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Linkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing
Abee L Boyles1, William K Scott, Eden R Martin
1Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA.
Human Heredity
|August 12, 2005
Summary
Linkage disequilibrium (LD) inflates nonparametric multipoint LOD scores when haplotype frequencies are misspecified. Evaluating LD is crucial for accurate linkage analysis, especially with high-density SNP screens.
Area of Science:
- Genetics
- Statistical genetics
Background:
- Nonparametric multipoint linkage analysis is a common tool in genetic studies.
- Linkage disequilibrium (LD) can potentially affect the accuracy of linkage analysis results.
Purpose of the Study:
- To describe the inflation of nonparametric multipoint LOD scores caused by inter-marker LD.
- To investigate the impact of varied allele frequencies on this inflation.
Main Methods:
- Simulated two-generation families (with and without parents) were used.
- Nonparametric multipoint linkage analysis was performed with 2 to 10 markers.
- Minor allele frequencies (MAF) of 0.5 and 0.1 were simulated.
Main Results:
- Misspecifying haplotype frequencies by assuming linkage equilibrium inflated multipoint LOD scores due to inter-marker LD when parental genotypes were absent.
- Inflation increased with more linked markers and decreased with markers in equilibrium.
- The r2 measure of LD better predicted inflation than D' when marker allele frequencies were unequal.
Conclusions:
- Evaluating LD is essential in multipoint linkage analyses.
- Disparities between two-point and multipoint analyses in regions with high r2 may indicate unaccounted LD.
- Inter-marker LD is a significant concern for high-density genome-wide SNP screens and future linkage studies.