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Ordered subset analysis in genetic linkage mapping of complex traits.

Publication ,  Journal Article
Hauser, ER; Watanabe, RM; Duren, WL; Bass, MP; Langefeld, CD; Boehnke, M
Published in: Genet Epidemiol
July 2004

Etiologic heterogeneity is a fundamental feature of complex disease etiology; genetic linkage analysis methods to map genes for complex traits that acknowledge the presence of genetic heterogeneity are likely to have greater power to identify subtle changes in complex biologic systems. We investigate the use of trait-related covariates to examine evidence for linkage in the presence of heterogeneity. Ordered-subset analysis (OSA) identifies subsets of families defined by the level of a trait-related covariate that provide maximal evidence for linkage, without requiring a priori specification of the subset. We propose that examining evidence for linkage in the subset directly may result in a more etiologically homogeneous sample. In turn, the reduced impact of heterogeneity will result in increased overall evidence for linkage to a specific region and a more distinct lod score peak. In addition, identification of a subset defined by a specific trait-related covariate showing increased evidence for linkage may help refine the list of candidate genes in a given region and suggest a useful sample in which to begin searching for trait-associated polymorphisms. This method provides a means to begin to bridge the gap between initial identification of linkage and identification of the disease predisposing variant(s) within a region when mapping genes for complex diseases. We illustrate this method by analyzing data on breast cancer age of onset and chromosome 17q [Hall et al., 1990, Science 250:1684-1689]. We evaluate OSA using simulation studies under a variety of genetic models.

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Published In

Genet Epidemiol

DOI

ISSN

0741-0395

Publication Date

July 2004

Volume

27

Issue

1

Start / End Page

53 / 63

Location

United States

Related Subject Headings

  • Sensitivity and Specificity
  • Nuclear Family
  • Models, Statistical
  • Models, Genetic
  • Male
  • Lod Score
  • Humans
  • Genetic Predisposition to Disease
  • Genetic Linkage
  • Genetic Heterogeneity
 

Citation

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Hauser, E. R., Watanabe, R. M., Duren, W. L., Bass, M. P., Langefeld, C. D., & Boehnke, M. (2004). Ordered subset analysis in genetic linkage mapping of complex traits. Genet Epidemiol, 27(1), 53–63. https://doi.org/10.1002/gepi.20000
Hauser, Elizabeth R., Richard M. Watanabe, William L. Duren, Meredyth P. Bass, Carl D. Langefeld, and Michael Boehnke. “Ordered subset analysis in genetic linkage mapping of complex traits.Genet Epidemiol 27, no. 1 (July 2004): 53–63. https://doi.org/10.1002/gepi.20000.
Hauser ER, Watanabe RM, Duren WL, Bass MP, Langefeld CD, Boehnke M. Ordered subset analysis in genetic linkage mapping of complex traits. Genet Epidemiol. 2004 Jul;27(1):53–63.
Hauser, Elizabeth R., et al. “Ordered subset analysis in genetic linkage mapping of complex traits.Genet Epidemiol, vol. 27, no. 1, July 2004, pp. 53–63. Pubmed, doi:10.1002/gepi.20000.
Hauser ER, Watanabe RM, Duren WL, Bass MP, Langefeld CD, Boehnke M. Ordered subset analysis in genetic linkage mapping of complex traits. Genet Epidemiol. 2004 Jul;27(1):53–63.
Journal cover image

Published In

Genet Epidemiol

DOI

ISSN

0741-0395

Publication Date

July 2004

Volume

27

Issue

1

Start / End Page

53 / 63

Location

United States

Related Subject Headings

  • Sensitivity and Specificity
  • Nuclear Family
  • Models, Statistical
  • Models, Genetic
  • Male
  • Lod Score
  • Humans
  • Genetic Predisposition to Disease
  • Genetic Linkage
  • Genetic Heterogeneity