Linking genes to diseases: it's all in the data

Historically, disease phenotype has informed the selection of candidate disease genes through observations of the effects of perturbations in these candidates in vitro, in tissue cultures and in animal models. This hypothesis-driven approach is increasingly being superseded by genome-wide analyses that assume no prior knowledge of the underlying genotype, and hypotheses about the associated genes are inferred from large-scale genetic studies of samples with the disease phenotype. These studies include genome-wide linkage and association studies in affected and healthy patient populations to identify chromosomal regions most likely to contain etiological genes [1-3], and the detailed analysis of genome-wide changes in the disease state by high-throughput techniques, such as single nucleotide polymorphism (SNP) [4] and microarray expression analysis [5], serial analysis of gene expression (SAGE) [6] and cap analysis of gene expression (CAGE) [7]. Current approaches include next generation sequencing of linked regions, high-density SNP analysis and the study of copy number variation [8].Typically, genome-wide approaches generate large sets of potential genetic associations for further analysis; for example, multifactorial disease loci identified by linkage analysis can be approximately 30 Mb in size and contain several hundred genes [9]. This synergizes with ongoing research on many complex diseases, in which multiple gene variations, rather than single dysfunctional genes, are believed to underlie the disease phenotype [10]. Genome-wide analyses have therefore massively increased the number of candidate genes to be investigated for a given phenotype.Concurrently, available genetic information has increased as a result of more sophisticated experimental methods and centralization of genetic information in public genome databases (such as Ensembl [11], NCBI [12] and UCSC [13]), gene expression databases (such as GEO [14]) and human variation databases (such as HapMap [1