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

TitleLinkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing.
Publication TypeJournal Article
Year of Publication2005
AuthorsBoyles AL, Scott WK, Martin ER, Schmidt S, Li Y-J, Ashley-Koch A, Bass MP, Schmidt M, Pericak-Vance MA, Speer MC, Hauser ER
JournalHum Hered
Volume59
Issue4
Pagination220-7
Date Published2005
ISSN0001-5652
KeywordsComputer Simulation, False Positive Reactions, Gene Frequency, Genetic Linkage, Genetic Markers, Genotype, Humans, Linkage Disequilibrium, Lod Score, Nuclear Family, Parents, Statistics, Nonparametric
Abstract

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.

DOI10.1159/000087122
Alternate JournalHum. Hered.
PubMed ID16093727
PubMed Central IDPMC1224705
Grant ListNS39818 / NS / NINDS NIH HHS / United States
ES11375 / ES / NIEHS NIH HHS / United States
AG19757 / AG / NIA NIH HHS / United States
U19 ES011375 / ES / NIEHS NIH HHS / United States
P01 NS026630 / NS / NINDS NIH HHS / United States
MH59528 / MH / NIMH NIH HHS / United States
P01 HD039948 / HD / NICHD NIH HHS / United States
NS26630 / NS / NINDS NIH HHS / United States
R01 HL073389 / HL / NHLBI NIH HHS / United States
P30 ES011961 / ES / NIEHS NIH HHS / United States
EY015216 / EY / NEI NIH HHS / United States
R01 NS039818 / NS / NINDS NIH HHS / United States
R03 EY015216 / EY / NEI NIH HHS / United States
R01 AG021547 / AG / NIA NIH HHS / United States
R01 AG019757 / AG / NIA NIH HHS / United States
R01 MH059528 / MH / NIMH NIH HHS / United States
ES11961 / ES / NIEHS NIH HHS / United States
HD39948 / HD / NICHD NIH HHS / United States
HL073389 / HL / NHLBI NIH HHS / United States
AG021547 / AG / NIA NIH HHS / United States