Large-Scale Identification of Novel Protein Biomarkers and Therapeutic Targets in Heart and Brain Disease.

Neurological complications frequently impact morbidity, mortality, and quality of life in patients with cardiovascular disease, yet the biological mediators connecting cardiovascular and neurological disease are poorly understood. Leveraging data from 53,014 individuals with plasma proteomic profiles and 50,228 with cardiac and brain MRI from the UK Biobank, we systematically identified circulating proteins correlated with MRI imaging-derived phenotypes (IDPs) (404 proteins with cardiac IDPs; 76 with brain IDPs; 37 with both). Identified proteins were remarkably enriched for biomarkers and mediators of disease in one or both organs. Expression analyses suggested these proteins largely originate from fibroblasts, smooth muscle cells, and macrophages in the arterial vasculature. Pathway analyses highlighted cytokine and vasculature-related processes for cardiac IDPs-associated proteins and extracellular matrix pathways in brain IDPs-associated proteins. Mendelian Randomization and genetic co-localization supported causal roles for most (>63%) of the proteins in disease pathogenesis in one or both organs. Over 90% of the implicated candidates have not previously been established as clinical biomarkers or therapeutic targets. These studies underscore the value of large-scale integrated multi-organ datasets, including plasma proteomics, imaging-derived endophenotypes, and genetics, in unraveling complex disease pathobiology, highlight the close connections between heart and brain disease, and provide a catalog of hundreds of novel candidate biomarkers and therapeutic targets.