TY  - JOUR
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
TI  - Deciphering the genetics and mechanisms of predisposition to multiple myeloma.
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2024-01594
SP  - 6644
PY  - 2024
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  - B-Lymphocytes: metabolism
KW  - Case-Control Studies
KW  - Transmembrane Activator and CAML Interactor Protein: genetics
KW  - Male
KW  - Telomere: genetics
KW  - B-Cell Maturation Antigen (NLM Chemicals)
KW  - TNFRSF13B protein, human (NLM Chemicals)
KW  - Transmembrane Activator and CAML Interactor Protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39103364
DO  - DOI:10.1038/s41467-024-50932-7
UR  - https://inrepo02.dkfz.de/record/292095
ER  -