Linkage Disequilibrium Inflates Type I Error Rates in Multipoint Linkage Analysis when Parental Genotypes Are MissingBoyles A.L. · Scott W.K. · Martin E.R. · Schmidt S. · Li Y.-J. · Ashley-Koch A. · Bass M.P. · Schmidt M. · Pericak-Vance M.A. · Speer M.C. · Hauser E.R.
Center for Human Genetics, Duke University Medical Center, Durham, N.C., USA
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.
© 2005 S. Karger AG, Basel
Received: November 19, 2004
Accepted after revision: May 6, 2005
Published online: July 26, 2005
Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 2, Number of References : 11
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 59, No. 4, Year 2005 (Cover Date: Released August 2005)
Journal Editor: Devoto, M. (Wilmington, Del.)
ISSN: 0001–5652 (print), 1423–0062 (Online)
For additional information: http://www.karger.com/hhe