Molly Went, Laura Duran-Lozano, Gisli H. Halldorsson, Andrea Gunnell, Nerea Ugidos-Damboriena et al.
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.
Molly Went, Laura Duran-Lozano, Gisli H. Halldorsson, Andrea Gunnell, Nerea Ugidos-Damboriena, Philip Law, Ludvig Ekdahl, Amit Sud, Gudmar Thorleifsson, Malte Thodberg, Thorunn Olafsdottir, Antton Lamarca-Arrizabalaga, Caterina Cafaro, Abhishek Niroula, Ram Ajore, Aitzkoa Lopez de Lapuente Portilla, Zain Ali, Maroulio Pertesi, Hartmut Goldschmidt, Lilja Stefansdottir, Sigurdur Y. Kristinsson, Simon N. Stacey, Thorvardur J. Love, Saemundur Rognvaldsson, Roman Hajek, Pavel Vodicka, Ulrika Pettersson-Kymmer, Florentin Späth, Carolina Schinke, Frits Van Rhee, Patrick Sulem, Egil Ferkingstad, Grimur Hjorleifsson Eldjarn, Ulf-Henrik Mellqvist, Ingileif Jonsdottir, Gareth Morgan, Pieter Sonneveld, Anders Waage, Niels Weinhold, Hauke Thomsen, Asta Försti, Markus Hansson, Annette Juul-Vangsted, Unnur Thorsteinsdottir, Kari Hemminki, Martin Kaiser, Thorunn Rafnar, Kari Stefansson, Richard Houlston, Björn Nilsson. Deciphering the genetics and mechanisms of predisposition to multiple myeloma. 2024-08-05. https://doi.org/10.1038/s41467-024-50932-7
The expanded MPRA library tested reference and alternate alleles of candidate multiple-myeloma risk variants in KMS11 cells. Candidate regulatory sequences were represented by 230-bp oligos, cloned into a lentiviral barcode reporter, and measured in three biological replicates by matched DNA and RNA sequencing.
The expanded MPRA library tested reference and alternate alleles of candidate multiple-myeloma risk variants in RPMI-8226 cells. Candidate regulatory sequences were represented by 230-bp oligos, cloned into a lentiviral barcode reporter, and measured in three biological replicates by matched DNA and RNA sequencing.
The expanded MPRA library tested reference and alternate alleles of candidate multiple-myeloma risk variants in L-363 cells. Candidate regulatory sequences were represented by 230-bp oligos, cloned into a lentiviral barcode reporter, and measured in three biological replicates by matched DNA and RNA sequencing.
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