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Novikova, Gloriia; T.C.W., Julia; Marcora, Edoardo; Kapoor, Manav; Renton, Alan E.; Efthymiou, Anastasia M.; Abud, Edsel M.; Bendl, Jaroslav M.; Cheng, Haoxiang M.; Fullard, John F.; Roussos, Panos; Poon, Wayne W.; Hao, Ke; Goate, Alison M.

Genetic studies of Alzheimer's disease risk implicate clearance of lipid rich debris in myeloid cells : Lipids in AD and FTD: From genes to interventions : Lipids in AD and FTD: From genes to interventions

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  • Medientyp: E-Artikel
  • Titel: Genetic studies of Alzheimer's disease risk implicate clearance of lipid rich debris in myeloid cells : Lipids in AD and FTD: From genes to interventions : Lipids in AD and FTD: From genes to interventions
  • Beteiligte: Novikova, Gloriia; T.C.W., Julia; Marcora, Edoardo; Kapoor, Manav; Renton, Alan E.; Efthymiou, Anastasia M.; Abud, Edsel M.; Bendl, Jaroslav M.; Cheng, Haoxiang M.; Fullard, John F.; Roussos, Panos; Poon, Wayne W.; Hao, Ke; Goate, Alison M.
  • Erschienen: Wiley, 2020
  • Erschienen in: Alzheimer's & Dementia
  • Sprache: Englisch
  • DOI: 10.1002/alz.040601
  • ISSN: 1552-5260; 1552-5279
  • Schlagwörter: Psychiatry and Mental health ; Cellular and Molecular Neuroscience ; Geriatrics and Gerontology ; Neurology (clinical) ; Developmental Neuroscience ; Health Policy ; Epidemiology
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Genome‐wide association studies (GWAS) have identified more than forty loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements and genes remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Earlier pathway analyses have implicated lipid metabolism, immune response and endocytosis.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>We used LDscore regression to determine the epigenomic annotations enriched for AD risk variants. We then integrated AD GWAS signals with epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification.</jats:p></jats:sec><jats:sec><jats:title>Result</jats:title><jats:p>We show that AD risk variants are specifically enriched in active enhancers of monocytes, macrophages and microglia. Using summary‐data based Mendelian Randomization nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine‐mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression specifically in myeloid cells. In the <jats:italic>APOE</jats:italic> locus we used genome editing to generate isogenic human induced pluripotent stem cells (hiPSC) combined with transcriptomics to demonstrate dyshomeostasis of lipid metabolism in <jats:italic>APOE44</jats:italic> glial cells from.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Combined, these results strongly implicate dysfunction of myeloid cell endo‐lysosomal pathways involved in clearance of lipid rich debris in the etiology of AD.</jats:p></jats:sec>