title: A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-susceptibility loci.
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.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Gabrielle S
authors.initials: GS
authors.lastname: Sellick
authors.forename: Emily L
authors.initials: EL
authors.lastname: Webb
authors.forename: Ruth
authors.initials: R
authors.lastname: Allinson
authors.forename: Estella
authors.initials: E
authors.lastname: Matutes
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.forename: Viggo
authors.initials: V
authors.lastname: Jonsson
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Mauro
authors.forename: Stephen
authors.initials: S
authors.lastname: Fuller
authors.forename: James
authors.initials: J
authors.lastname: Wiley
authors.forename: Matthew
authors.initials: M
authors.lastname: Lyttelton
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Callea
authors.forename: Martin
authors.initials: M
authors.lastname: Yuille
authors.forename: Daniel
authors.initials: D
authors.lastname: Catovsky
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: 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