The influence of ADH variations on risk was further investigated through linkage studies performed in non-Asian families. These analyses detected linkage of alcoholism to a broad region on chromosome 4q that included the ADH gene cluster (Long et al. 1998; Prescott et al. 2006; Reich 1996; Reich et al. 1998; Williams et al. 1999). Given the strong prior evidence for the role of the ADH genes in alcoholism susceptibility, the COGA investigators initially focused on the 262 families from the study with a very strong history of alcoholism. In these families, they determined the genotype for 110 DNA markers known as single-nucleotide polymorphisms (SNPs), which were distributed throughout the ADH gene cluster. These analyses detected significant evidence of association of alcoholism with 12 SNPs located in and around the ADH4 gene (Edenberg et al. 2006) and modest evidence of association with noncoding SNPs5 in ADH1A and ADH1B. Moreover, the analyses provided evidence that the ADH1B*3 allele was protective among African-American families (Edenberg et al. 2006). The association of several noncoding ADH polymorphisms with alcohol dependence has been replicated in other studies (Edenberg 2007; Macgregor et al. 2009).
