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
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
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.
U2 - 10.1038/s41467-024-50932-7
DO - 10.1038/s41467-024-50932-7
M3 - Article
C2 - 39103364
AN - SCOPUS:85200470126
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6644
ER -