دورية أكاديمية
أعرض في EDS

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's disease related proteins.

التفاصيل البيبلوغرافية
العنوان: Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's disease related proteins.
المؤلفون: Oatman SR; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Reddy JS; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., Quicksall Z; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., Carrasquillo MM; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Wang X; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., Liu CC; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Yamazaki Y; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Nguyen TT; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Malphrus K; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Heckman M; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., Biswas K; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Nho K; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.; School of Informatics and Computing, Indiana University School of Medicine, Indianapolis, IN, USA., Baker M; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Martens YA; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Zhao N; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Kim JP; Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA., Risacher SL; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA., Rademakers R; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.; VIB-UA Center for Molecular Neurology, VIB, University of Antwerp, Antwerp, Belgium., Saykin AJ; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA., DeTure M; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Murray ME; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Kanekiyo T; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Dickson DW; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Bu G; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Allen M; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Ertekin-Taner N; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Taner.Nilufer@mayo.edu.; Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Birdsall 3, Jacksonville, FL, 32224, USA. Taner.Nilufer@mayo.edu.
مؤلفون مشاركون: Alzheimer’s Disease Neuroimaging Initiative
المصدر: Molecular neurodegeneration [Mol Neurodegener] 2023 Jan 07; Vol. 18 (1), pp. 2. Date of Electronic Publication: 2023 Jan 07.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 101266600 Publication Model: Electronic Cited Medium: Internet ISSN: 1750-1326 (Electronic) Linking ISSN: 17501326 NLM ISO Abbreviation: Mol Neurodegener Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : BioMed Central, 2006-
مواضيع طبية MeSH: Alzheimer Disease*/metabolism, Humans ; Genome-Wide Association Study ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Plaque, Amyloid/pathology ; Phenotype ; Apolipoproteins E/metabolism ; tau Proteins/metabolism
مستخلص: Background: Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The main protein components of these hallmarks include Aβ40, Aβ42, tau, phosphor-tau, and APOE. We hypothesize that genetic variants influence the levels and solubility of these AD-related proteins in the brain; identifying these may provide key insights into disease pathogenesis.
Methods: Genome-wide genotypes were collected from 441 AD cases, imputed to the haplotype reference consortium (HRC) panel, and filtered for quality and frequency. Temporal cortex levels of five AD-related proteins from three fractions, buffer-soluble (TBS), detergent-soluble (Triton-X = TX), and insoluble (Formic acid = FA), were available for these same individuals. Variants were tested for association with each quantitative biochemical measure using linear regression, and GSA-SNP2 was used to identify enriched Gene Ontology (GO) terms. Implicated variants and genes were further assessed for association with other relevant variables.
Results: We identified genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways.
Conclusions: Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.
(© 2023. The Author(s).)
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معلومات مُعتمدة: U01 AG046139 United States AG NIA NIH HHS; R37AG027924 United States AG NIA NIH HHS; P50AG016574 United States AG NIA NIH HHS; RF1 AG051504 United States AG NIA NIH HHS; R01 AG061796 United States AG NIA NIH HHS; P30 AG010133 United States AG NIA NIH HHS; R01 AG057739 United States AG NIA NIH HHS; R01 LM013463 United States LM NLM NIH HHS; U01 AG024904 United States AG NIA NIH HHS; R01 AG019771 United States AG NIA NIH HHS; T32 AG071444 United States AG NIA NIH HHS; U01 AG072177 United States AG NIA NIH HHS; U24 AG021886 United States AG NIA NIH HHS; R01 AG069901 United States AG NIA NIH HHS; U01 AG068057 United States AG NIA NIH HHS; R01 AG068193 United States AG NIA NIH HHS; R01 LM012535 United States LM NLM NIH HHS; P01 AG003949 United States AG NIA NIH HHS; P30 AG072976 United States AG NIA NIH HHS
فهرسة مساهمة: Keywords: APOE; Alzheimer’s; Amyloid; Association; Biochemistry; Brain; Diseases; GWAS; Genetics; Neuroscience; Tau
المشرفين على المادة: 0 (Amyloid beta-Peptides)
0 (Apolipoproteins E)
0 (tau Proteins)
تواريخ الأحداث: Date Created: 20230107 Date Completed: 20230110 Latest Revision: 20240823
رمز التحديث: 20240823
مُعرف محوري في PubMed: PMC9825010
DOI: 10.1186/s13024-022-00592-2
PMID: 36609403
قاعدة البيانات: MEDLINE
الوصف
تدمد:1750-1326
DOI:10.1186/s13024-022-00592-2