Paper Details

ABSTRACT

Background: Multiple myeloma (MM) susceptibility has an inherited component, with first-degree relatives of affected individuals having an estimated two-fold increased risk (Schinasi et al). Prior European-ancestry genome-wide association studies (GWAS) identified 35 MM risk loci, but these explain only a small fraction of inherited risk (Went et al; Clay-Gilmour et al). To further characterize MM genetic risk, we conducted the largest MM GWAS meta-analysis to date, with fine-mapping, integrative bioinformatic analyses, and risk prediction modeling.

Methods: Discovery included 19,777 MM cases and 1,363,466 controls from 16 GWAS: 12 European-ancestry GWAS comprising 17,102 cases and 1,160,197 controls, and four additional GWAS including 2,675 cases and 203,269 controls from African ancestry, African American, and admixed ancestry populations. Separate European-ancestry and multi-ancestry analyses were performed, with European-ancestry participants included in the multi-ancestry analysis. Study-specific results were harmonized and meta-analyzed after adjustment for age, sex, and genetic ancestry. Conditional analysis identified independent genome-wide significant variants. Replication used fixed-effect meta-analysis of three independent case-control datasets totaling 3,521 cases and 403,651 controls. Previously reported MM loci were evaluated separately in the European-ancestry GWAS. Fine-mapping, multi-omics annotation, and pathway enrichment analyses prioritized candidate functional variants, effector genes, and biological pathways. Polygenic risk scores (PRS) derived from European-only and multi-ancestry GWAS were calculated as weighted sums of independent MM susceptibility variants using discovery GWAS effect estimates. PRS were evaluated in an independent Mayo Clinic European-American case-control dataset including 2,147 cases and 15,279 controls using per SD and decile models, and in the predominantly European ancestry All of Us cohort comprising 670 cases and 222,931 controls.

Results: In the discovery analysis, the European-ancestry analysis identified 70 independent common susceptibility variants and the multi-ancestry analysis identified 68 independent variants, for a total of 74 independent MM susceptibility loci, including 39 novel loci. All 35 previously reported loci replicated at nominal significance in the European-ancestry analysis (P<0.05), and 22 reached genome-wide significance (P<5×10^-8). In the independent replication meta-analysis, 98.6% of European-ancestry and 98.5% of multi-ancestry discovery variants showed directionally consistent effects. Fine-mapping and multi-omics annotation prioritized 81 candidate effector genes. Pathway analyses highlighted enrichment for mitotic cell cycle and replicative senescence biological processes (FDR=3.25×10-5 and 6.85×10-5, respectively), as well as MITF-related pathways (FDR=3.53×10-6), implicating inherited MM susceptibility loci in cell-cycle, senescence, and MITF-regulated transcriptional programs (Lee A et al). Directional effects of variants on MITF pathway activity remain under investigation, but prior work linking reduced MITF expression to B-cell activation and plasma cell differentiation provides a framework for follow-up (Lin L et al). In the Mayo Clinic cohort, both European-derived and multi-ancestry-derived MM-PRS demonstrated strong risk stratification. Per standard deviation increase in PRS, the odds ratio (OR per SD) for MM was 1.91 for the European-derived PRS (95% CI: 1.78-2.04) and 1.92 for the multi-ancestry-derived PRS (95% CI: 1.79-2.06). Compared with the lowest PRS decile, individuals in the highest decile had ORs of 8.72 and 12.85 for the European-derived and multi-ancestry-derived PRS, respectively. In All of Us, the European ancestry MM-PRS association replicated (OR per SD=1.48; 95% CI: 1.38-1.60).

Conclusions: As the largest MM GWAS to date, this study substantially expands the catalog of inherited susceptibility loci and highlights biological pathways relevant to MM development. The multi-ancestry analysis is a step toward broader evaluation of inherited MM risk, although further validation in larger diverse populations is needed. PRS analyses demonstrate strong inherited risk stratification, identifying individuals with markedly elevated MM risk. With further validation, these findings may improve our understanding of the biology of MM, inform risk prediction and early detection strategies, and support prevention efforts.