Are moment bounds on the recombination fraction between a marker and a disease locus too good to be true? Allelic association mapping revisited for simple genetic diseases in the Finnish population.

摘要

In the past several years, allelic association has helped map a number of rare genetic diseases in the human genome. A commonly used upper bound on the recombination fraction between the disease gene and an associated marker is known to be biased downward, so there is the possibility that an investigator could be misled. This upper bound is based on a moment equation that can be derived within the context of a Poisson branching process, so its performance can be compared with a recently proposed likelihood bound. We show that the confidence level of the moment upper bound is much lower than expected, while the confidence level of the likelihood bound is in line with expectation. The effects of mutation at either the marker or disease locus on the upper bounds are also investigated. Results indicate that mutation is not an important force for typical mutation rates, unless the recombination fraction between the marker and disease locus is very small or the disease allele is very rare in the general population. Finally, the impact of sample size on the likelihood bound is investigated. The results are illustrated with data on 10 simple genetic diseased in the Finnish population.