A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-susceptibility loci.
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.
Sellick
Gabrielle S
GS
Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom.
Webb
Emily L
EL
Allinson
Ruth
R
Matutes
Estella
E
Dyer
Martin J S
MJ
Jonsson
Viggo
V
Langerak
Anton W
AW
Mauro
Francesca R
FR
Fuller
Stephen
S
Wiley
James
J
Lyttelton
Matthew
M
Callea
Vincenzo
V
Yuille
Martin
M
Catovsky
Daniel
D
Houlston
Richard S
RS
D005060:Europe / Q000453:epidemiology; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000453:epidemiology / Q000235:genetics*; D008126:Lod Score; D008957:Models, Genetic; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide