Статья

Integrative metabolomics‐genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease

Emrin HorgusluogluDepartment of Genetics and Genomic Sciences Mount Sinai Center for Transformative Disease Modeling Icahn School of Medicine at Mount Sinai Icahn Institute of Genomics and Multiscale Biology New York New York USARyan NeffDepartment of Genetics and Genomic Sciences Mount Sinai Center for Transformative Disease Modeling Icahn School of Medicine at Mount Sinai Icahn Institute of Genomics and Multiscale Biology New York New York USAWon‐Min SongDepartment of Genetics and Genomic Sciences Mount Sinai Center for Transformative Disease Modeling Icahn School of Medicine at Mount Sinai Icahn Institute of Genomics and Multiscale Biology New York New York USAMinghui WangDepartment of Genetics and Genomic Sciences Mount Sinai Center for Transformative Disease Modeling Icahn School of Medicine at Mount Sinai Icahn Institute of Genomics and Multiscale Biology New York New York USAQian WangDepartment of Genetics and Genomic Sciences Mount Sinai Center for Transformative Disease Modeling Icahn School of Medicine at Mount Sinai Icahn Institute of Genomics and Multiscale Biology New York New York USAMatthias ArnoldDepartment of Psychiatry and Behavioral Sciences Duke University Durham North Carolina USAJan KrumsiekDepartment of Physiology and Biophysics Weill Cornell Medicine Institute for Computational Biomedicine Englander Institute for Precision Medicine New York New York USABeatriz Galindo‐PrietoDepartment of Physiology and Biophysics Weill Cornell Medicine Institute for Computational Biomedicine Englander Institute for Precision Medicine New York New York USAMing ChenDepartment of Genetics and Genomic Sciences Mount Sinai Center for Transformative Disease Modeling Icahn School of Medicine at Mount Sinai Icahn Institute of Genomics and Multiscale Biology New York New York USAKwangsik NhoDepartment of Radiology and Imaging Sciences; Indiana Alzheimer Disease Center Indiana University School of Medicine Indianapolis Indiana USAGabi KastenmüllerInstitute of Computational Biology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg GermanyXianlin HanBarshop Institute for Longevity and Aging Studies University of Texas Health Science Center at San Antonio San Antonio Texas USARebecca BaillieRosa & Co LLC San Carlos California USAQi ZengDepartment of Genetics and Genomic Sciences Mount Sinai Center for Transformative Disease Modeling Icahn School of Medicine at Mount Sinai Icahn Institute of Genomics and Multiscale Biology New York New York USAShea J. AndrewsDepartment of Neuroscience Ronald M. Loeb Center for Alzheimer's Disease Icahn School of Medicine at Mount Sinai New York New York USAHaoxiang ChengDepartment of Genetics and Genomic Sciences Mount Sinai Center for Transformative Disease Modeling Icahn School of Medicine at Mount Sinai Icahn Institute of Genomics and Multiscale Biology New York New York USAKe HaoDepartment of Genetics and Genomic Sciences Mount Sinai Center for Transformative Disease Modeling Icahn School of Medicine at Mount Sinai Icahn Institute of Genomics and Multiscale Biology New York New York USAAlison GoateDepartment of Neuroscience Ronald M. Loeb Center for Alzheimer's Disease Icahn School of Medicine at Mount Sinai New York New York USADavid A. BennettRush Alzheimer's Disease Center Rush University Medical Center Chicago Illinois USAAndrew J. SaykinDepartment of Radiology and Imaging Sciences; Indiana Alzheimer Disease Center Indiana University School of Medicine Indianapolis Indiana USARima Kaddurah‐DaoukDepartment of Medicine Duke University Durham North Carolina USABin ZhangDepartment of Genetics and Genomic Sciences Mount Sinai Center for Transformative Disease Modeling Icahn School of Medicine at Mount Sinai Icahn Institute of Genomics and Multiscale Biology New York New York USAfor the Alzheimer's Disease Neuroimaging Initiative (ADNI)

2021en

ABI

Аннотация

Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD-specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co-expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short-chain acylcarnitines/amino acids and medium/long-chain acylcarnitines are most associated with AD clinical outcomes, including episodic memory scores and disease severity. Integration of the gene expression data in both the blood from the ADNI and the brain from the Accelerating Medicines Partnership Alzheimer's Disease (AMP-AD) program reveals ABCA1 and CPT1A are involved in the regulation of acylcarnitines and amino acids in AD. Gene co-expression network analysis of the AMP-AD brain RNA-seq data suggests the CPT1A- and ABCA1-centered subnetworks are associated with neuronal system and immune response, respectively. Increased ABCA1 gene expression and adiponectin protein, a regulator of ABCA1, correspond to decreased short-chain acylcarnitines and amines in AD in the ADNI. In summary, our integrated analysis of large-scale multiomics data in AD systematically identifies novel metabolites and their potential regulators in AD and the findings pave a way for not only developing sensitive and specific diagnostic biomarkers for AD but also identifying novel molecular mechanisms of AD pathogenesis.

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Идентификаторы

DOI: 10.1002/alz.12468

Цитирования и источники

Цитирований: 3Использованных источников: 0

Показатели — AkademScholar