Went, MollyDuran-Lozano, LauraHalldorsson, Gisli H.Gunnell, AndreaUgidos-Damboriena, NereaLaw, PhilipEkdahl, LudvigSud, AmitThorleifsson, GudmarThodberg, MalteÓlafsdóttir, Þórunn ÁstaLamarca-Arrizabalaga, AnttonCafaro, CaterinaNiroula, AbhishekAjore, RamLopez de Lapuente Portilla, AitzkoaAli, ZainPertesi, MaroulioGoldschmidt, HartmutStefansdottir, LiljaKristinsson, Sigurður YngviStacey, Simon N.Löve, Þorvarður JónRögnvaldsson, SæmundurHajek, RomanVodicka, PavelPettersson-Kymmer, UlrikaSpäth, FlorentinSchinke, CarolinaVan Rhee, FritsSulem, PatrickFerkingstad, EgilHjorleifsson Eldjarn, GrimurMellqvist, Ulf HenrikJonsdottir, IngileifMorgan, GarethSonneveld, PieterWaage, AndersWeinhold, NielsThomsen, HaukeFörsti, AstaHansson, MarkusJuul-Vangsted, AnnetteThorsteinsdottir, UnnurHemminki, KariKaiser, MartinRafnar, ThorunnStefansson, KariHoulston, RichardNilsson, Björn2025-11-202025-11-202024-08-05Went, M, Duran-Lozano, L, Halldorsson, G H, Gunnell, A, Ugidos-Damboriena, N, Law, P, Ekdahl, L, Sud, A, Thorleifsson, G, Thodberg, M, Ólafsdóttir, Þ Á, 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, Löve, Þ J, Rögnvaldsson, 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/s41467-024-50932-72041-1723227842965d42aae86-ed35-4fb1-8fd2-1dcab40b5c758520047012639103364https://hdl.handle.net/20.500.11815/7583Publisher Copyright: © The Author(s) 2024.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.2669429eninfo:eu-repo/semantics/openAccessGeneral ChemistryGeneral Biochemistry,Genetics and Molecular BiologyGeneral Physics and Astronomy/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article10.1038/s41467-024-50932-7