Deciphering the genetics and mechanisms of predisposition to multiple myeloma.
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Date
2024-08-05ICR Author
Author
Went, M
Duran-Lozano, L
Halldorsson, GH
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, SY
Stacey, SN
Love, TJ
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
Type
Journal Article
Metadata
Show full item recordAbstract
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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Research team
Cancer Genomics
Language
eng
Date accepted
2024-07-24
License start date
2024-08-05
Citation
Nature Communications, 2024,
Publisher
Springer Science and Business Media LLC