Likelihood Approach for Detecting Imprinting and In Utero Maternal Effects Using General Pedigrees from Prospective Family-Based Association Studies

摘要

Genetic imprinting and in utero maternal effects are causes of parent-of-origin effect but they are confounded with each other. Tests attempting to detect only one of these effects would have a severely inflated type I error rate if the assumption of the absence of the other effect is violated. Some existing methods avoid the potential confounding by modeling imprinting and in utero maternal effect simultaneously. However, these methods are not amendable to extended families, which are commonly recruited in family-based studies. In this article, we propose a likelihood approach for detecting imprinting and maternal effects (LIME) using general pedigrees from prospective family-based association studies. LIME formulates the probability of familial genotypes without the Hardy-Weinberg equilibrium assumption by introducing a novel concept called conditional mating type between marry-in founders and their nonfounder spouses. Further, a logit link is used to model the penetrance. To deal with the issue of incomplete pedigree genotypic data, LIME imputes the unobserved genotypes implicitly by considering all compatible ones conditional on the observed genotypes. We carried out a simulation study to evaluate the relative power and type I error of LIME and two existing methods. The results show that the use of extended pedigree data, even with incomplete information, can achieve much greater power than using nuclear families for detecting imprinting and in utero maternal effects without leading to inflated type I error rates.