Deciphering the genetics and mechanisms of predisposition to multiple myeloma

Molly Went, Laura Duran-Lozano, Gisli H. Halldorsson, Andrea Gunnell, Nerea Ugidos-Damboriena, Philip Law, Ludvig Ekdahl, Amit Sud, Gudmar Thorleifsson, Malte Thodberg, Thorunn Olafsdottir, Antton Lamarca-Arrizabalaga, Caterina Cafaro, Abhishek Niroula, Ram Ajore, Aitzkoa Lopez de Lapuente Portilla, Zain Ali, Maroulio Pertesi, Hartmut Goldschmidt, Lilja Stefansdottir, Sigurdur Y. Kristinsson, Simon N. Stacey, Thorvardur J. Love, Saemundur Rognvaldsson, Roman Hajek, Pavel Vodicka, Ulrika Pettersson-Kymmer, Florentin Späth, Carolina Schinke, Frits Van Rhee, Patrick Sulem, Egil Ferkingstad, Grimur Hjorleifsson Eldjarn, Ulf-Henrik Mellqvist, Ingileif Jonsdottir, Gareth Morgan, Pieter Sonneveld, Anders Waage, Niels Weinhold, Hauke Thomsen, Asta Försti, Markus Hansson, Annette Juul-Vangsted, Unnur Thorsteinsdottir, Kari Hemminki, Martin Kaiser, Thorunn Rafnar, Kari Stefansson, Richard Houlston () and Björn Nilsson ()
Additional contact information
Molly Went: The Institute of Cancer Research
Laura Duran-Lozano: Lund University
Gisli H. Halldorsson: deCODE Genetics/Amgen
Andrea Gunnell: The Institute of Cancer Research
Nerea Ugidos-Damboriena: Lund University
Philip Law: The Institute of Cancer Research
Ludvig Ekdahl: Lund University
Amit Sud: The Institute of Cancer Research
Gudmar Thorleifsson: deCODE Genetics/Amgen
Malte Thodberg: Lund University
Thorunn Olafsdottir: deCODE Genetics/Amgen
Antton Lamarca-Arrizabalaga: Lund University
Caterina Cafaro: Lund University
Abhishek Niroula: Lund University
Ram Ajore: Lund University
Aitzkoa Lopez de Lapuente Portilla: Lund University
Zain Ali: Lund University
Maroulio Pertesi: Lund University
Hartmut Goldschmidt: University of Heidelberg
Lilja Stefansdottir: deCODE Genetics/Amgen
Sigurdur Y. Kristinsson: National University Hospital of Iceland
Simon N. Stacey: deCODE Genetics/Amgen
Thorvardur J. Love: National University Hospital of Iceland
Saemundur Rognvaldsson: National University Hospital of Iceland
Roman Hajek: University Hospital Ostrava and University of Ostrava
Pavel Vodicka: Academy of Sciences of the Czech Republic
Ulrika Pettersson-Kymmer: Umeå University
Florentin Späth: Umeå University
Carolina Schinke: University of Arkansas for Medical Sciences
Frits Van Rhee: University of Arkansas for Medical Sciences
Patrick Sulem: deCODE Genetics/Amgen
Egil Ferkingstad: deCODE Genetics/Amgen
Grimur Hjorleifsson Eldjarn: deCODE Genetics/Amgen
Ulf-Henrik Mellqvist: Southern Älvsborg Hospital
Ingileif Jonsdottir: deCODE Genetics/Amgen
Gareth Morgan: New York University
Pieter Sonneveld: Erasmus MC Cancer Institute
Anders Waage: Norwegian University of Science and Technology
Niels Weinhold: University of Heidelberg
Hauke Thomsen: MSB Medical School Berlin
Asta Försti: German Cancer Research Center (DKFZ)
Markus Hansson: Lund University
Annette Juul-Vangsted: University Hospital of Copenhagen at Rigshospitalet
Unnur Thorsteinsdottir: deCODE Genetics/Amgen
Kari Hemminki: German Cancer Research Center (DKFZ)
Martin Kaiser: The Institute of Cancer Research
Thorunn Rafnar: deCODE Genetics/Amgen
Kari Stefansson: deCODE Genetics/Amgen
Richard Houlston: The Institute of Cancer Research
Björn Nilsson: Lund University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50932-7

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