Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk

Abstract

To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.39; P = 2.11 x 10(-9)), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 x 10(-10)), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 x 10(-7)) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 x 10(-7)). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 x 10(-6)) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 x 10(-6)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy.

Figure 1. Forest plots of effect size and direction for the SNPs associated with CLL risk. (a) 2q37.3 (rs757978), (b) 8q24.21 (rs2456449), (c) 15q21.3 (rs7169431), (d) 16q24.1 (rs305061).

Boxes denote OR point estimates, their areas being proportional to the inverse variance weight of the estimate. Horizontal lines represent 95% confidence intervals. The diamond (and broken line) represents the summary OR computed under a fixed effects model, with 95% confidence interval given by the width of the diamond. The unbroken vertical line is at the null value (OR = 1.0).

Figure 2. Four previously unidentified loci, 2q37.3, 8q24.21, 15q21.3, and 16q24.1 showing genome-wide level of evidence of association to CLL.

(a) Illustration of the 2q37.3 locus, with the local recombination rate plotted in light blue over this 600-kb chromosomal segment centered on rs757978. Each square represents a SNP found in this locus and the most associated SNP in the combined analysis, rs757978, is marked by a blue diamond. The color intensity of each square reflects the extent of LD with rs757978 - red (r² > 0.8) through to white (r² < 0.3). Physical positions are based on build 36 of the human genome. rs757978 is located in exon 9 of FARP2. (b) Illustration of the 8q24.21 locus, with the most associated SNP in this locus, rs2456449, highlighted by a blue diamond. Here, we also present all SNPs found within a 600-kb window centered on rs2456449 and define SNP colors based on LD with rs2456449. (c) Illustration of the 15q21.3 locus, with the most associated SNP in this locus, rs7169431, highlighted by a blue diamond. Here, we also present all SNPs found within a 600-kb window centered on rs7169431 and define SNP colors based on LD with rs7169431. NEDD4 and RFXDC2 map centromeric and telomeric to rs7169431. (d) Illustration of the 16q24.1 locus, with the most associated SNP in this locus, rs305061, highlighted by a blue diamond. Here, we also present all SNPs found within a 600-kb window centered on rs305061 and define SNP colors based on LD with rs305061. In this case, IRF8 is the only gene found in the vicinity to the association signal. Linkage disequilibrium maps are presented for all four loci in Supplementary Figure 1a–d online.

Figure 3. Cumulative impact of the 10 variants on CLL risk.

(a) Distribution of risk alleles in controls (blue bars) and CLL cases (red bars) for the 10 loci (rs757978, rs2456449, rs7169431 and rs305061 and the six previously identified loci - rs17483466, rs13397985, rs872071, rs735665, rs7176508, and rs11083846); (b) Plot of the increasing ORs for CLL with increasing number of risk alleles. The ORs are relative to the median number of 7 risk alleles; Vertical bars correspond to 95% confidence intervals. The distribution of risk alleles follows a normal distribution in both case and controls, with a shift towards a higher number of risk alleles in cases. Analysis is based on data from Stages 1, 2 and UK-replication series 2. Horizontal line denotes the null value (OR=1.0).