Recently, the most fruitful work has focused on candidate genes that map within linkage peaks. Some of the best-supported AD risk loci map to two different regions of chromosome 4: an ADH gene cluster, which maps to the long arm, and a GABAA receptor subunit gene cluster, which maps to the short arm of the chromosome. As mentioned above, several genomewide linkage scans have implicated a region of chromosome 4q that contains an ADH gene cluster, and this prompted more intensive investigation of the ADHs. ADH4 (Luo et al. 2005a, b, 2006; Edenberg et al. 2006) is one of several disease-influencing loci in this cluster. Edenberg et al. (1999) demonstrated that the −75A allele, at a promoter polymorphic site in ADH4, has promoter activity that is more than twice that of the −75C allele. We reported strong associations of ADH4 markers to AD using a range of methods, including Hardy–Weinberg disequilibrium analysis, structured association, and family based association (Luo et al. 2005a, b). We have also reported association to AD of numerous other loci in the ADH cluster (Luo et al. 2006).
