Porcine model of BRD1 haploinsufficiency reveals neurodevelopmental, behavioral, and molecular altera-tions relevant to psychiatric disorders

Abstract

Psychiatric disorders are complex conditions characterized by substantial overlap in genetic risk and shared biological mechanisms. However, how individual risk genes contribute to shared disease mechanisms and disorder-specific phenotypes remains poorly understood. BRD1 has emerged as a chromatin-associated regulator with transdiagnostic relevance across psychiatric disorders and a central role in gene regulatory networks enriched for psychiatric risk genes. To investigate the biological consequences of reduced BRD1 function in a translationally relevant system, we generated a minipig model harboring a monoallelic deletion in BRD1 and performed longitudinal neuroimaging together with behavioral and multi-omics profiling. BRD1 haploinsufficient minipigs displayed normal growth and exploratory behavior but exhibited subtle age-dependent differences in motivational behavior. Despite the absence of overt developmental abnormalities, longitudinal neuroimaging revealed genotype-associated structural differences primarily involving the cerebral cortex and caudate nucleus, suggestive of altered neurodevelopmental trajectories. Integrated multi-omics analyses revealed striking convergence across transcriptomic and metabolomic datasets, identifying coordinated perturbations of mitochondrial function, redox regulation, and phospholipid metabolism across multiple brain regions. Notably, these molecular alterations were not restricted to the central nervous system, as peripheral multi-omics profiling revealed systemic metabolic alterations, including altered phospholipid composition and glucose metabolism. Together, these findings indicate that BRD1 haploinsufficiency is associated with coordinated neurodevelopmental and metabolic alterations across brain and peripheral tissues. More broadly, this study provides systems-level insight into how a psychiatric risk gene influences interconnected neurodevelopmental and metabolic processes across multiple levels of biological organization and highlights the value of large-animal multi-omics models for translational neuropsychiatric research.