Identification of Novel Risk Loci for Common B-Cell Lymphoma Subtypes Through Cross-Trait Analysis with Idiopathic Inflammatory Myopathies

Objectives: The genetic architecture of B-cell lymphomas is not fully characterized. We aimed to identify novel candidate variants associated with four common B-cell lymphoma subtypes—diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), and marginal zone lymphoma (MZL)—through cross-trait analyses with correlated idiopathic inflammatory myopathies subtypes, dermatomyositis (DM) and polymyositis (PM). Methods: Leveraging shared genetic susceptibility with DM and PM, we applied a pleiotropy-informed conditional false discovery rate (condFDR) method to recompute nominal single nucleotide polymorphism association p-values for each B-cell lymphoma subtype. Associations were considered significant at condFDR <0.01. Functional annotation was performed using FUMA (Functional Mapping and Annotation of Genome-Wide Association Studies), followed by Gene Ontology (GO) enrichment analysis via clusterProfiler, with similar GO terms clustered for interpretation and visualization. Results: We identified 4, 2, 13, and 6 novel candidate loci for DLBCL, FL, CLL, and MZL, respectively. Most loci exhibited regulatory effects on genes involved in adaptive immune responses and cell death pathways. Notably, for DLBCL locus 1q23.3 affects SLAMF genes implicated in natural killer and lymphocyte activation. A trans-eQTL at 2q13 for FL was associated with BCL11A, a multifunctional oncogene. For CLL, a novel locus at 16q24.1 regulates IRF8, a known CLL risk gene. Functional mapping of previously reported CLL risk loci revealed RIPK1 (6p25.2), linked to necroptosis. No enriched biological pathways were detected for MZL risk-associated genes. Conclusions: These findings advance our understanding of the genetic architecture of four B-cell lymphoma subtypes and aim to inform future genetic and functional studies.