Proteome-wide Mendelian randomization identifies protein associations and therapeutic targets for B-cell malignancy

● We used Mendelian randomisation to identify 27 circulating proteins associated with increased risk of B-cell malignancy. ● We integrated evidence from genetic colocalisation, ligand structure and single-cell expression data, identifying 23 potential drug targets. Despite therapeutic advances in B-cell malignancies many patients continue to experience relapse or refractory disease, highlighting an unmet need for novel drug targets. The high attrition rate of drug development programs, however, represents a productivity-limiting step. To prioritise candidate drug targets, we employed Mendelian Randomisation to evaluate causal associations between 2,923 circulating proteins and six B-cell malignancies (22,922 cases and 388,978 controls). We identified 27 protein-disease associations, including TNFSF13 (APRIL) and TNFRS13B (TACI) in multiple myeloma, CD40 in Hodgkin’s lymphoma and FAS in chronic lymphocytic leukaemia. All results are interactively accessible via our R/Shiny application ( https://software.icr.ac.uk/app/mrcan ). Integrating single-cell RNA-sequencing from 183,355 haematolymphoid cells, Bayesian colocalisation and clinical trial evidence, we prioritised 23 proteins as candidate drug targets. This study demonstrates the potential of human genetics to guide therapeutic discovery for B-cell neoplasia.