Deciphering the genetics and mechanisms of predisposition to multiple myeloma
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.
Authors
- Gísli H. Halldórsson (ORCID: https://orcid.org/0000-0001-7067-9862)
- Sigurður Y. Kristinsson (ORCID: https://orcid.org/0000-0002-4964-7476)
- Maroulio Pertesi (ORCID: https://orcid.org/0000-0002-4869-8925)
- Pieter Sonneveld (ORCID: https://orcid.org/0000-0002-0808-2237)
- Zain Ali (ORCID: https://orcid.org/0000-0002-1880-8046)
- Pavel Vodička (ORCID: https://orcid.org/0000-0003-2376-1243)
- Hauke Thomsen (ORCID: https://orcid.org/0000-0001-5951-3116)
- Grímur Hjörleifsson Eldjárn (ORCID: https://orcid.org/0000-0002-9580-6685)
- Lilja Stefánsdóttir (ORCID: https://orcid.org/0009-0001-2407-2661)
- Asta Försti (ORCID: https://orcid.org/0000-0002-9857-4728)
- Kāri Stefánsson (ORCID: https://orcid.org/0000-0003-1676-864X)
- Nerea Ugidos-Damboriena (ORCID: https://orcid.org/0000-0003-4938-3973)
- Richard S. Houlston (ORCID: https://orcid.org/0000-0002-5268-0242)
- Guðmar Þorleifsson (ORCID: https://orcid.org/0000-0003-4623-9087)
- Antton Lamarca Arrizabalaga (ORCID: https://orcid.org/0009-0008-3426-2347)
- Aitzkoa Lopez de Lapuente Portilla (ORCID: https://orcid.org/0000-0002-7407-3830)
- Abhishek Niroula (ORCID: https://orcid.org/0000-0002-5904-0635)
- Malte Thodberg (ORCID: https://orcid.org/0000-0001-6244-3841)
- Ulf‐Henrik Mellqvist (ORCID: https://orcid.org/0009-0004-0456-2657)
- Carolina Schinke (ORCID: https://orcid.org/0000-0002-2699-1741)
- Ram Ajore
- Simon Stacey (ORCID: https://orcid.org/0000-0002-4732-7380)
- Caterina Cafaro (ORCID: https://orcid.org/0000-0002-1201-7171)
- Unnur Þorsteinsdóttir (ORCID: https://orcid.org/0000-0002-7049-2827)
- Molly Went (ORCID: https://orcid.org/0000-0003-3271-975X)
- Ingileif Jónsdóttir (ORCID: https://orcid.org/0000-0001-8339-150X)
- Anders Waage (ORCID: https://orcid.org/0000-0001-9072-1220)
- Philip Law (ORCID: https://orcid.org/0000-0001-9663-4611)
- Niels Weinhold (ORCID: https://orcid.org/0000-0002-5464-3234)
- Hartmut Goldschmidt (ORCID: https://orcid.org/0000-0003-0961-0035)
- Florentin Späth (ORCID: https://orcid.org/0000-0002-0711-0830)
- Björn Nilsson (ORCID: https://orcid.org/0000-0001-5542-0254)
- Andrea Gunnell (ORCID: https://orcid.org/0000-0001-5162-5391)
- Ludvig Ekdahl (ORCID: https://orcid.org/0000-0002-4257-7284)
- Amit Sud (ORCID: https://orcid.org/0000-0002-6133-0164)
- Þórunn Rafnar (ORCID: https://orcid.org/0000-0003-0491-7046)
- Patrick Sulem (ORCID: https://orcid.org/0000-0001-7123-6123)
- Thorunn A. Olafsdottir (ORCID: https://orcid.org/0000-0001-5454-938X)
- Egil Ferkingstad (ORCID: https://orcid.org/0000-0001-8090-7988)
- Sæmundur Rögnvaldsson (ORCID: https://orcid.org/0000-0003-2162-8414)
- Annette Juul Vangsted (ORCID: https://orcid.org/0000-0002-2131-731X)
- U. Pettersson (ORCID: https://orcid.org/0000-0002-0557-9803)
- Martin Kaiser (ORCID: https://orcid.org/0000-0002-3677-4804)
- Markus Hansson (ORCID: https://orcid.org/0000-0002-7715-4548)
- Þorvarður Jón Löve (ORCID: https://orcid.org/0000-0002-2680-6120)
- Laura Duran-Lozano (ORCID: https://orcid.org/0000-0003-3557-5018)
- Frits van Rhee (ORCID: https://orcid.org/0000-0001-9959-1282)
- Kari Hemminki (ORCID: https://orcid.org/0000-0002-2769-3316)
- Roman Hájek (ORCID: https://orcid.org/0000-0001-6955-6267)
- Gareth J. Morgan (ORCID: https://orcid.org/0000-0002-4271-6360)
Institutions
- Broad Institute (US)
- deCODE Genetics (Iceland) (IS)
- Institute of Cancer Research (GB)
- University of Iceland (IS)
- German Cancer Research Center (DE)
- University of Ostrava (CZ)
- Lund University (SE)
- Norwegian University of Science and Technology (NO)
- Charles University (CZ)
- Heidelberg University (DE)
- Sahlgrenska University Hospital (SE)
- Rigshospitalet (DK)
- NYU Langone Health (US)
- University Hospital Ostrava (CZ)
- MSB Medical School Berlin (DE)
- National University Hospital of Iceland (IS)
- Södra Älvsborg Hospital (SE)
- Hopp Children's Cancer Center Heidelberg (DE)
- Czech Academy of Sciences, Institute of Experimental Medicine (CZ)
- Skåne University Hospital (SE)
- Erasmus MC Cancer Institute (NL)
- University of Arkansas for Medical Sciences (US)
- Umeå University (SE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-05
- DOI
- https://doi.org/10.1038/s41467-024-50932-7
- Citations
- 21
- Primary Topic
- Multiple Myeloma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 9.54
Funders
- Cancer Research UK
- European Commission
- Cancerfonden
- Lunds Universitet
- Vetenskapsrådet