Work

Characterizing the genetic basis of Cardio-Renal-Metabolic multimorbidity using multivariate genomic modelling

Year: 2026

Type: preprint

Study design: Observational Study

Abstract: Cardio-renal-metabolic multimorbidity (CRMM) denotes co-occurring cardiovascular, kidney, and metabolic diseases. The shared genetic architecture of CRMM across diverse ancestries remains incompletely understood. Using ancestry-specific GWAS-summary statistics from >3.5 million participants across seven biobanks, we applied genomic structural equation modelling to characterise shared genetic architecture of hypertension, heart failure, ischaemic heart disease, chronic kidney disease, and type 2 diabetes in European (EUR), East Asian (EAS), and African (AFR) populations. Conditional analysis of the hierarchical latent-factor model identified 148, 16, and 138 independent CRMM-associated loci in EUR, AFR, and EAS populations, respectively. Integrative analyses implicated neurological pathways and brain-tissue enrichment, nominating ATXN2L as a putative functional gene. Drug repurposing analyses highlighted existing diabetes and hypertension therapies as potential therapeutic candidates, while Mendelian randomisation identified adiposity, cholesterol, and other traits as candidate causal risk factors for CRMM. These findings delineate cross-ancestry and ancestry-specific CRMM genetics, informing therapeutic targets and precision medicine.

Source: medRxiv

DOI: 10.64898/2026.06.16.26355643

Authors: Abhiram D. B., Vignesh Arunachalam, Rodney A Lea, Kim Ngan Tran, Rohit Mishra, Prasad Challa, Sree K Venuthurupalli, Samuel Sidharta, Shivashankar H. Nagaraj

Institutions: Griffith University, University of California, San Francisco, Queensland University of Technology, The University of Queensland, Queensland Health, Logan Hospital, Toowoomba Hospital, Central Queensland Hospital and Health Service

Language: English

Topic: Genetic Associations and Epidemiology

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, Medical Research Council, National Health and Medical Research Council

Awards: Illinois Precision Medicine Consortium , Healthy Americas: All of Us Research Program, G1969433312, G2187930703, Empowerment-focused Outreach, Education and Enrollment of Tennessee Older Adults in the All of Us Research Program through Community Efforts by FiftyForward, Research Matters: Creating Possibilities to Achieve Health and Wellness for All of Us Research Program, Intersecting epidemics: genetic and clinical determinants of comorbid chronic kidney disease and diabetes in Indigenous Australians, Precision Medicine Initiative Cohort Program Biobank, Communications Design and Development for NIH Precision Medicine Initiative Research Projects, New York City Consortium for Precision Medicine, Technology to Empower Changes in Health (TECH) Network Participant Technologies Center, University of Arizona-Banner Health All of Us Research Program , The New England Precision Medicine Consortium of the All of Us Research Program, All of Us Wisconsin , Data and Research Support Center , All of Us Pennsylvania, Trans-America Consortium of the Health Care Systems Research Network for the All of Us Research Program, Southern All of Us Network, SouthEast Enrollment Center (SEEC) , Adaptive Platform for Personalized Engagement, G8355735039, Communication Implementation and Coordination for NIH Precision Medicine Initiative Research Projects, PRIDEnet for the All of Us Research Program

OpenAlex ID: W7165028030

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