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

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

doi:10.1182/blood-2007-05-091561

Abstract

AbstractChronic 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 × 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.

Highlights

Following publication of 2 previous linkage studies that failed to identify significant linkage, we combined the extant families from diverse institutions worldwide, and 2 existing consortia, to generate the largest collection of familial Chronic lymphocytic leukemia (CLL) to date
Our results provide evidence for a major susceptibility locus on chromosome 2 influencing the risk of CLL—with characteristics consistent with an autosomal recessive model of inheritance
We did not find any significant evidence for linkage in the combined dataset to any of the regions of the genome commonly associated with cytogenetically detectable chromosomal losses (6q, 13q14, or 17p) or gains in CLL.[25,26,27]

Summary

Introduction

In 2005, a second genome-wide scan of 105 families segregating CLL with or without additional B-cell LPD cases was conducted using the Affymetrix Mapping 10Kv131 array, which contained approximately 11 500 single nucleotide polymorphisms (SNPs).[12] In both studies, analyses provided evidence for susceptibility at a number of loci, but none achieved statistical significance, suggesting that a much larger familial sample was required to identify CLL predisposition loci. A genome-wide linkage search of the 101 families in phase 2 was undertaken using the GeneChip Mapping 10K 2.0 Xba Array containing approximately 10 200 SNP markers (Affymetrix, Santa Clara, CA).

Results

Conclusion