Deciphering the genetics and mechanisms of predisposition to multiple myeloma
Nature Communications, 2024
Went M., Duran-Lozano L., Halldorsson G., Gunnell A., Ugidos-Damboriena N., Law P., Ekdahl L., Sud A., Thorleifsson G., Thodberg M., Olafsdottir T., Lamarca-Arrizabalaga A., Cafaro C., Niroula A., Ajore R., Lopez de Lapuente Portilla A., Ali Z., Pertesi M., Goldschmidt H., Stefansdottir L., Kristinsson S., Stacey S., Love T., Rognvaldsson S., Hajek R., Vodicka P., Pettersson-Kymmer U., Späth F., Schinke C., Van Rhee F., Sulem P., Ferkingstad E., Hjorleifsson Eldjarn G., Mellqvist U., 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.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology | Pathophysiology | Plasma | O Olink Explore 3072/384 |
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.