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Deciphering the genetics and mechanisms of predisposition to multiple myeloma

Went, Molly ; Duran-Lozano, Laura LU ; Halldorsson, Gisli H. ; Gunnell, Andrea ; Ugidos-Damboriena, Nerea LU ; Law, Philip ; Ekdahl, Ludvig LU ; Sud, Amit LU ; Thorleifsson, Gudmar and Thodberg, Malte LU , et al. (2024) In Nature Communications 15(1).
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
15
issue
1
article number
6644
publisher
Nature Publishing Group
external identifiers
  • scopus:85200470126
  • pmid:39103364
ISSN
2041-1723
DOI
10.1038/s41467-024-50932-7
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2024.
id
611a8bdc-3765-404c-9d42-a4a798435741
date added to LUP
2024-08-11 08:42:22
date last changed
2024-12-30 00:14:56
@article{611a8bdc-3765-404c-9d42-a4a798435741,
  abstract     = {{<p>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.</p>}},
  author       = {{Went, Molly and Duran-Lozano, Laura and Halldorsson, Gisli H. and Gunnell, Andrea and Ugidos-Damboriena, Nerea and Law, Philip and Ekdahl, Ludvig and Sud, Amit and Thorleifsson, Gudmar and Thodberg, Malte and Olafsdottir, Thorunn and Lamarca-Arrizabalaga, Antton and Cafaro, Caterina and Niroula, Abhishek and Ajore, Ram and Lopez de Lapuente Portilla, Aitzkoa and Ali, Zain and Pertesi, Maroulio and Goldschmidt, Hartmut and Stefansdottir, Lilja and Kristinsson, Sigurdur Y. and Stacey, Simon N. and Love, Thorvardur J. and Rognvaldsson, Saemundur and Hajek, Roman and Vodicka, Pavel and Pettersson-Kymmer, Ulrika and Späth, Florentin and Schinke, Carolina and Van Rhee, Frits and Sulem, Patrick and Ferkingstad, Egil and Hjorleifsson Eldjarn, Grimur and Mellqvist, Ulf Henrik and Jonsdottir, Ingileif and Morgan, Gareth and Sonneveld, Pieter and Waage, Anders and Weinhold, Niels and Thomsen, Hauke and Försti, Asta and Hansson, Markus and Juul-Vangsted, Annette and Thorsteinsdottir, Unnur and Hemminki, Kari and Kaiser, Martin and Rafnar, Thorunn and Stefansson, Kari and Houlston, Richard and Nilsson, Björn}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Deciphering the genetics and mechanisms of predisposition to multiple myeloma}},
  url          = {{http://dx.doi.org/10.1038/s41467-024-50932-7}},
  doi          = {{10.1038/s41467-024-50932-7}},
  volume       = {{15}},
  year         = {{2024}},
}