Porcine model of BRD1 haploinsufficiency reveals neurodevelopmental, behavioral, and molecular alterations relevant to psychiatric disorders

Psychiatric disorders are heritable and biologically complex, with overlapping genetic architectures and shared molecular pathways. Among implicated genes, BRD1 has emerged as an epigenetic regulator of neurodevelopment with broad relevance for several psychiatric or mental diagnostic categories. To investigate its functional impact, we generated a genetically modified Göttingen minipig model harboring a monoallelic deletion in BRD1 , enabling translational analyses of its role in brain development and systemic physiology.

BRD1 haploinsufficient minipigs showed normal growth and exploratory behavior but displayed subtle, age-progressive alterations in reward processing. Longitudinal brain imaging revealed structural changes, particularly in the cerebral cortex and caudate nucleus, that attenuated over time, thus mirroring developmental trajectories observed in psychiatric disorders. Transcriptomic profiling across brain regions uncovered differential expression of genes involved in synaptic signaling, mitochondrial function, and metabolic regulation. These changes were accompanied by brain metabolomic shifts, notably in glutathione and selenoamino acid metabolism.

Crucially, these alterations extended beyond the brain. Peripheral transcriptomics revealed systemic metabolic reprogramming, paralleled by consistent shifts in plasma metabolomic and lipidomic profiles, including altered sucrose and phospholipid species, and modestly reduced blood glucose levels.

Together, these findings demonstrate that BRD1 haploinsufficiency disrupts neurodevelopmental and metabolic homeostasis and is accompanied by systemic molecular signatures detectable in peripheral tissues. This work provides mechanistic insight into the biological consequences of psychiatric genetic risk and underscores the value of cross-species, multi-omics models in psychiatric research.