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.
Sellick
Gabrielle S
GS
Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, UK.
Goldin
Lynn R
LR
Wild
Ruth W
RW
Slager
Susan L
SL
Ressenti
Laura
L
Strom
Sara S
SS
Dyer
Martin J S
MJ
Mauro
Francesca R
FR
Marti
Gerald E
GE
Fuller
Stephen
S
Lyttelton
Matthew
M
Kipps
Thomas J
TJ
Keating
Michael J
MJ
Call
Timothy G
TG
Catovsky
Daniel
D
Caporaso
Neil
N
Houlston
Richard S
RS
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