Large meta-analysis studies and systematic reviews have shown that at best no more than half of original associations can be consistently replicated. This lack of consistency is widely recognized limitation of the association studies. The explanation for why the results of HLA-associations vary between cohorts includes mistakes in genotyping (deviation from Hardy-Weinberg equilibrium) in controls is usually an indication of problems with typing rather than selection, admixture, non-random mating or other reasons for violation of Hardy-Weinberg equilibrium, poor control selection, design problems including statistical power issue (negative results due to lack of statistical power should be distinguished from truly negative results), publication bias, disease misclassification or misclassification bias, excessive type I errors, unjustified multiple comparisons, failure to consider the mode of inheritance in a genetic disease and likelihood that the gene studied account for a small proportion of the variability in risk and true variability in risk and true variability among different populations in allele frequencies.
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