Linkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing.
OBJECTIVE
Describe the inflation in nonparametric multipoint LOD scores due to inter-marker linkage disequilibrium (LD) across many markers with varied allele frequencies.


METHODS
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'.


CONCLUSIONS
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.
Boyles
Abee L
AL
Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA.
Scott
William K
WK
Martin
Eden R
ER
Schmidt
Silke
S
Li
Yi-Ju
YJ
Ashley-Koch
Allison
A
Bass
Meredyth P
MP
Schmidt
Michael
M
Pericak-Vance
Margaret A
MA
Speer
Marcy C
MC
Hauser
Elizabeth R
ER
D003198:Computer Simulation; D005189:False Positive Reactions; D005787:Gene Frequency; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D009679:Nuclear Family; D010290:Parents; D018709:Statistics, Nonparametric
D005819:Genetic Markers