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

  • Boyles A
  • Scott W
  • Martin E
 et al. 
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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 nonparametric 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.

Author-supplied keywords

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

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  • Abee L. Boyles

  • William K. Scott

  • Eden R. Martin

  • Silke Schmidt

  • Yi Ju Li

  • Allison Ashley-Koch

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