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RISS 인기검색어
- 검색키워드
- 저자 : Gandal, Michael J (검색결과 2 건)
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The road to precision psychiatry: translating genetics into disease mechanisms
Gandal, Michael J,Leppa, Virpi,Won, Hyejung,Parikshak, Neelroop N,Geschwind, Daniel H NATURE AMERICA 2016 NATURE NEUROSCIENCE Vol.19 No.11
Hundreds of genetic loci increasing risk for neuropsychiatric disorders have recently been identified. This success, perhaps paradoxically, has posed challenges for therapeutic development, which are amplified by the highly polygenic and pleiotropic nature of these genetic contributions. Success requires understanding the biological impact of single genetic variants and predicting their effects within an individual. Comprehensive functional genomic annotation of risk loci provides a framework for interpretation of neurobiological impact, requiring experimental validation with in vivo or in vitro model systems. Systems-level, integrative pathway analyses are beginning to elucidate the additive, polygenic contributions of risk variants on specific cellular, molecular, developmental, or circuit-level processes. Although most neuropsychiatric disease modeling has focused on genes disrupted by rare, large-effect-size mutations, common smaller-effect-size variants may also provide solid therapeutic targets to inform precision medicine approaches. Here we enumerate the promise and challenges of a genomics-driven approach to uncovering neuropsychiatric disease mechanisms and facilitating therapeutic development.
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Chromosome conformation elucidates regulatory relationships in developing human brain
Won, Hyejung,de la Torre-Ubieta, Luis,Stein, Jason L.,Parikshak, Neelroop N.,Huang, Jerry,Opland, Carli K.,Gandal, Michael J.,Sutton, Gavin J.,Hormozdiari, Farhad,Lu, Daning,Lee, Changhoon,Eskin, Elea Nature Publishing Group 2016 Nature Vol. No.
Three-dimensional physical interactions within chromosomes dynamically regulate gene expression in a tissue-specific manner. However, the 3D organization of chromosomes during human brain development and its role in regulating gene networks dysregulated in neurodevelopmental disorders, such as autism or schizophrenia, are unknown. Here we generate high-resolution 3D maps of chromatin contacts during human corticogenesis, permitting large-scale annotation of previously uncharacterized regulatory relationships relevant to the evolution of human cognition and disease. Our analyses identify hundreds of genes that physically interact with enhancers gained on the human lineage, many of which are under purifying selection and associated with human cognitive function. We integrate chromatin contacts with non-coding variants identified in schizophrenia genome-wide association studies (GWAS), highlighting multiple candidate schizophrenia risk genes and pathways, including transcription factors involved in neurogenesis, and cholinergic signalling molecules, several of which are supported by independent expression quantitative trait loci and gene expression analyses. Genome editing in human neural progenitors suggests that one of these distal schizophrenia GWAS loci regulates FOXG1 expression, supporting its potential role as a schizophrenia risk gene. This work provides a framework for understanding the effect of non-coding regulatory elements on human brain development and the evolution of cognition, and highlights novel mechanisms underlying neuropsychiatric disorders.
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