%0 Journal Article
%A Went, Molly
%A Duran-Lozano, Laura
%A Halldorsson, Gisli H
%A Gunnell, Andrea
%A Ugidos-Damboriena, Nerea
%A Law, Philip
%A Ekdahl, Ludvig
%A Sud, Amit
%A Thorleifsson, Gudmar
%A Thodberg, Malte
%A Olafsdottir, Thorunn
%A Lamarca-Arrizabalaga, Antton
%A Cafaro, Caterina
%A Niroula, Abhishek
%A Ajore, Ram
%A Lopez de Lapuente Portilla, Aitzkoa
%A Ali, Zain
%A Pertesi, Maroulio
%A Goldschmidt, Hartmut
%A Stefansdottir, Lilja
%A Kristinsson, Sigurdur Y
%A Stacey, Simon N
%A Love, Thorvardur J
%A Rognvaldsson, Saemundur
%A Hajek, Roman
%A Vodicka, Pavel
%A Pettersson-Kymmer, Ulrika
%A Späth, Florentin
%A Schinke, Carolina
%A Van Rhee, Frits
%A Sulem, Patrick
%A Ferkingstad, Egil
%A Hjorleifsson Eldjarn, Grimur
%A Mellqvist, Ulf-Henrik
%A Jonsdottir, Ingileif
%A Morgan, Gareth
%A Sonneveld, Pieter
%A Waage, Anders
%A Weinhold, Niels
%A Thomsen, Hauke
%A Försti, Asta
%A Hansson, Markus
%A Juul-Vangsted, Annette
%A Thorsteinsdottir, Unnur
%A Hemminki, Kari
%A Kaiser, Martin
%A Rafnar, Thorunn
%A Stefansson, Kari
%A Houlston, Richard
%A Nilsson, Björn
%T Deciphering the genetics and mechanisms of predisposition to multiple myeloma.
%J Nature Communications
%V 15
%N 1
%@ 2041-1723
%C [London]
%I Nature Publishing Group UK
%M DKFZ-2024-01594
%P 6644
%D 2024
%X 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.
%K Multiple Myeloma: genetics
%K Humans
%K Genetic Predisposition to Disease
%K Genome-Wide Association Study
%K B-Cell Maturation Antigen: genetics
%K Polymorphism, Single Nucleotide
%K Mendelian Randomization Analysis
%K B-Lymphocytes: immunology
%K B-Lymphocytes: metabolism
%K Case-Control Studies
%K Transmembrane Activator and CAML Interactor Protein: genetics
%K Male
%K Telomere: genetics
%K B-Cell Maturation Antigen (NLM Chemicals)
%K TNFRSF13B protein, human (NLM Chemicals)
%K Transmembrane Activator and CAML Interactor Protein (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39103364
%R 10.1038/s41467-024-50932-7
%U https://inrepo02.dkfz.de/record/292095