Abstract
The development and progression of cardiometabolic diseases and depression multimorbidity involves pathophysiological processes across multiple organs. Using multi-organ imaging data from 31,246 UK Biobank participants, we investigate the multi-organ manifestations and their phenotypic connections and shared genetic architecture underlying the multimorbidity. Phenotypic analyses identify seven abdominal, 16 cardiac, and 107 brain traits forming 1418 abdomen-heart-brain cliques, with liver volume, myocardial wall thickness, and white matter hyperintensity volume as central nodes. Genetic analyses reveal 43 distinct genomic loci (21 novel) shared by these cliques, with the most widely shared loci mapped to genes NUDC, ARID1A, and CRHR1. The 224 protein-coding genes mapped by these loci are enriched in 39 biological processes related to cardiometabolic and neuropsychiatric functions, with 15 genes expressed across liver-heart-brain axis tissues. Combining biochemical and multi-organ imaging indicators significantly improves multimorbidity prediction. These findings uncover multi-organ network underlying physical-mental multimorbidity and highlight the necessity of holistic management.