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.