A handful of susceptibility genes for common and complex diseases such as BRCA1 and BRCA2 in breast cancer (19,20), Calpain10 in NIDDM (21), NOD2 in Crohn's disease (22,23), Neuregulin 1 in schizophrenia (24), and ADAM33 in asthma (25) have been identified. Despite these successes, linkage studies of complex diseases have been difficult to replicate. A review of the linkage findings of 31 complex human diseases based on whole genome scan concluded that genetic localization of most susceptibility loci is still imprecise and difficult to replicate (26).
This difficulty is, in part, because of the inability to measure the precise underlying phenotype, small sample sizes, genetic heterogeneity, inaccurate genetic model, and statistical methods employed in analysis. In another similar review, Hirschhorn et al. (27) reviewed genetic association studies and concluded that only a few were reproducible. Success has been elusive because almost all complex diseases are the combination of multiple genes and environmental factors. Unlike the so-called monogenic diseases, there is no "smoking gun," that is, associated disease mutations obviously deleterious to protein function. Instead, there are likely to be alleles with subtle functional changes that are neither necessary nor sufficient to cause disease.
Replication of initial linkage signals from independent samples is considered an important and crucial step toward distinguishing between true positives and false positives (28). The basis of all scientific research is hypothesis testing and validation of results by independent researchers or data. Independent replication is typically viewed as the sine qua non for accepting a hypothesis, but this is an extremely difficult issue in genetic studies for a complex disease, especially when genetic effects are weak and possibly context dependent (e.g., incidence may vary by sex, ethnicity, or precision of diagnosis), even with a reasonably large sample (29,30).
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