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@ARTICLE{Went:292095,
author = {M. Went and L. Duran-Lozano and G. H. Halldorsson and A.
Gunnell and N. Ugidos-Damboriena and P. Law and L. Ekdahl
and A. Sud and G. Thorleifsson and M. Thodberg and T.
Olafsdottir and A. Lamarca-Arrizabalaga and C. Cafaro and A.
Niroula and R. Ajore and A. Lopez de Lapuente Portilla and
Z. Ali and M. Pertesi and H. Goldschmidt and L.
Stefansdottir and S. Y. Kristinsson and S. N. Stacey and T.
J. Love and S. Rognvaldsson and R. Hajek and P. Vodicka and
U. Pettersson-Kymmer and F. Späth and C. Schinke and F. Van
Rhee and P. Sulem and E. Ferkingstad and G. Hjorleifsson
Eldjarn and U.-H. Mellqvist and I. Jonsdottir and G. Morgan
and P. Sonneveld and A. Waage and N. Weinhold$^*$ and H.
Thomsen and A. Försti$^*$ and M. Hansson and A.
Juul-Vangsted and U. Thorsteinsdottir and K. Hemminki$^*$
and M. Kaiser and T. Rafnar and K. Stefansson and R.
Houlston and B. Nilsson},
title = {{D}eciphering the genetics and mechanisms of predisposition
to multiple myeloma.},
journal = {Nature Communications},
volume = {15},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Nature Publishing Group UK},
reportid = {DKFZ-2024-01594},
pages = {6644},
year = {2024},
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.},
keywords = {Multiple Myeloma: genetics / Humans / Genetic
Predisposition to Disease / Genome-Wide Association Study /
B-Cell Maturation Antigen: genetics / Polymorphism, Single
Nucleotide / Mendelian Randomization Analysis /
B-Lymphocytes: immunology / B-Lymphocytes: metabolism /
Case-Control Studies / Transmembrane Activator and CAML
Interactor Protein: genetics / Male / Telomere: genetics /
B-Cell Maturation Antigen (NLM Chemicals) / TNFRSF13B
protein, human (NLM Chemicals) / Transmembrane Activator and
CAML Interactor Protein (NLM Chemicals)},
cin = {B062 / Z999},
ddc = {500},
cid = {I:(DE-He78)B062-20160331 / I:(DE-He78)Z999-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39103364},
doi = {10.1038/s41467-024-50932-7},
url = {https://inrepo02.dkfz.de/record/292095},
}