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Functional characterization of Alzheimer's disease genetic variants in microglia.
Yang, Xiaoyu; Wen, Jia; Yang, Han; Jones, Ian R; Zhu, Xiaodong; Liu, Weifang; Li, Bingkun; Clelland, Claire D; Luo, Wenjie; Wong, Man Ying; Ren, Xingjie; Cui, Xiekui; Song, Michael; Liu, Hongjiang; Chen, Cady; Eng, Nicolas; Ravichandran, Mirunalini; Sun, Yang; Lee, David; Van Buren, Eric; Jiang, Min-Zhi; Chan, Candace S Y; Ye, Chun Jimmie; Perera, Rushika M; Gan, Li; Li, Yun; Shen, Yin.
Afiliação
  • Yang X; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Wen J; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
  • Yang H; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Jones IR; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Zhu X; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • Liu W; Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York City, NY, USA.
  • Li B; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
  • Clelland CD; Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
  • Luo W; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Wong MY; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
  • Ren X; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
  • Cui X; Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York City, NY, USA.
  • Song M; Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York City, NY, USA.
  • Liu H; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Chen C; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Eng N; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Ravichandran M; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • Sun Y; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Lee D; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Van Buren E; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Jiang MZ; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
  • Chan CSY; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Ye CJ; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Perera RM; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Gan L; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Li Y; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Shen Y; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
Nat Genet ; 55(10): 1735-1744, 2023 Oct.
Article em En | MEDLINE | ID: mdl-37735198
ABSTRACT
Candidate cis-regulatory elements (cCREs) in microglia demonstrate the most substantial enrichment for Alzheimer's disease (AD) heritability compared to other brain cell types. However, whether and how these genome-wide association studies (GWAS) variants contribute to AD remain elusive. Here we prioritize 308 previously unreported AD risk variants at 181 cCREs by integrating genetic information with microglia-specific 3D epigenome annotation. We further establish the link between functional variants and target genes by single-cell CRISPRi screening in microglia. In addition, we show that AD variants exhibit allelic imbalance on target gene expression. In particular, rs7922621 is the effective variant in controlling TSPAN14 expression among other nominated variants in the same cCRE and exerts multiple physiological effects including reduced cell surface ADAM10 and altered soluble TREM2 (sTREM2) shedding. Our work represents a systematic approach to prioritize and characterize AD-associated variants and provides a roadmap for advancing genetic association to experimentally validated cell-type-specific phenotypes and mechanisms.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Alzheimer Limite: Humans Idioma: En Revista: Nat Genet Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Alzheimer Limite: Humans Idioma: En Revista: Nat Genet Ano de publicação: 2023 Tipo de documento: Article