The genetic basis of alcoholism: multiple phenotypes, many genes, complex networks

Abstract

Alcoholism is a significant public health problem. A picture of the genetic architecture underlying alcohol-related phenotypes is emerging from genome-wide association studies and work on genetically tractable model organisms.

Figure 1

Alcohol metabolism. Ethanol is converted to acetaldehyde by alcohol dehydrogenase (ADH) and subsequently to acetate by aldehyde dehydrogenase (ALDH). Acetate is conjugated to coenzyme A and the resulting acetyl-CoA can be metabolized in the Krebs cycle, or utilized for the synthesis of fatty acids. In addition, a small fraction of ethanol is metabolized by cytochrome P450 2E1 (CYP2E1) and in the brain by catalase. The diagram presents only those members of the ADH and ALDH families referred to in the text. Accumulation of acetaldehyde is responsible for the physiological malaise commonly known as 'hangover'.

Figure 2

The malic enzyme metabolic switch. Malic enzyme mediates the conversion of malate to pyruvate, which is accompanied by the production of NADPH. NADPH is a necessary cofactor for the biosynthesis of fatty acids along with acetyl-CoA, generated by the metabolism of ethanol. The diagram highlights auxiliary pathways for the biosynthesis of fatty acids. Pyruvate carboxylase and malic enzyme mediate a cyclic metabolic pathway, which via the mitochondrial citrate and pyruvate transporters results in the transport of acetyl-CoA across the mitochondrial membrane and generation of cytosolic NADPH. An alternative metabolic pathway is the direct conversion of pyruvate into acetyl-CoA via the pyruvate dehydrogenase complex. This metabolic switch channels excess metabolic energy into the synthesis of fatty acids and contributes to the development of fatty liver syndrome during excessive alcohol consumption. Modified from [94].