Comparisons of multi-marker association methods to detect association between a candidate region and disease.
The joint use of information from multiple markers may be more effective to reveal association between a genomic region and a trait than single marker analysis. In this article, we compare the performance of seven multi-marker methods. These methods include (1) single marker analysis (either the best-scoring single nucleotide polymorphism in a candidate region or a combined test based on Fisher's method); (2) fixed effects regression models where the predictors are either the observed genotypes in the region, principal components that explain a proportion of the genetic variation, or predictors based on Fourier transformation for the genotypes; and (3) variance components analysis. In our simulation studies, we consider genetic models where the association is due to one, two, or three markers, and the disease-causing markers have varying allele frequencies. We use information from either all the markers in a region or information only from tagging markers. Our simulation results suggest that when there is one disease-causing variant, the best-scoring marker method is preferred whereas the variance components method and the principal components method work well for more common disease-causing variants. When there is more than one disease-causing variant, the principal components method seems to perform well over all the scenarios studied. When these methods are applied to analyze associations between all the markers in or near a gene and disease status for an inflammatory bowel disease data set, the analysis based on the principal components method leads to biologically more consistent discoveries than other methods.
Ballard
David H
DH
Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut 06511, USA. david.ballard@yale.edu
Cho
Judy
J
Zhao
Hongyu
H
D003198:Computer Simulation; D005583:Fourier Analysis; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D023281:Genomics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008957:Models, Genetic; D017720:Molecular Epidemiology / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis
D005819:Genetic Markers