A chromosomal connectome for psychiatric and metabolic risk variants in adult dopaminergic neurons
Sergio Espeso‐Gil, Tobias Halene, Jaroslav Bendl, Bibi Kassim, Gabriella Ben Hutta, Marina Iskhakova, Neda Shokrian, Pavan K. Auluck, Behnam Javidfar, Prashanth Rajarajan, Sandhya Chandrasekaran, Cyril Peter, Alanna C. Cote, Rebecca Birnbaum, Will Liao, Tyler Borrman, Jennifer Wiseman, Aaron Bell, Michael J. Bannon, Panagiotis Roussos, John F. Crary, Zhiping Weng, Stefano Marenco, Barbara K. Lipska, Nadejda M. Tsankova, Laura M. Huckins, Yan Jiang, Schahram Akbarian
Abstract
BACKGROUND: Midbrain dopaminergic neurons (MDN) represent 0.0005% of the brain's neuronal population and mediate cognition, food intake, and metabolism. MDN are also posited to underlay the neurobiological dysfunction of schizophrenia (SCZ), a severe neuropsychiatric disorder that is characterized by psychosis as well as multifactorial medical co-morbidities, including metabolic disease, contributing to markedly increased morbidity and mortality. Paradoxically, however, the genetic risk sequences of psychosis and traits associated with metabolic disease, such as body mass, show very limited overlap. METHODS: dopaminergic and other cell-specific nuclei collected by fluorescence-activated nuclei sorting from the adult human midbrain. RESULTS: The Hi-C-reconstructed MDN spatial genome revealed 11 "Euclidean hot spots" of clustered chromatin domains harboring risk sequences for SCZ and elevated BMI. Inter- and intra-chromosomal contacts interconnecting SCZ and BMI risk sequences showed massive enrichment for brain-specific expression quantitative trait loci (eQTL), with gene ontologies, regulatory motifs and proteomic interactions related to adipogenesis and lipid regulation, dopaminergic neurogenesis and neuronal connectivity, and reward- and addiction-related pathways. CONCLUSIONS: We uncovered shared nuclear topographies of cognitive and metabolic risk variants. More broadly, our PsychENCODE sponsored Hi-C study offers a novel genomic approach for the study of psychiatric and medical co-morbidities constrained by limited overlap of their respective genetic risk architectures on the linear genome.