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Keywords Human genetics Disease Genetic epidemiology Population studies Biomarkers Human Genome scans Complex diseaseSince the completion of the human genome project, therehas been a huge effort in establishing maps of geneticmarkers, especially of the most abundant source of DNAvariation, the single nucleotide polymorphism (SNP). Asubsequent major quest is to identify the variation in thehuman genome causally involved in the genetic etiology ofcomplex diseases and traits in concordance with environ-mental inuences such as nutrition. Genetic research ofcomplex traits (diseases, risk factors and intermediatephenotypes) requires large well-characterised study popu-lations of patients and healthy subjects. The aim is toidentify at which loci genetic similarity of study subjectscorresponds to phenotypic similarity. Genetic similaritycan be measured at different genotyping platforms thathave different specicities and an ever increasingthroughput of genotypes. Studies to explore which genesare involved in a trait include essentially two majorapproaches. In the hypothesis based approaches theinvolvement of candidate genes and pathways is beinginvestigated by testing for genetic association in order tond signicant frequency differences of marker alleles incases and controls. Alternatively, explorative approachesare applied which include genome-wide scans that rstlocalize the gene(s) and subsequently identify the causalgenetic variation at that locus. Genome-wide scans can beperformed by genetic association analysis or by linkageanalysis in related subjects from selected families (Fig. 1).A decade of family- and twin-based linkage studies hasrevealed the approximate location of numerous traits anddisease conditions [7, 2]. Regions of potential linkagecould be replicated only in some studies, however [1].Ample patient and population based studies revealedassociations of disease related phenotypes to patterns ofSNPs marking regions of linkage disequilibrium thatharbor the causal effects. In only a few studies, however,could the complex phenotype be assigned to the inuenceof common [11] or rare [6] functional gene variants. Thegenome-wide association scan (300,000–500,000 SNPsper subject) is currently the most complete assessment ofgenetic background that is still feasible in populationstudies [12, 13]. Such scans will identify common vari-ants contributing to a trait but the effect of rare variantswill be missed. In addition, the approach needs largesample sizes and various steps of replication to nd truepositive results because of the huge number of statisticaltests that are being performed. Clearly, the hypothesis andexplorative approaches in genetic studies each have theirlimitations.Demonstrating replication of ndings in genetic studiesof complex traits has been difcult for a number of reasons[1] of which the (small) sample size of studies is the mostfrequent item of concern. In addition replication dependson the phenotype denition, patient registries, the size andheterogeneity of the genetic component. Improvement ofthis situation may be expected by the identication offunctionally relevant SNPs in coding and regulatory

Molecular epidemiology, candidate genes versus genome-wide scans