Journal Article

DKFZ-2024-01594

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Deciphering the genetics and mechanisms of predisposition to multiple myeloma.

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. ; Stefansdottir, L. ; Kristinsson, S. Y. ; Stacey, S. N. ; Love, T. J. ; 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.DKFZ* ; Thomsen, H. ; Försti, A.DKFZ* ; Hansson, M. ; Juul-Vangsted, A. ; Thorsteinsdottir, U. ; Hemminki, K.DKFZ* ; Kaiser, M. ; Rafnar, T. ; Stefansson, K. ; Houlston, R. ; Nilsson, B.

2024
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-024-50932-7

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.

Keyword(s): Multiple Myeloma: genetics (MeSH) ; Humans (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Genome-Wide Association Study (MeSH) ; B-Cell Maturation Antigen: genetics (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Mendelian Randomization Analysis (MeSH) ; B-Lymphocytes: immunology (MeSH) ; B-Lymphocytes: metabolism (MeSH) ; Case-Control Studies (MeSH) ; Transmembrane Activator and CAML Interactor Protein: genetics (MeSH) ; Male (MeSH) ; Telomere: genetics (MeSH) ; B-Cell Maturation Antigen ; TNFRSF13B protein, human ; Transmembrane Activator and CAML Interactor Protein

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. Erimitus im DKFZ (Z999)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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