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.
- MeSH
- B-lymfocyty imunologie metabolismus MeSH
- celogenomová asociační studie * MeSH
- genetická predispozice k nemoci * MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé MeSH
- maturační antigen B-buněk * genetika MeSH
- mendelovská randomizace MeSH
- mnohočetný myelom * genetika MeSH
- receptor TACI genetika MeSH
- studie případů a kontrol MeSH
- telomery genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.
- MeSH
- adaptorové proteiny signální transdukční genetika imunologie MeSH
- B-lymfocyty imunologie patologie MeSH
- chromatin chemie imunologie MeSH
- chromozomální proteiny, nehistonové genetika imunologie MeSH
- genetická predispozice k nemoci * MeSH
- hodnocení rizik MeSH
- intergenová DNA genetika imunologie MeSH
- lidé MeSH
- lokus kvantitativního znaku MeSH
- mnohočetný myelom farmakoterapie genetika imunologie patologie MeSH
- nádorové proteiny genetika imunologie MeSH
- plazmatické buňky imunologie patologie MeSH
- polymorfismus genetický MeSH
- primární buněčná kultura MeSH
- proteiny buněčného cyklu genetika imunologie MeSH
- protokoly protinádorové kombinované chemoterapie MeSH
- regulace genové exprese u nádorů MeSH
- represorové proteiny genetika imunologie MeSH
- sekvence nukleotidů MeSH
- transkripční elongační faktory genetika imunologie MeSH
- typy dědičnosti MeSH
- výměnné faktory guaninnukleotidů genetika imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
