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A Powerful Test of Parent-of-Origin Effects for Quantitative Traits Using Haplotypes

By Rui Feng, Yinghua Wu, Gun Ho Jang, Jose M. Ordovas and Donna Arnett

Abstract

Imprinting is an epigenetic phenomenon where the same alleles have unequal transcriptions and thus contribute differently to a trait depending on their parent of origin. This mechanism has been found to affect a variety of human disorders. Although various methods for testing parent-of-origin effects have been proposed in linkage analysis settings, only a few are available for association analysis and they are usually restricted to small families and particular study designs. In this study, we develop a powerful maximum likelihood test to evaluate the parent-of-origin effects of SNPs on quantitative phenotypes in general family studies. Our method incorporates haplotype distribution to take advantage of inter-marker LD information in genome-wide association studies (GWAS). Our method also accommodates missing genotypes that often occur in genetic studies. Our simulation studies with various minor allele frequencies, LD structures, family sizes, and missing schemes have uniformly shown that using the new method significantly improves the power of detecting imprinted genes compared with the method using the SNP at the testing locus only. Our simulations suggest that the most efficient strategy to investigate parent-of-origin effects is to recruit one parent and as many offspring as possible under practical constraints. As a demonstration, we applied our method to a dataset from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to test the parent-of-origin effects of the SNPs within the PPARGC1A, MTP and FABP2 genes on diabetes-related phenotypes, and found that several SNPs in the MTP gene show parent-of-origin effects on insulin and glucose levels

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3236760
Provided by: PubMed Central

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Citations

  1. (1971). A general model for the genetic analysis of pedigree data.
  2. (2004). A haplotype-based test of association using data from cohort and nested case-control epidemiologic studies.
  3. (2003). A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting.
  4. (1992). Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.
  5. (2004). Affected-sib-pair test for linkage based on constraints for identical-by-descent distributions corresponding to disease models with imprinting.
  6. (2004). Algorithms for inferring haplotypes.
  7. (2007). Are Linkage Analysis and the Collection of Family Data Dead? Perspects for Family Studies in the Age of Genome-Wide Association.
  8. (2001). Assessment of parentof-origin effects in linkage analysis of quantitative traits.
  9. (2004). Case/pseudocontrol analysis in genetic association studies: A unified framework for detection of genotype and haplotype associations, gene-gene and gene-environment interactions, and parent-of-origin effects.
  10. (2006). ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver.
  11. (2001). Comparison of multivariate tests for genetic linkage.
  12. (1997). Comparison of sib-pair and variance-components methods for genomic screening.
  13. (1999). Comparison of variance components and sibpairbased approaches to quantitative trait linkage analysis in unselected samples.
  14. (2004). Conditional probability methods for haplotyping in pedigrees.
  15. (2007). Effects of glucose metabolism on the regulation of genes of fatty acid synthesis and triglyceride secretion in the liver.
  16. (1986). Effects of misspecifying genetic parameters in lod score analysis.
  17. (2003). Estimation and testing of parent-of-origin effects for quantitative traits.
  18. (1995). Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect.
  19. (2000). Exact multipoint quantitative-trait linkage analysis in pedigrees by variance components.
  20. (2007). Fenofibrate effect on triglyceride and postprandial response of apolipoprotein A5 variants: the GOLDN study.
  21. (2003). Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees.
  22. (2003). Genomic imprinting and linkage test for quantitative-trait Loci in extended pedigrees.
  23. (1999). Genomic imprinting: implications for human disease.
  24. (2005). Haploview: analysis and visualization of LD and haplotype maps.
  25. (2007). Imprinting detection by extending a regression-based QTL analysis method.
  26. (2010). Improved IBD detection using incomplete haplotype information.
  27. (1986). Localization of intracellular triacylglycerol and cholesteryl ester transfer activity in rat tissues.
  28. (2002). Merlin–rapid analysis of dense genetic maps using sparse gene flow trees.
  29. (1999). Methods for detection of parent-of-origin effects in genetic studies of case-parents triads.
  30. (1995). Microsomal triglyceride transfer protein (MTP) regulation in HepG2 cells: insulin negatively regulates MTP gene expression.
  31. (2002). Minimum-recombinant haplotyping in pedigrees.
  32. (1999). Multipoint genomic scanning for quantitative loci: effects of map density, sibship size and computational approach.
  33. (1996). Parametric and nonparametric linkage analysis: a unified multipoint approach.
  34. (2000). Parametric and nonparametric multipoint linkage analysis with imprinting and two-locus-trait models: application to mite sensitization.
  35. (1994). Parental origin of diabetesassociated HLA types in sibling pairs with type I diabetes.
  36. (2009). Parental origin of sequence variants associated with complex diseases.
  37. (1999). Petronis A
  38. (2001). Powerful SNP-set analysis for case-control genome-wide association studies.
  39. (2006). Quantifying genomic imprinting in the presence of linkage.
  40. (2006). Quantitative trait linkage analysis using Gaussian copulas.
  41. (1997). Statistical properties of a variance components method for quantitative trait linkage analysis in nuclear families and extended pedigrees.
  42. (2002). Testing for genetic linkage in families by a variancecomponents approach in the presence of genomic imprinting.
  43. (1996). The future of genetic studies of complex human diseases. Science 273: 1516–1517. Test of Parent-of-Origin Effects Using Haplotypes PLoS
  44. (2000). Zero-recombinant haplotyping: Applications to fine mapping using SNPs.

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