Linkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing.
Title | Linkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing. |
Publication Type | Journal Article |
Year of Publication | 2005 |
Authors | Boyles, AL, Scott, WK, Martin, ER, Schmidt, S, Li, Y-J, Ashley-Koch, A, Bass, MP, Schmidt, M, Pericak-Vance, MA, Speer, MC, Hauser, ER |
Journal | Hum Hered |
Volume | 59 |
Issue | 4 |
Pagination | 220-7 |
Date Published | 2005 |
ISSN | 0001-5652 |
Keywords | Computer 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. |
DOI | 10.1159/000087122 |
Alternate Journal | Hum. Hered. |
PubMed ID | 16093727 |
PubMed Central ID | PMC1224705 |
Grant List | NS39818 / 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 |