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A high-density SNP genome-wide linkage search of 206 families identifies susceptibility loci for chronic lymphocytic leukemia.

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posted on 2008-12-08, 16:21 authored by Gabrielle S. Sellick, Lynn R. Goldin, Ruth W. Wild, Susan L. Slager, Laura Ressenti, Sara S. Strom, Martin J. S. Dyer, Francesca R. Mauro, Gerald E. Marti, Stephen Fuller, Matthew Lyttelton, Thomas J. Kipps, Michael J. Keating, Timothy G. Call, Daniel Catovsky, Neil Caporaso, Richard S. Houlston
Chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders display familial aggregation. To identify a susceptibility gene for CLL we assembled families from the major European (ICLLC) and American (GEC) consortia to conduct a genome-wide linkage analysis of 101 new CLL pedigrees using a high-density single nucleotide polymorphism (SNP) array and combined the results with data from our previously reported analysis of 105 families. Here we report on the combined analysis of the 206 families. Multipoint linkage analyses were undertaken using both non-parametric (model-free) and parametric (model-based) methods. After the removal of high linkage disequilibrium SNPs we obtained a maximum NPL of 3.02 (P= 1.3 x 10-3) on chromosome 2q21.2. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a common recessive model of disease susceptibility (HLOD = 3.11; P= 7.7 x 10-5) which was significant at the genome-wide level. In addition, 2 other chromosomal positions 6p22.1 (corresponding to the major histocompatibility locus) and 18q21.1 displayed HLOD scores >2.1 (P < 0.002). None of the regions coincided with areas of common chromosomal abnormalities frequently observed in CLL. These findings provide direct evidence for Mendelian predisposition to CLL and evidence for the location of disease loci.

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Citation

Blood, 2007, 110 (9), pp. 3326-3333.

Published in

Blood

Publisher

American Society of Hematology

issn

0006-4971

Copyright date

2007

Available date

2008-12-08

Publisher version

http://www.bloodjournal.org/content/110/9/3326?sso-checked=true

Language

en

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