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

doi:10.1038/s41467-024-50932-7

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 StefansdottirSigurdur 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^*

^*Corresponding author af dette arbejde

Afdeling for Blodsygdomme CKO

15 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	6644
Tidsskrift	Nature Communications
Vol/bind	15
Udgave nummer	1
ISSN	2041-1722
DOI	https://doi.org/10.1038/s41467-024-50932-7
Status	Udgivet - 5 aug. 2024

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Went, M., Duran-Lozano, L., Halldorsson, G. H., 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., ... Nilsson, B. (2024). Deciphering the genetics and mechanisms of predisposition to multiple myeloma. Nature Communications, 15(1), Artikel 6644. https://doi.org/10.1038/s41467-024-50932-7

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 2024, 'Deciphering the genetics and mechanisms of predisposition to multiple myeloma', Nature Communications, bind 15, nr. 1, 6644. https://doi.org/10.1038/s41467-024-50932-7

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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.",

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AU - Halldorsson, Gisli H

AU - Gunnell, Andrea

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AU - Law, Philip

AU - Ekdahl, Ludvig

AU - Sud, Amit

AU - Thorleifsson, Gudmar

AU - Thodberg, Malte

AU - Olafsdottir, Thorunn

AU - Lamarca-Arrizabalaga, Antton

AU - Cafaro, Caterina

AU - Niroula, Abhishek

AU - Ajore, Ram

AU - Lopez de Lapuente Portilla, Aitzkoa

AU - Ali, Zain

AU - Pertesi, Maroulio

AU - Goldschmidt, Hartmut

AU - Stefansdottir, Lilja

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AU - Rognvaldsson, Saemundur

AU - Hajek, Roman

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AU - Pettersson-Kymmer, Ulrika

AU - Späth, Florentin

AU - Schinke, Carolina

AU - Van Rhee, Frits

AU - Sulem, Patrick

AU - Ferkingstad, Egil

AU - Hjorleifsson Eldjarn, Grimur

AU - Mellqvist, Ulf-Henrik

AU - Jonsdottir, Ingileif

AU - Morgan, Gareth

AU - Sonneveld, Pieter

AU - Waage, Anders

AU - Weinhold, Niels

AU - Thomsen, Hauke

AU - Försti, Asta

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AB - 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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KW - Mendelian Randomization Analysis

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KW - Transmembrane Activator and CAML Interactor Protein/genetics

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KW - Telomere/genetics

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Deciphering the genetics and mechanisms of predisposition to multiple myeloma

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