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 1,333 male in-patients with severe DSM-IV AD and 2,168 controls. These included 487 patients and 1,358 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 SNP rs1789891, which is located between the ADH1B and ADH1C genes, achieved genome-wide significance (p=1.27E–8; 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 suggests that many more AD susceptibility genes still await identification.

Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder

“…The genetic contribution to vulnerability to develop alcohol or drug dependence has generally been estimated in the range 40-70%, depending on the substance, consistent with complex inheritance in which multiple genes exert a small effect of vulnerability or protection, A genetic meta-analysis D Li et al along with the environment (Frank et al, 2012;Gelernter and Kranzler, 2009;Goldman et al, 2005;Heath et al, 2011;Kendler et al, 2007;Wang et al, 2013). By analyzing potential associations between specific alleles and multiple substance phenotypes, our analyses may represent a necessary step toward identifying the effects of phenotypeinfluencing genes with improved certainty.…”

Genome-wide association analysis on five isolated populations identifies variants of the HLA-DOA gene associated with white wine liking

“…7,10,11 The relevant role of genetic factors both on alcohol consumption and dependence has been clearly demonstrated by genome-wide association study (GWAS) studies. [12][13][14][15][16] Moreover, studies on the genetic variations in bitter taste receptors have also shown that variations in TAS2R16 and TAS2R38 genes can influence alcohol intake [17][18][19] but not dependence. 19 On the contrary, very little is known about the possible contribution of genetic factors to alcohol preferences in humans.…”

What is in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

“…flush, nausea, and sweating) which reduces the likelihood of continued EtOH consumption (Peng and Yin, 2009). Recent research has established a polygenic contribution of the ADH gene cluster outlining a likely role for several ADH genes in the development of alcoholism (Frank et al, 2011). Alterations in the ALDH2 gene, and the subsequent increase in ACD following EtOH consumption, have been thoroughly documented as protective in nature, with regard to the development of alcoholism amongst Asian populations (Ball, 2008).…”