Sven
authors: S
authors: Cichon
authors: Jens
authors: J
authors: Treutlein
authors: Monika
authors: M
authors: Ridinger
authors: Manuel
authors: M
authors: Mattheisen
authors: Per
authors: P
authors: Hoffmann
authors: Stefan
authors: S
authors: Herms
authors: Norbert
authors: N
authors: Wodarz
authors: Michael
authors: M
authors: Soyka
authors: Peter
authors: P
authors: Zill
authors: Wolfgang
authors: W
authors: Maier
authors: Rainald
authors: R
authors: Mössner
authors: Wolfgang
authors: W
authors: Gaebel
authors: Norbert
authors: N
authors: Dahmen
authors: Norbert
authors: N
authors: Scherbaum
authors: Christine
authors: C
authors: Schmäl
authors: Michael
authors: M
authors: Steffens
authors: Susanne
authors: S
authors: Lucae
authors: Marcus
authors: M
authors: Ising
authors: Bertram
authors: B
authors: Müller-Myhsok
authors: Markus M
authors: MM
authors: Nöthen
authors: Karl
authors: K
authors: Mann
authors: Falk
authors: F
authors: Kiefer
authors: Marcella
authors: M
authors: Rietschel
mesh_terms: D000328:Adult; D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000437:Alcoholism / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005858:Germany; D006801:Humans; D008297:Male; D005810:Multigene Family / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: C489332:ADH1B protein, human; C420272:ADH1C protein, human; D000426:Alcohol Dehydrogenase