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Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain.
Wen, Cindy; Margolis, Michael; Dai, Rujia; Zhang, Pan; Przytycki, Pawel F; Vo, Daniel D; Bhattacharya, Arjun; Matoba, Nana; Tang, Miao; Jiao, Chuan; Kim, Minsoo; Tsai, Ellen; Hoh, Celine; Aygün, Nil; Walker, Rebecca L; Chatzinakos, Christos; Clarke, Declan; Pratt, Henry; Peters, Mette A; Gerstein, Mark; Daskalakis, Nikolaos P; Weng, Zhiping; Jaffe, Andrew E; Kleinman, Joel E; Hyde, Thomas M; Weinberger, Daniel R; Bray, Nicholas J; Sestan, Nenad; Geschwind, Daniel H; Roeder, Kathryn; Gusev, Alexander; Pasaniuc, Bogdan; Stein, Jason L; Love, Michael I; Pollard, Katherine S; Liu, Chunyu; Gandal, Michael J.
Afiliação
  • Wen C; Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Margolis M; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Dai R; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Zhang P; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Przytycki PF; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Vo DD; Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • Bhattacharya A; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Matoba N; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Tang M; Gladstone Institute of Data Science and Biotechnology, San Francisco, CA 94158, USA.
  • Jiao C; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Kim M; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Tsai E; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Hoh C; Lifespan Brain Institute, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Aygün N; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Walker RL; Institute for Quantitative and Computational Biosciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Chatzinakos C; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Clarke D; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Pratt H; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Peters MA; Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • Gerstein M; Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Team Krebs, 75014 Paris, France.
  • Daskalakis NP; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Weng Z; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Jaffe AE; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Kleinman JE; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Hyde TM; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Weinberger DR; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Bray NJ; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Sestan N; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Geschwind DH; Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Roeder K; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Gusev A; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Pasaniuc B; Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA.
  • Stein JL; McLean Hospital, Belmont, MA 02478, USA.
  • Love MI; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Pollard KS; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
  • Liu C; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Science ; 384(6698): eadh0829, 2024 May 24.
Article em En | MEDLINE | ID: mdl-38781368
ABSTRACT
Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Encéfalo / Processamento Alternativo / Regulação da Expressão Gênica no Desenvolvimento / Transtornos Mentais Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Encéfalo / Processamento Alternativo / Regulação da Expressão Gênica no Desenvolvimento / Transtornos Mentais Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article