A powerful genome-wide feasible approach to detect parent-of-origin effects in studies of quantitative traits

There is currently a lot of interest in the role of genomic imprinting in mammalian development. Many human diseases, such as cancer, obesity, diabetes and behavioral traits, may be related to imprinted genes. When searching for genes related to complex disorders, the power of genome-wide association analysis can be improved by introducing parent-of-origin effects into the analyses. For quantitative traits, family-based TDT analysis has successfully implemented such an approach. Although attractive for several reasons, TDT-based tests are known to be less powerful than methods based on measured genotype approaches. In this study, we describe a fast, powerful method for detecting parent-of-origin effects in studies of quantitative traits using a measured genotype framework. First, for each locus studied, we estimate the probabilities of an allele's parental origin using multipoint haplotype reconstruction. Next, we introduce the parental origin of these alleles as a covariate in regression models during the second step of GRAMMAR, a fast approximation to the measured genotype approach. We show that, compared with a TDT-based analysis, our method has a higher power to detect a locus exhibiting a parent-of-origin effect. Moreover, our method is applicable to a wider range of data, including pedigree structures that are not very informative for TDT. The method gives no false positives in the absence of parent-of-origin effects, under both additive and dominant models. As this method is an extension of the rapid GRAMMAR analysis, it is fast enough to be suitable for genome-wide association scans.