Detection of parent-of-origin effects using general pedigree data

Abstract

Genomic imprinting is an important epigenetic factor in complex traits study, which has generally been examined by testing for parent-of-origin effects of alleles. For a diallelic marker locus, the parental-asymmetry test (PAT) based on case-parents trios and its extensions to incomplete nuclear families (1-PAT and C-PAT) are simple and powerful for detecting parent-oforigin effects. However, these methods are suitable only for nuclear families and thus are not amenable to general pedigree data. Use of data from extended pedigrees, if available, may lead to more powerful methods than randomly selecting one two-generation nuclear family from each pedigree. In this study, we extend PAT to accommodate general pedigree data by proposing the pedigree PAT (PPAT) statistic, which uses all informative family trios from pedigrees. To fully utilize pedigrees with some missing genotypes, we further develop the Monte Carlo (MC) PPAT (MCPPAT) statistic based on MC sampling and estimation. Extensive simulations were carried out to evaluate the performance of the proposed methods. Under the assumption that the pedigrees and their associated affection patterns are randomly drawn from a population of pedigrees with at least one affected offspring, we demonstrated that MCPPAT is a valid test for parent-of-origin effects in the presence of association. Further, MCPPAT is much more powerful compared to PAT for trios or even PPAT for all informative family trios from the same pedigrees if there is missing data. Application of the proposed methods to a rheumatoid arthritis dataset further demonstrates the advantage of MCPPAT. © 2009 Wiley-Liss, Inc.