Genome-wide association studies: providers of candidate genes for identification of rare variants?

Classical linkage analysis is a powerful approach to associate new genes with disease without any a priori pathophysiological hypothesis. Linkage analysis evaluates markers widely spaced across the genome to determine whether they are inherited along with disease in families with numerous affected individuals. Using this strategy, several ion channel-encoding genes have been associated with monogenic electrophysiological disorders including the identification of KCNQ1 as a gene underlying familial atrial fibrillation (AF).1 This approach may not, however, be generally applicable since in many cases the size of the affected family is too small. Consequently, some researchers have resorted to candidate gene analysis for identification of new genes underlying AF.2 Success of the candidate gene approach relies strongly on a relevant prior hypothesis. However, although some pathways are highly suspected to play a role in pre-disposition to arrhythmia, unknown mechanisms are also very likely involved. Over the last years we have seen a flurry of genome-wide association studies (GWAS) in the literature addressing a number of electrophysiological and arrhythmia phenotypes. In these studies, single-nucleotide polymorphisms (SNPs) that are relatively common in the general population are tested for association with the phenotype of interest. This approach has also been applied to AF and has …