Ordered-subset analysis (OSA) for family-based association mapping of complex traits

Ren Hua Chung, Sike Schmidt, Eden R. Martin, Elizabeth R. Hauser

Research output: Contribution to journalArticle

9 Scopus citations


Association analysis provides a powerful tool for complex disease gene mapping. However, in the presence of genetic heterogeneity, the power for association analysis can be low since only a fraction of the collected families may carry a specific disease susceptibility allele. Ordered-subset analysis (OSA) is a linkage test that can be powerful in the presence of genetic heterogeneity. OSA uses trait-related covariates to identify a subset of families that provide the most evidence for linkage. A similar strategy applied to genetic association analysis would likely result in increased power to detect association. Association in the presence of linkage (APL) is a family-based association test (FBAT) for nuclear families with multiple affected siblings that properly infers missing parental genotypes when linkage is present. We propose here APL-OSA, which applies the OSA method to the APL statistic to identify a subset of families that provide the most evidence for association. A permutation procedure is used to approximate the distribution of the APL-OSA statistic under the null hypothesis that there is no relationship between the family-specific covariate and the family-specific evidence for allelic association. We performed a comprehensive simulation study to verify that APL-OSA has the correct type I error rate under the null hypothesis. This simulation study also showed that APL-OSA can increase power relative to other commonly used association tests (APL, FBAT and FBAT with covariate adjustment) in the presence of genetic heterogeneity. Finally, we applied APL-OSA to a family study of age-related macular degeneration, where cigarette smoking was used as a covariate.

Original languageEnglish (US)
Pages (from-to)627-637
Number of pages11
JournalGenetic Epidemiology
Issue number7
StatePublished - Dec 1 2008



  • Covariate
  • Family-based association analysis
  • Genetic heterogeneity
  • Linkage
  • Ordered-subset analysis

ASJC Scopus subject areas

  • Genetics(clinical)
  • Epidemiology

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