Issues concerning association studies for fine mapping a susceptibility gene for a complex disease

Genetic Epidemiology
N L Kaplan, R Morris

Abstract

The usefulness of association studies for fine mapping loci with common susceptibility alleles for complex genetic diseases in outbred populations is unclear. We investigate this issue for a battery of tightly linked anonymous genetic markers spanning a candidate region centered around a disease locus, and study the joint behavior of chi-square statistics used to discover and to localize the disease locus. We used simulation methods based on a coalescent process with mutation, recombination, and genetic drift to examine 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 cases, 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 candi...Continue Reading

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Citations

Sep 2, 2003·Theoretical Population Biology·Martin O'Hely, Montgomery Slatkin
Jun 27, 2003·Lancet·Stephen B Harrap
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Sep 16, 2004·Genetic Epidemiology·Andrew G Clark
Jun 9, 2004·Genetic Epidemiology·Weiwei ZhaiRasmus Nielsen
May 10, 2007·Genetic Epidemiology·Zhaoxia Yu, Daniel J Schaid

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