Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Germany.
Addiction Biology (Impact Factor: 5.36). 01/2012; 17(1):171-80. DOI: 10.1111/j.1369-1600.2011.00395.x
Source: PubMed


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.

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    • "vidence that vari - ants in these two genes independently affect drinking habits in European populations ( Tolstrup et al . 2008 ; Macgregor et al . 2009 ) . Finally , in a recent GWAS undertaken in a large population of German men , only one SNP , rs1789891 , which is located between ADH1B and ADH1C , achieved genome - wide significance for ADS ( Frank et al . 2012 ) ."
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    • "Moreover, another GWAS of African-Americans and European-Americans, combining evidence from the case–control and follow-up study, suggested the association of a cluster of genes on chromosome 11 with AD (Edenberg et al. 2010). In a GWAS of people of German descent, rs1789891, which is located between ADH1B and ADH1C and tightly linked with the function of ADH1C R272Q, was observed to be significantly associated with the risk of AD (Frank et al. 2011). However, a few results from GWASs have not found genome-wide significance (Bierut et al. 2010; Edenberg et al. 2010) or failed to replicate their association in independent samples (Bierut et al. 2010). "
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