Nature Communications (Aug 2024)
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,
- Björn Nilsson
Affiliations
- Molly Went
- Division of Genetics and Epidemiology, The Institute of Cancer Research
- Laura Duran-Lozano
- Department of Laboratory Medicine, Lund University
- Gisli H. Halldorsson
- deCODE Genetics/Amgen
- Andrea Gunnell
- Division of Genetics and Epidemiology, The Institute of Cancer Research
- Nerea Ugidos-Damboriena
- Department of Laboratory Medicine, Lund University
- Philip Law
- Division of Genetics and Epidemiology, The Institute of Cancer Research
- Ludvig Ekdahl
- Department of Laboratory Medicine, Lund University
- Amit Sud
- Division of Genetics and Epidemiology, The Institute of Cancer Research
- Gudmar Thorleifsson
- deCODE Genetics/Amgen
- Malte Thodberg
- Department of Laboratory Medicine, Lund University
- Thorunn Olafsdottir
- deCODE Genetics/Amgen
- Antton Lamarca-Arrizabalaga
- Department of Laboratory Medicine, Lund University
- Caterina Cafaro
- Department of Laboratory Medicine, Lund University
- Abhishek Niroula
- Department of Laboratory Medicine, Lund University
- Ram Ajore
- Department of Laboratory Medicine, Lund University
- Aitzkoa Lopez de Lapuente Portilla
- Department of Laboratory Medicine, Lund University
- Zain Ali
- Department of Laboratory Medicine, Lund University
- Maroulio Pertesi
- Department of Laboratory Medicine, Lund University
- Hartmut Goldschmidt
- Department of Internal Medicine V, University of Heidelberg
- Lilja Stefansdottir
- deCODE Genetics/Amgen
- Sigurdur Y. Kristinsson
- Landspitali, National University Hospital of Iceland
- Simon N. Stacey
- deCODE Genetics/Amgen
- Thorvardur J. Love
- Landspitali, National University Hospital of Iceland
- Saemundur Rognvaldsson
- Landspitali, National University Hospital of Iceland
- Roman Hajek
- University Hospital Ostrava and University of Ostrava
- Pavel Vodicka
- Institute of Experimental Medicine, Academy of Sciences of the Czech Republic
- Ulrika Pettersson-Kymmer
- Department of Integrative Medical Biology, Umeå University
- Florentin Späth
- Department of Radiation Sciences, Umeå University
- Carolina Schinke
- Myeloma Center, University of Arkansas for Medical Sciences
- Frits Van Rhee
- Myeloma Center, 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
- Perlmutter Cancer Center, Langone Health, New York University
- Pieter Sonneveld
- Department of Hematology, Erasmus MC Cancer Institute
- Anders Waage
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology
- Niels Weinhold
- Department of Internal Medicine V, University of Heidelberg
- Hauke Thomsen
- MSB Medical School Berlin
- Asta Försti
- German Cancer Research Center (DKFZ)
- Markus Hansson
- Department of Laboratory Medicine, Lund University
- Annette Juul-Vangsted
- Department of Haematology, University Hospital of Copenhagen at Rigshospitalet
- Unnur Thorsteinsdottir
- deCODE Genetics/Amgen
- Kari Hemminki
- German Cancer Research Center (DKFZ)
- Martin Kaiser
- Division of Genetics and Epidemiology, The Institute of Cancer Research
- Thorunn Rafnar
- deCODE Genetics/Amgen
- Kari Stefansson
- deCODE Genetics/Amgen
- Richard Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research
- Björn Nilsson
- Department of Laboratory Medicine, Lund University
- DOI
- https://doi.org/10.1038/s41467-024-50932-7
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
