Multi-organ genetic causal connections inferred from imaging and clinical data through Mendelian randomization

Functional and morphological architectures of major human organs have been well characterized using imaging biomarkers. Nevertheless, deciphering the causal relationships between imaging biomarkers and major clinical outcomes, as well as understanding the causal interplay across multiple organs, remains a formidable challenge. Mendelian randomization (MR) presents a framework for inferring causality by using genetic variants as instrumental variables. Here we report a systematic multi-organ MR analysis between 402 imaging biomarkers and 88 clinical outcomes. We identified 488 genetic causal links for 62 diseases and 130 imaging biomarkers from 9 organs, tissue, or systems, including the brain, heart, liver, kidney, lung, pancreas, spleen, adipose tissue, and skeleton system. We prioritized crucial 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 adverse impact of heart diseases on brain health. Our findings uncover the genetic causal links spanning multiple organs, offering a more profound understanding of the intricate relationships between organ imaging biomarkers and clinical outcomes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study has been partially supported by funding from the Wharton Dean's Research Fund and Analytics at Wharton, as well as start-up funds from Purdue Statistics Department. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for the UK Biobank study was secured from the North West Multicentre Research Ethics Committee (approval number: 11/NW/0382). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes We used summary-level GWAS data in this study, which can be obtained from the FinnGen project (https://www.finngen.fi/en/access_results), BIG-KP (https://bigkp.org/), Heart-KP (https://heartkp.org/), and project-specific resources detailed in Liu., et al and Kun., et al. Our multi-organ MR results can be explored at https://mr4mo.org/