Interpretable deep learning translation of GWAS and multi-omics findings to identify pathobiology and drug repurposing in Alzheimer's disease.

Journal: Cell reports
Published Date: Nov 29, 2022

Abstract

Translating human genetic findings (genome-wide association studies [GWAS]) to pathobiology and therapeutic discovery remains a major challenge for Alzheimer's disease (AD). We present a network topology-based deep learning framework to identify disease-associated genes (NETTAG). We leverage non-coding GWAS loci effects on quantitative trait loci, enhancers and CpG islands, promoter regions, open chromatin, and promoter flanking regions under the protein-protein interactome. Via NETTAG, we identified 156 AD-risk genes enriched in druggable targets. Combining network-based prediction and retrospective case-control observations with 10 million individuals, we identified that usage of four drugs (ibuprofen, gemfibrozil, cholecalciferol, and ceftriaxone) is associated with reduced likelihood of AD incidence. Gemfibrozil (an approved lipid regulator) is significantly associated with 43% reduced risk of AD compared with simvastatin using an active-comparator design (95% confidence interval 0.51-0.63, p < 0.0001). In summary, NETTAG offers a deep learning methodology that utilizes GWAS and multi-genomic findings to identify pathobiology and drug repurposing in AD.

Authors

  • Jielin Xu
    Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • Chengsheng Mao
    Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
  • Yuan Hou
    Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, United States.
  • Yuan Luo
    Department of Preventive Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
  • Jessica L Binder
    Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
  • Yadi Zhou
    Department of Chemistry and Biochemistry , Ohio University , Athens , Ohio 45701 , United States.
  • Lynn M Bekris
    Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
  • Jiyoung Shin
    Division of Health and Biomedical Informatics, Department of Preventive Medicine, Northwestern University, Chicago, IL 60611, USA.
  • Ming Hu
    Department of Civil and Environmental Engineering and Earth Sciences, College of Engineering, University of Notre Dame, Notre Dame, IN, 46556, USA.
  • Fei Wang
    Department of Population Health Sciences, Weill Cornell Medicine, Cornell University, New York, NY, United States.
  • Charis Eng
    Cleveland Clinic, Cleveland, Ohio, USA.
  • Tudor I Oprea
    Department of Internal Medicine, Translational Informatics Division, University of New Mexico School of Medicine, Albuquerque, NM, USA. toprea@salud.unm.edu.
  • Margaret E Flanagan
    Department of Pathology, Northwestern University, Evanston, IL, 60208, USA.
  • Andrew A Pieper
    Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106, USA; Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland 44106, OH, USA; Department of Neuroscience, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
  • Jeffrey Cummings
    Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV 89154, USA.
  • James B Leverenz
    Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • Feixiong Cheng
    Genomic Medicine Institute, Lerner Research Institute , Cleveland Clinic , Cleveland , Ohio 44106 , United States.

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