GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma

Abstract

Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL-associated locus on 6p21.32, rs2647012 (OR(combined) = 0.64, P(combined) = 2 × 10(-21)) located 962 bp away from rs10484561 (r(2)<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:OR(adjusted) = 0.70, P(adjusted) = 4 × 10(-12); rs10484561:OR(adjusted) = 1.64, P(adjusted) = 5 × 10(-15)). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL-associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (OR(combined) = 1.36, P(combined) = 1.4 × 10(-7)). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.

Figure 1. Schematic representation of the three-stage study design.

Summary of contributing studies and number of samples per case/control status. Abbreviations: FL: follicular lymphoma, NHL: non-Hodgkin lymphoma, DLBCL: diffuse large B-cell lymphoma, CLL/SLL: chronic lymphocytic leukemia/small lymphocytic lymphoma, SNP: single nucleotide polymorphism, GWAS: genome-wide association study, SCALE: Scandinavian lymphoma etiology, SF: San Francisco, BC: British Columbia, NCI-SEER: National Cancer Institute-Surveillance, Epidemiology and End Results, NSW: New South Wales, Yale: Yale University, Mayo: Mayo Clinic. The complete list of the number of other NHL subtypes in each study is detailed in Table S1.

Figure 2. Recombination plot showing associations in 6p21.32 in Stage 1.

Plot showing the pattern of associations in Stage 1, the recombination rate (build 36, HapMap CEU) and genes located in the region. The two SNPs showing independent association and their respective P-values are labeled (blue: rs2647012, green: rs10484561); other SNPs are color-coded according to their LD with rs2647012 (red r²>0.8, orange 0.5–0.8, grey 0.2–0.5, white <0.2).

Figure 3. Forest plots of main associations with risk of FL.

Forest plots showing the associations in each study (ORs and P-values) at rs2647012 before adjustment (P_{heterogeneity} = 0.32), and at rs2647012 (P_{heterogeneity} = 0.67) and rs10484561 (P_{heterogeneity} = 0.54) after mutual adjustment. Squares indicate the odds ratios, with the size proportional to the weight of the study in the meta-analysis. Abbreviations: CI: confidence interval, SCALE: Scandinavian lymphoma etiology, SF: San Francisco, BC: British Columbia, NCI: National Cancer Institute-Surveillance, Epidemiology and End Results, NSW: New South Wales, YALE: Yale University, MAYO: Mayo Clinic.

Figure 4. Coalescence analysis of rs2647012 and rs10484561.

Median-joining network of haplotypes constructed using seven SNPs (Table S9). Circles represent haplotypes with area proportional to their frequency. SNPs are shown on the links (black lines). SNPs and haplotypes associated with increased or decreased FL risk are labeled in red or blue, respectively. The percentage of alleles of the imputed SNP rs9378212 (C/T) phased on each haplotype are shown in bold.