To identify susceptibility loci for non-Hodgkin lymphoma (NHL) subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma (FL) in 1,465 FL cases/6,958 controls at 6p21.32 (rs10484561, rs7755224, r2=1.0; combined p-values=1.12×10-29, 2.00×10-19), providing further support that MHC genetic variation influences FL susceptibility. Confirmatory evidence of a previously reported association was also found between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined p-value=4.24×10-9).

Folate metabolism plays an essential role in DNA synthesis and methylation processes. Deviations in the flux of folate due to genetic variation could result in selective growth and genomic instability and affect susceptibility to various cancers including lymphoma. To test this hypothesis, genetic polymorphisms in the folate metabolic pathway were investigated using DNA from a population-based case-control study of nonHodgkin lymphoma (

We conducted genome-wide association studies of non-Hodgkin lymphoma using Illumina HumanHap550 BeadChips to identify subtype-specific associations in follicular, diffuse large B-cell and chronic lymphocytic leukemia/small lymphocytic lymphomas. We found that rs6457327 on 6p21.33 was associated with susceptibility to follicular lymphoma (FL, N=189 cases/592 controls) with validation in an additional 456 FL cases and 2,785 controls (combined allelic pvalue=4.7×10 −11 ). The region of strongest association overlaps C6orf15(STG), located near psoriasis susceptibility region 1(PSORS1).Non-Hodgkin lymphoma (NHL) is a heterogeneous group of neoplasms of B-and T-cells that vary in their causes and molecular profiles 1 . With the fifth highest incidence amongst all cancers in the U.S., the annual incidence of NHL has doubled since the 1970s. With the increasing evidence supporting the importance of genetic determinants in lymphomagenesis 2 , there is a strong impetus to identify genetic risk factors. Epidemiological and biological evidence suggest that environmental and genetic risk factors differ for the common NHL subtypes, follicular (FL), diffuse large B-cell (DLBCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) 1 . We therefore conducted genome-wide association studies (GWAS) using separate DNA pools from 189 FL, 221 9Correspondance to: Dr. Christine Skibola, School of Public Health, 237A Hildebrand Hall, University of California, Berkeley, California 94720-7356, 510) 643-5041 tel/(510) 642-0427 fax/ chrisfs@berkeley.edu. Author Contributions CFS, JS, AB-W, EAH and NB are principal investigators for the participating studies; LA and JR did DNA extraction, normalization and quality control; KB and KI prepared DNA pools and performed the genome scan and analysis; DC, CFS, KB, MTS and LZ consulted on study design; LA undertook genotyping; JC performed expression analysis; DC, PMB, AN and LC performed the statistical analyses; LC and EH conducted bioinformatics analyses; CSF, LC and KB wrote the manuscript. Fig. 1; for description of study populations see Supplementary Table 1). We restricted genotyping to DNA collected from individuals with European ancestry as determined by AIMS genotyping 4 to diminish potential underlying population stratification. Self-reported ethnicity and ancestry data were highly correlated (95%) and used to construct homogeneous DNA pools of participants of European descent. NIH Public AccessIn the first phase, pools were hybridized to Human Hap550v.3 BeadChips (Illumina, San Diego, CA), and SNPs were ranked after adjusting for pooling error 5 . The top 30 ranked SNPs for each NHL subtype were subsequently individually genotyped across the NC1 sample set to confirm the accuracy of estimated allele frequency differences from the pooled data. 87% of raw allelic p-values were <0.05 (Supplementary Tables2a-c), and genotype frequencies did not significantly differ from Hardy-Weinberg equilibrium. 32 SNPs with subtype-specific allelic q-values (corrected p) <0.05 ...