Neural–genetic–environmental evidence for a disease factor in mental and physical health multimorbidity

Jin Chen, Yuning Zhang, Shu Liu, Miguel Garcia-Argibay, Tianye Jia, Jujiao Kang, Wei Li, Marco Solmi, Hongyi Sun, Wenqi Liu, Congying Chu (), Samuele Cortese () and Jiaojian Wang ()
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Jin Chen: Kunming University of Science and Technology
Yuning Zhang: University of Southampton
Shu Liu: National Research Facility for Phenotypic and Genetic Analysis of Model
Miguel Garcia-Argibay: University of Southampton
Tianye Jia: Fudan University
Jujiao Kang: Fudan University
Wei Li: Kunming University of Science and Technology
Marco Solmi: University of Ottawa
Hongyi Sun: University of Southampton
Wenqi Liu: Kunming University of Science and Technology
Congying Chu: Chinese Academy of Sciences
Samuele Cortese: University of Southampton
Jiaojian Wang: Kunming University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Increasing evidence reveals the presence of multimorbidity across physical and mental disorders. A general disease factor (d factor) has been recently identified to capture the shared liability across these conditions, yet its biological basis remains poorly understood. Here, using data from the UK Biobank, we reveal the d factor’s neural, genetic, and environmental underpinnings. We show that the d factor is associated with extreme negative deviations in grey matter volume and white matter microstructure. A genome-wide association study identifies its genetic loci and correlations with unhealthy lifestyle, anthropometric measures, and mood-related phenotypes. Furthermore, Mendelian randomization suggests a causal effect of living environmental deprivation on the d factor. Mediation analysis further reveals that the d factor links this environmental adversity to individual differences in brain structure. Our findings establish a multi-level biological characterization of general disease liability, connecting environmental, genetic, and neural factors and inform transdiagnostic approaches to prevention and treatment.

Date: 2025
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DOI: 10.1038/s41467-025-65055-w

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