Abstract
BackgroundFor dichotomous traits, the generalized disequilibrium test with the moment estimate of the variance (GDT-ME) is a powerful family-based association method. Genomic imprinting is an important epigenetic phenomenon and currently, there has been increasing interest of incorporating imprinting to improve the test power of association analysis. However, GDT-ME does not take imprinting effects into account, and it has not been investigated whether it can be used for association analysis when the effects indeed exist.ResultsIn this article, based on a novel decomposition of the genotype score according to the paternal or maternal source of the allele, we propose the generalized disequilibrium test with imprinting (GDTI) for complete pedigrees without any missing genotypes. Then, we extend GDTI and GDT-ME to accommodate incomplete pedigrees with some pedigrees having missing genotypes, by using a Monte Carlo (MC) sampling and estimation scheme to infer missing genotypes given available genotypes in each pedigree, denoted by MCGDTI and MCGDT-ME, respectively. The proposed GDTI and MCGDTI methods evaluate the differences of the paternal as well as maternal allele scores for all discordant relative pairs in a pedigree, including beyond first-degree relative pairs. Advantages of the proposed GDTI and MCGDTI test statistics over existing methods are demonstrated by simulation studies under various simulation settings and by application to the rheumatoid arthritis dataset. Simulation results show that the proposed tests control the size well under the null hypothesis of no association, and outperform the existing methods under various imprinting effect models. The existing GDT-ME and the proposed MCGDT-ME can be used to test for association even when imprinting effects exist. For the application to the rheumatoid arthritis data, compared to the existing methods, MCGDTI identifies more loci statistically significantly associated with the disease.ConclusionsUnder complete and incomplete imprinting effect models, our proposed GDTI and MCGDTI methods, by considering the information on imprinting effects and all discordant relative pairs within each pedigree, outperform all the existing test statistics and MCGDTI can recapture much of the missing information. Therefore, MCGDTI is recommended in practice.
Highlights
For dichotomous traits, the generalized disequilibrium test with the moment estimate of the variance (GDT-ME) is a powerful family-based association method
Advantages of the proposed generalized disequilibrium test with imprinting (GDTI) and Monte Carlo GDTI (MCGDTI) test statistics over existing methods are demonstrated by simulation studies under various simulation settings and by application to the rheumatoid arthritis (RA) dataset [20]
Size and power Under 9 simulation settings given in Table 1, the empirical type I error rates of GDTI, MCGDTIT, MCGDTIE, MCGDT-MET, MCGDT-MEE, GDT-ME, GDT, MCPDTIT and MCPDTIE are demonstrated in Table 3, based on 90 and 150 pedigrees at the 1% significance level, respectively
Summary
The generalized disequilibrium test with the moment estimate of the variance (GDT-ME) is a powerful family-based association method. Genomic imprinting is an important epigenetic phenomenon and currently, there has been increasing interest of incorporating imprinting to improve the test power of association analysis. The pedigree disequilibrium test with imprinting (PDTI) and its extension Monte Carlo (MC) PDTI (MCPDTI) to accommodate pedigrees with missing genotypes were proposed to test for association, which consider the influence of imprinting on association study [17]. They only utilize the genotype differences between all firstdegree relative pairs in a family, which may reduce their test powers if ignoring the information on the genotype differences between beyond first-degree relatives
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