The development of alcohol dependence has been proposed to be related to the metabolism of alcohol, so that the genes in alcohol metabolism pathway, e.g., alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes, are candidates for alcohol dependence. Alcohol dependence is, however, considered to be a brain disorder, so that the genes related to the neurotransmitters are also hypothesized to be candidate genes. These hypotheses help in finding many risk genes for alcohol dependence. Most of the risk genes implicated have been from (1) classical neurotransmitter signaling systems, including the dopaminergic (e.g., MAOA, COMT, and NCAM1-TTC12-ANKK1-DRD2), serotoninergic (e.g., SLC6A4 and HTR2B), GABAergic (e.g., GABRA2 and GABRG1), and cholinergic systems (e.g., CHRM2 and CHRNA5-CHRNA3-CHRNB4) (4); (2) non-classical neurotransmitter signaling systems (e.g., CRHR1) (5); (3) the ethanol metabolic pathway (e.g., ADH1B, ADH1C, ADH4, ADH5 and ALDH2) (6–8); and (4) the opioidergic signaling pathway (e.g., OPRM1, OPRD1 and OPRK1) (9) (reviewed by Zuo et al. (10)). With the development of genotyping technology and the significantly decreased costs, scientists have scanned the whole genome to search for risk genes since 2010. These data-driven genome-wide association studies (GWASs) found novel risk genes, breaking through the limitation of the need for an a priori hypothesis.
