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Brain-trait-associated variants impact cell-type-specific gene regulation during neurogenesis.
Aygün, Nil; Elwell, Angela L; Liang, Dan; Lafferty, Michael J; Cheek, Kerry E; Courtney, Kenan P; Mory, Jessica; Hadden-Ford, Ellie; Krupa, Oleh; de la Torre-Ubieta, Luis; Geschwind, Daniel H; Love, Michael I; Stein, Jason L.
Affiliation
  • Aygün N; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Elwell AL; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Liang D; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Lafferty MJ; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Cheek KE; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Courtney KP; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Mory J; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Hadden-Ford E; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Krupa O; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • de la Torre-Ubieta L; Neurogenetics Program, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095
  • Geschwind DH; Neurogenetics Program, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095
  • Love MI; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Stein JL; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: jason_stein@med.unc.edu.
Am J Hum Genet ; 108(9): 1647-1668, 2021 09 02.
Article in En | MEDLINE | ID: mdl-34416157
ABSTRACT
Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n = 85) and their sorted neuronal progeny (n = 74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type-specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Chromosomal Proteins, Non-Histone / Gene Expression Regulation, Developmental / Neocortex / Quantitative Trait Loci / Neurogenesis / Neurons Type of study: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Language: En Journal: Am J Hum Genet Year: 2021 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Chromosomal Proteins, Non-Histone / Gene Expression Regulation, Developmental / Neocortex / Quantitative Trait Loci / Neurogenesis / Neurons Type of study: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Language: En Journal: Am J Hum Genet Year: 2021 Document type: Article Affiliation country: Estados Unidos