Powerful Tests For Imprinting Effects And Haplotype-based Hardy-Weinberg Equilibrium

Motivation:Genomic imprinting is an important epigenetic phenomenon in studying complex traits and has generally been examined by detecting parent-of-origin effects of alleles. The parental-asymmetry test based on nuclear families with both parents and its extensions to deal with missing parental genotypes are simple and powerful for such a task. However, these methods only use case (affected) children in nuclear families and thus do not make full use of information on control (unaffected) children, if available, in these families. In addition, there have been many case-control studies proposed to test for association between haplotypes and disease recently, which require the Hardy-Weinberg equilibrium (HWE) assumption of haplotype frequencies. As such, haplotype inference of unphased genotypes and development of haplotype-based HWE tests are crucial prior to fine mapping. The goodness-of-fit test is a frequently-used method to test for HWE for multiple tightly-linked loci. However, its degrees of freedom dramatically increase with the increase of the number of loci, which may lack the test power.Methods:(1) We propose a novel parent-of-origin effects test C-PATu by using both the control and case children in nuclear families with one or both parents. C-PATu is essentially a weighted framework, in which the test based on all the control children and their parents and that based on all the case children and their parents are weighted according to the population disease prevalence.(2) To improve the test power for haplotype-based HWE, we first write out two likelihood functions of the observed data based on the Niu’s model (NM) and inbreeding model (IM), respectively, which can cause the departure from HWE. Then, we use two expectation-maximization algorithms and one expectation-conditional-maximization algorithm to estimate the model parameters under the HWE, IM and NM models, respectively. Finally, we propose the likelihood ratio tests LRT1and LRT2for haplotype-based HWE under the NM and IM models, respectively.Results:(1) Simulation results demonstrate that the proposed tests control the size well under no parent-of-origin effects and using additional information from control children improves the power of the tests under the imprinting alternative.(2) We simulate the HWE, Niu’s, inbreeding and population stratification models to assess the validity and compare the performance of these two LRT tests. The simulation results show that both of the tests control the type I error rates well in testing for haplotype-based HWE. If the NM model is true, then LRT1is more powerful. While, if the true model is the IM model, then LRT2has better performance in power. Under the population stratification model, LRT2is still more powerful.Conclusions:(1) C-PATu which incorporates the information of control children into analysis is valid in testing for imprinting effects and is more powerful than the existing methods.(2) LRT2is generally recommended for detecting haplotype-based HWE due to its better performance in power.