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Originally published as Genetics Published Articles Ahead of Print on December 6, 2006.
Genetics, Vol. 175, 763-776, February 2007, Copyright © 2007
doi:10.1534/genetics.106.058164
Simulations Provide Support for the Common Disease–Common Variant Hypothesis
Bo Peng*,1 and
Marek Kimmel*,
* Department of Statistics, Rice University, Houston, Texas 77005 and Institute of Automation, Silesian Technical University, 44-100 Gliwice, Poland
1 Corresponding author: Department of Epidemiology, University of Texas, M. D. Anderson Cancer Center, 1155 Pressler Blvd., Unit 1340, Houston, TX 77030.
E-mail: bpeng{at}mdanderson.org
The success of mapping genes involved in complex diseases, using association or linkage disequilibrium methods, depends heavily on the number and frequency of susceptibility alleles of these genes. These methods will be economically and statistically feasible if common diseases are usually influenced by one or a few susceptibility alleles at each locus (common disease–common variant, CDCV, hypothesis), but not so if there is a high degree of allelic heterogeneity. Here, we use forward-time population simulations to investigate the impact of various genetic and demographic factors on the allelic spectra of human diseases, on the basis of two models proposed by Reich and Lander and by Pritchard. Factors considered are more complex demographies, a finite-allele mutation model, population structure and migration, and interaction between disease susceptibility loci. The conclusion is that the CDCV hypothesis holds and that the phenomenon is caused by transient effects of demography (population expansion). As a result, we devise a multilocus generalization of the Reich and Lander model and demonstrate how interaction between loci with respect to their response to selection may lead to complex effects. We discuss the implications for mapping of complex diseases.
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