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

Molecular Neurodegeneration

Research Article

Matthew Baker¹  Mariet Allen¹  Kristi Biswas¹  Melissa E. Murray¹  Yuka A. Martens¹  Guojun Bu¹  Michael DeTure¹  Chia-Chen Liu¹  Takahisa Kanekiyo¹  Dennis W. Dickson¹  Stephanie R. Oatman¹  Minerva M. Carrasquillo¹  Yu Yamazaki¹  Thuy T. Nguyen¹  Na Zhao¹  Kimberly Malphrus¹  Nilüfer Ertekin-Taner²  Rosa Rademakers³  Michael Heckman⁴  Zachary Quicksall⁴  Joseph S. Reddy⁴  Xue Wang⁴  Jun Pyo Kim⁵  Andrew J. Saykin⁶  Shannon L. Risacher⁷  Kwangsik Nho⁸ 

[1] Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, 32224, Jacksonville, FL, USA;Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, 32224, Jacksonville, FL, USA;Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Birdsall 3, 32224, Jacksonville, FL, USA;Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, 32224, Jacksonville, FL, USA;VIB-UA Center for Molecular Neurology, VIB, University of Antwerp, Antwerp, Belgium;Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA;Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA;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;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;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;

关键词: Alzheimer’s;    Genetics;    APOE;    Amyloid;    Tau;    Association;    Brain;    GWAS;    Neuroscience;    Diseases;    Biochemistry;   

DOI  :  10.1186/s13024-022-00592-2

 received in 2022-07-19, accepted in 2022-12-19,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundAlzheimer’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.MethodsGenome-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.ResultsWe 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.ConclusionsAlthough 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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