Deciphering the genetics and mechanisms of predisposition to multiple myeloma.
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Authors
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
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
Document Type
Journal Article
Date
2024-08-05
Date Accepted
2024-07-24
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.
Citation
Nature Communications, 2024,
DOI
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723
Collections
Research Team
Cancer Genomics