Inferring Haplotype/Disease Association by Joint Use of Case-Parents Trios and Case-Parent Pairs

Abstract

Recently interest has been increasing in genetic association studies using several closely linked loci. The HAP-TDT method, which uses case-parents trios is powerful for such a task. However, it is not uncommon in practice that one parent is missing for some reason, such as late onset. The case-parents trios are thus reduced to case-parent pairs. Discarding such data could lead to a severe loss of power. In this paper, we propose the HAP-1-TDT method based on case-parent pairs to detect haplotype/disease association. A permutation-based randomisation technique is devised to assess the significance of the test statistic. Furthermore, the combined statistic HAP-C-TDT is developed to use jointly case-parents trios and case-parent pairs. These test statistics can be applied to either phase-known or phase-unknown data. A number of simulation studies are conducted to investigate the validity of the proposed tests; these studies show that the statistics are robust to population structure. Using several disease genes from the literature, we illustrate that incorporating case-parent pairs into an association study leads to noticeable power gain. Moreover, our simulation results suggest that our method has better size and power than UNPHASED. Finally, in simulated scenarios where there are only a few SNPs and risk is determined by two haplotypes that are complementary or near-complementary, our method has better power than TRIMM. © 2010 The Authors Journal compilation © 2010 Blackwell Publishing Ltd/University College London.