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Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain.
Fujita, Masashi; Gao, Zongmei; Zeng, Lu; McCabe, Cristin; White, Charles C; Ng, Bernard; Green, Gilad Sahar; Rozenblatt-Rosen, Orit; Phillips, Devan; Amir-Zilberstein, Liat; Lee, Hyo; Pearse, Richard V; Khan, Atlas; Vardarajan, Badri N; Kiryluk, Krzysztof; Ye, Chun Jimmie; Klein, Hans-Ulrich; Wang, Gao; Regev, Aviv; Habib, Naomi; Schneider, Julie A; Wang, Yanling; Young-Pearse, Tracy; Mostafavi, Sara; Bennett, David A; Menon, Vilas; De Jager, Philip L.
Affiliation
  • Fujita M; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
  • Gao Z; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
  • Zeng L; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
  • McCabe C; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • White CC; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
  • Ng B; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
  • Green GS; Edmond & Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
  • Rozenblatt-Rosen O; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Phillips D; Genentech, South San Francisco, CA, USA.
  • Amir-Zilberstein L; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lee H; Genentech, South San Francisco, CA, USA.
  • Pearse RV; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Khan A; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA.
  • Vardarajan BN; Harvard Medical School, Boston, MA, USA.
  • Kiryluk K; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA.
  • Ye CJ; Harvard Medical School, Boston, MA, USA.
  • Klein HU; Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
  • Wang G; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Regev A; Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY, USA.
  • Habib N; The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Schneider JA; Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
  • Wang Y; Institute for Human Genetics, University of California, San Francisco, CA, USA.
  • Young-Pearse T; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
  • Mostafavi S; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
  • Bennett DA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
  • Menon V; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
  • De Jager PL; Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY, USA.
Nat Genet ; 56(4): 605-614, 2024 Apr.
Article in En | MEDLINE | ID: mdl-38514782
ABSTRACT
The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Alzheimer Disease Limits: Humans Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2024 Document type: Article Affiliation country:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Alzheimer Disease Limits: Humans Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2024 Document type: Article Affiliation country: