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 for this work

Department of Haematology

17 Citations (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.

Original language	English
Article number	6644
Journal	Nature Communications
Volume	15
Issue number	1
ISSN	2041-1722
DOIs	https://doi.org/10.1038/s41467-024-50932-7
Publication status	Published - 5 Aug 2024

Keywords

Multiple Myeloma/genetics
Humans
Genetic Predisposition to Disease
Genome-Wide Association Study
B-Cell Maturation Antigen/genetics
Polymorphism, Single Nucleotide
Mendelian Randomization Analysis
B-Lymphocytes/immunology
Case-Control Studies
Transmembrane Activator and CAML Interactor Protein/genetics
Male
Telomere/genetics

Access to Document

10.1038/s41467-024-50932-7

Cite this

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), Article 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, vol. 15, no. 1, 6644. https://doi.org/10.1038/s41467-024-50932-7

@article{9b157e3fc89643dc81e08b08320d266a,

title = "Deciphering the genetics and mechanisms of predisposition to multiple myeloma",

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.",

keywords = "Multiple Myeloma/genetics, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study, B-Cell Maturation Antigen/genetics, Polymorphism, Single Nucleotide, Mendelian Randomization Analysis, B-Lymphocytes/immunology, Case-Control Studies, Transmembrane Activator and CAML Interactor Protein/genetics, Male, Telomere/genetics",

author = "Molly Went and Laura Duran-Lozano and Halldorsson, \{Gisli H\} and Andrea Gunnell and Nerea Ugidos-Damboriena and Philip Law and Ludvig Ekdahl and Amit Sud and Gudmar Thorleifsson and Malte Thodberg and Thorunn Olafsdottir and Antton Lamarca-Arrizabalaga and Caterina Cafaro and Abhishek Niroula and Ram Ajore and \{Lopez de Lapuente Portilla\}, Aitzkoa and Zain Ali and Maroulio Pertesi and Hartmut Goldschmidt and Lilja Stefansdottir and Kristinsson, \{Sigurdur Y\} and Stacey, \{Simon N\} and Love, \{Thorvardur J\} and Saemundur Rognvaldsson and Roman Hajek and Pavel Vodicka and Ulrika Pettersson-Kymmer and Florentin Sp{\"a}th and Carolina Schinke and \{Van Rhee\}, Frits and Patrick Sulem and Egil Ferkingstad and \{Hjorleifsson Eldjarn\}, Grimur and Ulf-Henrik Mellqvist and Ingileif Jonsdottir and Gareth Morgan and Pieter Sonneveld and Anders Waage and Niels Weinhold and Hauke Thomsen and Asta F{\"o}rsti and Markus Hansson and Annette Juul-Vangsted and Unnur Thorsteinsdottir and Kari Hemminki and Martin Kaiser and Thorunn Rafnar and Kari Stefansson and Richard Houlston and Bj{\"o}rn Nilsson",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

month = aug,

day = "5",

doi = "10.1038/s41467-024-50932-7",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1722",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Deciphering the genetics and mechanisms of predisposition to multiple myeloma

AU - Went, Molly

AU - Duran-Lozano, Laura

AU - Halldorsson, Gisli H

AU - Gunnell, Andrea

AU - Ugidos-Damboriena, Nerea

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

AU - Kristinsson, Sigurdur Y

AU - Stacey, Simon N

AU - Love, Thorvardur J

AU - Rognvaldsson, Saemundur

AU - Hajek, Roman

AU - Vodicka, Pavel

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

AU - Hansson, Markus

AU - Juul-Vangsted, Annette

AU - Thorsteinsdottir, Unnur

AU - Hemminki, Kari

AU - Kaiser, Martin

AU - Rafnar, Thorunn

AU - Stefansson, Kari

AU - Houlston, Richard

AU - Nilsson, Björn

PY - 2024/8/5

Y1 - 2024/8/5

N2 - 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.

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.

KW - Multiple Myeloma/genetics

KW - Humans

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - B-Cell Maturation Antigen/genetics

KW - Polymorphism, Single Nucleotide

KW - Mendelian Randomization Analysis

KW - B-Lymphocytes/immunology

KW - Case-Control Studies

KW - Transmembrane Activator and CAML Interactor Protein/genetics

KW - Male

KW - Telomere/genetics

UR - https://www.scopus.com/pages/publications/85200470126

U2 - 10.1038/s41467-024-50932-7

DO - 10.1038/s41467-024-50932-7

M3 - Journal article

C2 - 39103364

SN - 2041-1722

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6644

ER -

Deciphering the genetics and mechanisms of predisposition to multiple myeloma

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this