A chromosomal connectome for psychiatric and metabolic risk variants in adult dopaminergic neurons

• Published in: Genome medicine Vol. 12; no. 1; p. 19
• Main Authors: Espeso-Gil, Sergio, Halene, Tobias, Bendl, Jaroslav, Kassim, Bibi, Ben Hutta, Gabriella, Iskhakova, Marina, Shokrian, Neda, Auluck, Pavan, Javidfar, Behnam, Rajarajan, Prashanth, Chandrasekaran, Sandhya, Peter, Cyril J, Cote, Alanna, Birnbaum, Rebecca, Liao, Will, Borrman, Tyler, Wiseman, Jennifer, Bell, Aaron, Bannon, Michael J, Roussos, Panagiotis, Crary, John F, Weng, Zhiping, Marenco, Stefano, Lipska, Barbara, Tsankova, Nadejda M, Huckins, Laura, Jiang, Yan, Akbarian, Schahram
• Format: Journal Article
• Language: English
• Published: England BioMed Central 19.02.2020; BMC
• Subjects: Addictions; Adipogenesis; Animals; BMI GWAS; Body Mass Index; Brain; chrom3D; Chromatin; Chromosomes - genetics; Cognition; Cognitive ability; Deoxyribonucleic acid; DNA; Dopamine receptors; Dopaminergic Neurons - metabolism; Euclidean hot spots; Flow cytometry; Food intake; Gene expression; Genomes; Homeostasis; Humans; Immunoglobulins; Lipid Metabolism; Mental disorders; Mesencephalon; Mesencephalon - cytology; Mesencephalon - metabolism; Metabolic disorders; Metabolism; Mice; Mice, Inbred C57BL; Morbidity; Neural networks; Neurogenesis; Polymorphism, Genetic; Proteins; Proteomics; Protocol; Psychosis; Quantitative Trait Loci; Reinforcement; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Schizophrenia - pathology; Schizophrenia GWAS; Shared nuclear territories; Spatial genome; Obesity; Schizophrenia GWAS; Dopamine; Euclidean hot spots; Shared nuclear territories; Neurons; Spatial genome; BMI GWAS; chrom3D; Schizophrenia; Metabolic syndrome
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-020-0715-x

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. We investigated the genomic interaction of SCZ with medical conditions and traits, including body mass index (BMI), by exploring the MDN's "spatial genome," including chromosomal contact landscapes as a critical layer of cell type-specific epigenomic regulation. Low-input Hi-C protocols were applied to 5-10 × 10 dopaminergic and other cell-specific nuclei collected by fluorescence-activated nuclei sorting from the adult human midbrain. 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. 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.