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Cited by 30Multiple Myeloma Research and TreatmentsGenetic Associations and EpidemiologyMultiple Sclerosis Research Studies

Deciphering the genetics and mechanisms of predisposition to multiple myeloma

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Went, Molly, Duran-Lozano, Laura, Halldorsson, Gisli H., Gunnell, Andrea, Ugidos-Damboriena, Nerea, Law, Philip, Ekdahl, Ludvig, Sud, Amit +42 more·2024·Nature Communications
DOI 10.1038/s41467-024-50932-7PMC PMC11300596
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Abstract

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.

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  • A list of loci specific to multiple myeloma and MGUS/SMM exists.

    “The second group included a list of loci that are specific to multiple myeloma and MGUS/SMM .43-46”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [44]

    The Methods section ('Genome-wide association study'; page unavailable) says the authors compiled a list of MM risk loci, and the Results ('Genetic architecture of MM risk'; page unavailable) report a correlation between MM risk variants and MGUS effects. The copy does not establish that these loci are specific to MM and MGUS/SMM: it reports associations with other conditions and does not address SMM separately. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Genetic predisposition plays an important role in the initial transformation and is driven by both germline variants and multiple myeloma-specific loci influencing risk.

    “Genetic predisposition plays an important role in the initial transformation and is driven by both germline variants and MM-specific loci influencing risk.”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [44]

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Authors
Went, M., Duran-Lozano, L., Halldorsson, G. H., Gunnell, A., Ugidos-Damboriena, N., Law, P., Ekdahl, L., Sud, A., Thorleifsson, G., Thodberg, M., Olafsdottir, T., Lamarca-Arrizabalaga, A., Cafaro, C., Niroula, A., Ajore, R., Lopez de Lapuente Portilla, A., Ali, Z., Pertesi, M., Goldschmidt, H., Stefansdottir, L., Kristinsson, S. Y., Stacey, S. N., Love, T. J., Rognvaldsson, S., Hajek, R., Vodicka, P., Pettersson-Kymmer, U., Späth, F., Schinke, C., Van Rhee, F., Sulem, P., Ferkingstad, E., Hjorleifsson Eldjarn, G., Mellqvist, U.-H., Jonsdottir, I., Morgan, G., Sonneveld, P., Waage, A., Weinhold, N., Thomsen, H., Försti, A., Hansson, M., Juul-Vangsted, A., Thorsteinsdottir, U., Hemminki, K., Kaiser, M., Rafnar, T., Stefansson, K., Houlston, R., & Nilsson, B.
Affiliations
  • Institute of Cancer Research (GB)
  • Lund University (SE)
  • deCODE Genetics (Iceland) (IS)
  • Heidelberg University (DE)
  • University of Iceland (IS)
  • Umeå University (SE)
  • University of Arkansas for Medical Sciences (US)
  • Södra Älvsborg Hospital (SE)
  • NYU Langone Health (US)
  • Erasmus MC Cancer Institute (NL)
  • Norwegian University of Science and Technology (NO)
  • German Cancer Research Center (DE)
  • MSB Medical School Berlin (DE)
  • Broad Institute (US)
Corresponding author
  • Houlston, Richard
  • Nilsson, Björn
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-08-05
Volume
15
Issue
1
Pages
6644-6644
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-50932-7
PMC
PMC11300596
OpenAlex
W4401324937
Cited by
30
References
8
Citations by year
2026: 11 · 2025: 15 · 2024: 4
FWCI
9.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • Opin vísindi (Opin vísindi) (submittedVersion, cc-by-nc-sa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Lund University Publications (Lund University) (submittedVersion)
  • Opin vísindi (Opin vísindi) (submittedVersion, other-oa)
Funders
Vetenskapsrådet (2017-02023, 2018-00424)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
multiple myeloma, genetic susceptibility, heritability, genetic susceptibility loci, telomere length, BCMA, IL5RA, TNFRSF13B, B-cell immunodeficiency, B cell response, plasma cells, Mendelian randomization, fine mapping
MeSH terms
B-Lymphocytes, Humans, Male, Multiple Myeloma, Case-Control Studies, Telomere, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, B-Cell Maturation Antigen, Transmembrane Activator and CAML Interactor Protein, Genome-Wide Association Study, Mendelian Randomization Analysis

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