Inferring Multi-Organ Genetic Causal Connections using Imaging and Clinical Data through Mendelian Randomization

Abstract Deciphering the complex causal relationships between multiple organs and major clinical outcomes and the causal interplay among multiple organs remains a significant challenge. By utilizing imaging biomarkers, we can characterize the functional and structural architectures of major human organs. Mendelian randomization (MR) provides a valuable framework for inferring causality by leveraging genetic variants as instrumental variables. In this study, we conducted a systematic multi-organ MR analysis involving 402 imaging biomarkers and 88 clinical outcomes. Our analysis revealed 488 genetic causal links for 62 diseases and 130 imaging biomarkers across various organs, tissues, and systems, including the brain, heart, liver, kidney, lung, pancreas, spleen, adipose tissue, and skeletal system. We specifically focused on critical intra-organ causal connections, such as the bidirectional genetic links between Alzheimer’s disease and brain function, as well as inter-organ causal effects, such as the detrimental impact of heart diseases on brain health. These findings shed light on the genetic causal links spanning multiple organs, contributing to a deeper understanding of the intricate relationships between organ imaging biomarkers and clinical outcomes. Our multi-organ MR results can be explored at https://mr4mo.org/ .