MUTATE: A Human Genetic Atlas of Multi-organ AI Endophenotypes using GWAS Summary Statistics

Artificial intelligence (AI) has been increasingly integrated into imaging genetics to provide intermediate phenotypes (i.e., endophenotypes) that bridge the genetics and clinical manifestations of human disease. However, the genetic architecture of these AI endophenotypes remains largely unexplored in the context of human multi-organ system diseases. Using publicly available GWAS summary statistics from the UK Biobank, FinnGen, and the Psychiatric Genomics Consortium, we comprehensively depicted the genetic architecture of 2024 multi-organ AI endophenotypes (MAEs). Two AI- and imaging-derived subtypes1 showed lower polygenicity and weaker negative selection effects than schizophrenia disease diagnoses2, supporting the endophenotype hypothesis3. Genetic correlation and Mendelian randomization results demonstrate both within-organ connections and cross-organ talk. Bi-directional causal relationships were established between chronic human diseases and MAEs across multiple organ systems, including Alzheimer's disease for the brain, diabetes for the metabolic system, asthma for the pulmonary system, and hypertension for the cardiovascular system. Finally, we derived the polygenic risk scores of the 2024 MAEs. Our findings underscore the promise of the MAEs as new instruments to ameliorate overall human health. All results are encapsulated into the MUTATE genetic atlas and are publicly available at https://labs-laboratory.com/mutate. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement NA ### 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: We only used GWAS summary statistics, not individual data, from UK Biobank, FinnGen, and PGC. Therefore, they are all publicly available. For UK Biobank data, the study used only GWAS summary statistics rather than individual-level data from the UK Biobank. However, the 2024 MAE GWAS data was initially derived from previous studies conducted under Application Numbers 35148 and 60698 from the UK Biobank. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 The results of the MUTATE atlas are disseminated at the MUTATE knowledge portal: https://labs-laboratory.com/mutate. The GWAS summary statistics for the 2024 MAEs can be accessed publicly through the MEDICINE knowledge portal: https://labs-laboratory.com/medicine and the BRIDGEPORT knowledge portal: https://labs-laboratory.com/bridgeport. The GWAS summary statistics for the 521 DEs from FinnGen are publicly available at: https://finngen.gitbook.io/documentation/v/r9/. The GWAS summary statistics for the 4 DEs from PGC are publicly available at: https://pgc.unc.edu/for-researchers/download-results/. The study used only GWAS summary statistics rather than individual-level data from the UK Biobank. However, the 2024 MAE GWAS data was initially derived from previous studies conducted under Application Numbers 35148 and 60698 from the UK Biobank.