Deciphering the genetics and mechanisms of predisposition to multiple myeloma
Molly Went, Laura Duran-Lozano, Gísli H. Halldórsson, Andrea Gunnell, Nerea Ugidos-Damboriena, Philip Law, Ludvig Ekdahl, Amit Sud, Guðmar Þorleifsson, Malte Thodberg, Thorunn A. Olafsdottir, Antton Lamarca Arrizabalaga, Caterina Cafaro, Abhishek Niroula, Ram Ajore, Aitzkoa Lopez de Lapuente Portilla, Zain Ali, Maroulio Pertesi, Hartmut Goldschmidt, Lilja Stefánsdóttir, Sigurður Y. Kristinsson, Simon Stacey, Þorvarður Jón Löve, Sæmundur Rögnvaldsson, Roman Hájek, Pavel Vodička, U. Pettersson, Florentin Späth, Carolina Schinke, Frits van Rhee, Patrick Sulem, Egil Ferkingstad, Grímur Hjörleifsson Eldjárn, Ulf‐Henrik Mellqvist, Ingileif Jónsdóttir, Gareth J. Morgan, Pieter Sonneveld, Anders Waage, Niels Weinhold, Hauke Thomsen, Asta Försti, Markus Hansson, Annette Juul Vangsted, Unnur Þorsteinsdóttir, Kari Hemminki, Martin Kaiser, Þórunn Rafnar, Kāri Stefánsson, Richard S. Houlston, Björn Nilsson
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.