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A Novel Approach to Detect Parent‐of‐Origin Effects from Pedigree Data with Application to Beckwith‐Wiedemann Syndrome
Author(s) -
Shete Sanjay,
Elston Robert C.,
Lu Yue
Publication year - 2007
Publication title -
annals of human genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.537
H-Index - 77
eISSN - 1469-1809
pISSN - 0003-4800
DOI - 10.1111/j.1469-1809.2007.00378.x
Subject(s) - penetrance , imprinting (psychology) , pedigree chart , genetics , genetic linkage , beckwith–wiedemann syndrome , genomic imprinting , proband , covariate , locus (genetics) , biology , evolutionary biology , statistics , gene , mutation , mathematics , phenotype , gene expression , dna methylation
Summary The parent‐of‐origin phenomenon in humans is now well recognized, and the deregulation of imprinted genes has been implicated in a number of human diseases. Recently, several linkage analysis methods have been developed to allow for parent‐of‐origin effects in the analysis of pedigree data. However, in general, one does not know a priori if disease‐causing loci are imprinted or not. Linkage methods that allow for imprinting can lose power if there is no imprinting. Conversely, linkage methods that do not allow for imprinting will lose power if there is imprinting, because of penetrance values not being correctly specified. Therefore, it is important to know whether imprinting is a possible mode of disease inheritance before performing linkage analyses. In this paper we describe a simple covariate‐coding scheme to test for the presence of parent‐of‐origin effects, and provide a formula for calculating parent‐specific penetrance values prior to any linkage analysis. In simulation studies our coding scheme successfully detected parent‐of‐origin effects and, when pedigrees were ascertained sequentially or through a single proband, inclusion of this covariate more accurately estimated penetrance values than when such a covariate was not included. The use of accurate penetrance values in a linkage analysis that allows for imprinting can provide higher power when the disease locus is imprinted. Finally, we applied our approach to 27 pedigrees affected with Beckwith‐Wiedemann syndrome (BWS), an overgrowth syndrome, and found that a maternally expressed parent‐of‐origin model based on the likelihood ratio test was the most parsimonious, suggesting a role for paternally imprinted genes in BWS.

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