title: Linkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing.
abstract: 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.
authors.affiliation: Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Abee L
authors.initials: AL
authors.lastname: Boyles
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.forename: Silke
authors.initials: S
authors.lastname: Schmidt
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Li
authors.forename: Allison
authors.initials: A
authors.lastname: Ashley-Koch
authors.forename: Meredyth P
authors.initials: MP
authors.lastname: Bass
authors.forename: Michael
authors.initials: M
authors.lastname: Schmidt
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Marcy C
authors.initials: MC
authors.lastname: Speer
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
mesh_terms: 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
chemical_list: D005819:Genetic Markers