Gene-based Genomewide Association Analysis: A Comparison Study.

The study of gene-based genetic associations has gained conceptual popularity recently. Biologic insight into the etiology of a complex disease can be gained by focusing on genes as testing units. Several gene-based methods (e.g., minimum p-value (or maximum test statistic) or entropy-based method) have been developed and have more power than a single nucleotide polymorphism (SNP)-based analysis. The objective of this study is to compare the performance of the entropy-based method with the minimum p-value and single SNP-based analysis and to explore their strengths and weaknesses. Simulation studies show that: 1) all three methods can reasonably control the false-positive rate; 2) the minimum p-value method outperforms the entropy-based and the single SNP-based method when only one disease-related SNP occurs within the gene; 3) the entropy-based method outperforms the other methods when there are more than two disease-related SNPs in the gene; and 4) the entropy-based method is computationally more efficient than the minimum p-value method. Application to a real data set shows that more significant genes were identified by the entropy-based method than by the other two methods.