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Comparative Study
. 2005 Sep;77(3):420-9.
doi: 10.1086/444472. Epub 2005 Aug 2.

A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-susceptibility loci

Gabrielle S Sellick  1 , Emily L Webb, Ruth Allinson, Estella Matutes, Martin J S Dyer, Viggo Jonsson, Anton W Langerak, Francesca R Mauro, Stephen Fuller, James Wiley, Matthew Lyttelton, Vincenzo Callea, Martin Yuille, Daniel Catovsky, Richard S Houlston
Affiliations
Comparative Study

A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-susceptibility loci

Gabrielle S Sellick et al. Am J Hum Genet. 2005 Sep.

Abstract

Chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders (LPDs) show clear evidence of familial aggregation, but the inherited basis is largely unknown. To identify a susceptibility gene for CLL, we conducted a genomewide linkage analysis of 115 pedigrees, using a high-density single-nucleotide polymorphism (SNP) array containing 11,560 markers. Multipoint linkage analyses were undertaken using both nonparametric (model-free) and parametric (model-based) methods. Our results confirm that the presence of high linkage disequilibrium (LD) between SNP markers can lead to inflated nonparametric linkage (NPL) and LOD scores. After the removal of high-LD SNPs, we obtained a maximum NPL of 3.14 (P=.0008) on chromosome 11p11. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under both dominant (HLOD 1.95) and recessive (HLOD 2.78) models. In addition, four other chromosomal positions (5q22-23, 6p22, 10q25, and 14q32) displayed HLOD scores >1.15 (which corresponds to a nominal P value <.01). None of the regions coincided with areas of common chromosomal abnormalities frequently observed for CLL. These findings strengthen the argument for an inherited predisposition to CLL and related B-cell LPDs.

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Figures

Figure 1
Figure 1
Distribution of pairwise D′ and r2 according to pairwise distance between SNP markers. The horizontal line shows the criterion used to define high-LD SNPs: r2>0.4.
Figure 2
Figure 2
Distribution of pairwise D′ and r2 in the data set
Figure 3
Figure 3
NPL scores across each chromosome. In each plot, the dashed line shows NPL statistics obtained using all SNPs (n=11,244), whereas the solid line shows NPL statistics obtained after exclusion of high-LD SNPs (n=9,276).
Figure 4
Figure 4
Plots of linkage statistics after the removal of high-LD SNPs for chromosomes 5, 6, 10, 11, and 14. HLOD scores under the dominant model are shown in black, HLOD scores under the recessive model are shown in red, and NPL P values transformed by formula image are shown in blue.
See this image and copyright information in PMC

References

Web Resources

    1. Affymetrix NetAffx, http://www.affymetrix.com/analysis/index.affx
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for CLL, NHL, HL, and AT)
    1. SNPLINK, http://www.icr.ac.uk/cancgen/molgen/MolPopGen_Bioinformatics.htm
    1. University of California–Santa Cruz Human Genome Browser, http://genome.ucsc.edu/cgi-bin/hgGateway

References

    1. Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101 - PubMed
    1. Bevan S, Catovsky D, Marossy A, Matutes A, Popat S, Antonovic P, Bell A, Berrebi A, Gaminara E, Quabeck K, Ribeiro I, Mauro FR, Stark P, Sykes H, van Dongen J, Wimperis J, Wright S, Yuille MR, Houlston RS (1999) Linkage analysis for ATM in familial B cell chronic lymphocytic leukaemia. Leukemia 13:1497–1500 - PubMed
    1. Cartwright RA, Bernard SM, Bird CC, Darwin CM, O’Brien C, Richards ID, Roberts B, McKinney PA (1987) Chronic lymphocytic leukaemia: case-control epidemiological study in Yorkshire. Brit J Cancer 56:79–82 - PMC - PubMed
    1. Devlin B, Risch N (1995) A comparison of linkage disequilibrium measure for fine-scale mapping. Genomics 29:311–322 - PubMed
    1. Evans DM, Cardon LR (2004) Guidelines for genotyping in genomewide linkage studies: single-nucleotide–polymorphism maps versus microsatellite maps. Am J Hum Genet 75:687–692 - PMC - PubMed

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