Prospects for association-based fine mapping of a susceptibility gene for a complex disease.
The potential of association studies for fine-mapping loci with common disease susceptibility alleles for complex genetic diseases in outbred populations is unclear. For a battery of tightly linked anonymous genetic markers spanning a candidate region centered around a disease locus, simulation methods based on a coalescent process with mutation, recombination, and genetic drift were used to study the spatial distribution of markers with large noncentrality parameters in a case-control study design. Simulations with a disease allele at intermediate frequency, presumably representing an old mutation, tend to exhibit the largest noncentrality parameter values at markers near the disease locus. In contrast, simulations with a disease allele at low frequency, presumably representing a young mutation, often exhibit the largest noncentrality parameter values at markers scattered over the candidate region. In the former case, sample sizes or marker densities sufficient to detect association are likely to lead to useful localization, whereas, in the latter case, localization of the disease locus within the candidate region is much less likely, regardless of the sample size or density of the map. The simulations suggest that for a single marker analysis, the simple strategy of choosing the marker with smallest associated P value to begin a laboratory search for the disease locus performs adequately for a common disease allele.
Kaplan
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Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Morris
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R
D000483:Alleles; D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic
D005819:Genetic Markers