Downregulated transcription in chromosomal domains of midbrain dopamine neurons linked to schizophrenia

Ventral midbrain dopaminergic neurons are a key cell type for schizophrenia pathophysiology but information about cell type-specific genomic dysregulation in diseased brains is missing. We generated a unique midbrain functional genomics resource with 97 RNA-seq and 34 Hi-C chromosomal contact libraries for Nurr1 + /NeuN+ dopaminergic and their surrounding Nurr1-/NeuN- nuclei, collected from donors diagnosed with schizophrenia (SCZ), bipolar disorder (BD) and compared to neurotypical controls. Among the 954 dopamine neuron genes specifically dysregulated in SCZ, 331 were downregulated, with selective enrichment for risk-associated synaptic plasticity and neuronal connectivity pathways and embedded within dopamine neuron-specific topologically associated chromosomal domains (TAD). Transcript-resolved analysis revealed 2,350 transcripts with altered expression in SCZ dopamine neurons, affecting key susceptibility genes such as the FOXP1, MAPK10, PCM1 and NRXN1. Therefore, genomic dysregulation in the ventral midbrain of subjects diagnosed with SCZ selectively affects dopaminergic neurons, and includes a unilateral association of genetic risk with down-, but not upregulated transcription at the sites of highly organized chromosomal domains harboring neuron-specific genes with complex transcriptional architectures.