Empirical assessment of the validity of the 'fundamental theorem of the HapMap' in the light of 'cryptic' tagging of multiple susceptibility loci

Underestimation of the sample size needed to detect genetic association may occur as a result of deviations from the 'fundamental theorem of the HapMap'. A biologically plausible mechanism that might cause this deviation is 'cryptic' tagging of multiple susceptibility loci by the same neutral marker. For complex disorders, the existence of multiple susceptibility loci on the same chromosome is probably the rule rather than the exception. Our results show that conditional on the known haplotype structure of the genome the probability that a tagging SNP that is in linkage disequilibrium (LD) with a susceptibility gene is also in LD with another susceptibility gene is not negligible. Consequently, we were able to estimate the extent and the prevalence of the bias in the necessary sample size to find association induced by 'cryptic' tagging. In general, the underestimation of the necessary sample size is modest: 5% of all association studies will underestimate the sample size by 5-30%. On the basis of our results, a safe bet is to use a sample that is 10% larger than otherwise deemed necessary.