Deciphering the genetics and mechanisms of predisposition to multiple myeloma

Journal article

Publisher Copyright: © The Author(s) 2024.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.Peer reviewe

Authors: Went, M; Duran-Lozano, L; Halldorsson, GH; Gunnell, A; Ugidos-Damboriena, N

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 15
• Issue: 1
• Pages: 6644-6644
• Publication date: 2024-08-05
• DOI: 10.1038/s41467-024-50932-7
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Immunology; Genetic association; Genetic predisposition; Genome-wide association study; Malignancy; Genetic variants; Plasma cell; Gene; Single-nucleotide polymorphism; Biology; Genetics; Mendelian randomization; Multiple myeloma; Genotype