Linkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing

Abee L. Boyles, William K. Scott, Eden R. Martin, Silke Schmidt, Yi Ju Li, Allison Ashley-Koch, Meredyth P. Bass, Michael Schmidt, Margaret A. Pericak-Vance, Marcy C. Speer, Elizabeth R. Hauser

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Objectives: Describe the inflation in nonparametric multipoint LOD scores due to inter-marker linkage disequilibrium (LD) across many markers with varied allele frequencies. Method: Using simulated two-generation families with and without parents, we conducted non-parametric multipoint linkage analysis with 2 to 10 markers with minor allele frequencies (MAF) of 0.5 and 0.1. Results: Misspecification of population haplotype frequencies by assuming linkage equilibrium caused inflated multipoint LOD scores due to inter-marker LD when parental genotypes were not included. Inflation increased as more markers in LD were included and decreased as markers in equilibrium were added. When marker allele frequencies were unequal, the r2 measure of LD was a better predictor of inflation than D′. Conclusion: This observation strongly supports the evaluation of LD in multipoint linkage analyses, and further suggests that unaccounted for LD may be suspected when two-point and multipoint linkage analyses show a marked disparity in regions with elevated r2 measures of LD. Given the increasing popularity of high-density genome-wide SNP screens, inter-marker LD should be a concern in future linkage studies.

Original languageEnglish (US)
Pages (from-to)220-227
Number of pages8
JournalHuman Heredity
Volume59
Issue number4
DOIs
StatePublished - Aug 1 2005
Externally publishedYes

Keywords

  • False positive rate
  • Linkage analysis
  • Linkage disequilibrium
  • Measures of linkage disequilibrium
  • Parameter misspecification

ASJC Scopus subject areas

  • Genetics(clinical)

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