Abstract
Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.
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Data availability
Genotype data from the NCI NHL GWAS is available on dbGaP (phs000801.v2.p1) for research purposes in accordance with dbGaP data access policies. Other data in this manuscript is available for shared research purposes through the InterLymph Consortium upon approval in accordance with institutional review boards and general data protection regulations.
Change history
04 September 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41375-023-01978-x
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Acknowledgements
This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. The authors thank Mr. William Wheeler (Information Management Services, Inc.) for his analytic support. A complete list of funding sources and acknowledgements for individual studies is listed in the Supplementary Material.
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Conceptualization: SIB, JV, YB, NJC, AN, ZW, KES, GK, HH, CB, CFS, LMM, ARB, LRT, KO, WC, XW, JRC, SJC, SLS, NR. Collected/contributed study data or samples: SIB, JV, YB, NJC, AN, ZW, KES, GK, HH, CB, CFS, LMM, ARB, LRT, HOA, DA, KCA, SMA, DWS, BB, NB, PB, BMB, PB, PMB, PB, EEB, LB, LAC, ETC, BCHC, CCC, JC, PC, GC, LC, DVC, DGC, KC, DC, IDV, AD, WRD, AD, CKE, LF, JFF, AG, HG, GGG, SG, MG, BG, JG, TMH, CAH, CH, JNH, TRH, EAH, AH, AI, RDJ, RFJ, RK, EK, LNK, YK, PK, AK, AL, QL, CL, DL, ML, BKL, CM, MM, JM, MM, LM, RLM, TJM, AM, RM, KEN, AJN, KO, MPP, KAR, ER, JR, ER, GS, RKS, TDS, MTS, AS, KWS, MCS, JJS, AS, HJS, KT, CAT, HT, LFT, RCT, DS, JT, CMV, AVDB, DJVDB, RCHV, PV, SSW, EW, GJW, SW, NWD, YY, MY, AZ, YZ, TZ, EZ. Formal analysis: SIB, ZW, GK, LS, KY, CB, JA, JS, NC. Writing – original draft: SIB, JV, YB, NJC, AN, ZW, JRC, SJC, SLS, NR. Writing-review & editing: All authors.
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TS received research support to his institution from Genetech, Pharacyclics, AbbVie, Cephalon, Hospira, GlaxoSmithKline, Polyphenon E International, Merck, and Celgene and holds a patent (US14/292,075) on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia. KS received research funding from Janssen Pharmaceuticals AB for research unrelated to this project. CH received honoraria from Novartis, Amgen, Servier/Pfizer, and Gilead Sciences, acted as a consultant or advisor to Roche, Celgene, Janssen-Cilag, Gilead Sciences, Takeda, Miltenyi Biotec, Abbvie, and ADC Therapeutics, and received travel, accommodations and/or expenses from Roche, Celgene, and Amgen. KO is currently a full-time employee at Sema4. TH is on the data monitoring boards for Seagen and Tessa Therapeutics, scientific advisory boards for Eli Lilly, Morpohsys, Incyte, Biegene, and Loxo Oncology, and received research support from Genentech and Sorrento Therapeutics. The other authors declare no competing interests.
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Berndt, S.I., Vijai, J., Benavente, Y. et al. Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes. Leukemia 36, 2835–2844 (2022). https://doi.org/10.1038/s41375-022-01711-0
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DOI: https://doi.org/10.1038/s41375-022-01711-0
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