Brain-heart-eye axis revealed by multi-organ imaging genetics and proteomics

Abstract

Multiorgan research investigates interconnections among multiple human organ systems, enhancing our understanding of human aging and disease mechanisms. Here, we used multiorgan imaging (N=105,433), individual and summary level genetics, and proteomics (N=53,940) from the UK Biobank, Baltimore Longitudinal Study of Aging, FinnGen, and Psychiatric Genomics Consortium to delineate a brain-heart-eye axis via 2003 brain patterns of structural covariance (PSC), 82 heart imaging-derived phenotypes (IDP) and 84 eye IDPs. Cross-organ phenotypic associations highlight the central autonomic network between the brain and heart and the central visual pathway between the brain and eye. Proteome wide associations of the PSCs and IDPs show both within organ specificity and cross-organ interconnections, verified by the RNA and protein expression profiles of the 2923 plasma proteins. Pleiotropic effects of common genetic variants are observed across multiple organs, and key genetic parameters, such as SNP-based heritability, polygenicity, and selection signatures, are comparatively evaluated among the three organs. A gene-drug-disease network shows the potential of drug repurposing for cross-organ diseases. Colocalization and causal analyses reveal cross-organ causal relationships between PSC/IDP and chronic diseases, such as Alzheimer's disease, heart failure, and glaucoma. Finally, integrating multi-organ/omics features improves prediction for systemic disease categories and cognition compared to single-organ/omics features. This study depicts a detailed brain-heart-eye axis and highlights future avenues for modeling human aging and disease across multiple scales. All results are publicly available at https://labs-laboratory.com/medicine/.