A high-density SNP genome-wide linkage search of 206 families identifies susceptibility loci for chronic lymphocytic leukemia.
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 nonparametric (model-free) and parametric (model-based) methods. After the removal of high linkage disequilibrium SNPs, we obtained a maximum nonparametric linkage (NPL) score of 3.02 (P = .001) 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 higher than 2.1 (P < .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.
Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, UK.
Gabrielle S
GS
Sellick
Lynn R
LR
Goldin
Ruth W
RW
Wild
Susan L
SL
Slager
Laura
L
Ressenti
Sara S
SS
Strom
Martin J S
MJ
Dyer
Francesca R
FR
Mauro
Gerald E
GE
Marti
Stephen
S
Fuller
Matthew
M
Lyttelton
Thomas J
TJ
Kipps
Michael J
MJ
Keating
Timothy G
TG
Call
Daniel
D
Catovsky
Neil
N
Caporaso
Richard S
RS
Houlston
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D002877:Chromosomes, Human; D004252:DNA Mutational Analysis / Q000379:methods; D005190:Family; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide