Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus

Clinical Epigenetics

Research

Yiyi Ma¹  Philip L. De Jager²  Daniel Levy³  Ching-Ti Liu⁴  Chunyu Liu⁴  Josée Dupuis⁵  Jose C. Florez⁶  Honghuang Lin⁷  Charles S. DeCarli⁸  Marie-France Hivert⁹  James B. Meigs^1,10  Chloé Sarnowski^1,11  Alanna C. Morrison^1,11  Tianxiao Huan^1,12  Roby Joehanes^1,13  David A. Bennett^1,14  Nancy L. Heard-Costa^1,15  Alexa Beiser^1,16  Sudha Seshadri^1,17  Claudia L. Satizabal^1,18 

[1] Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA;Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA;Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA;Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA;The Framingham Heart Study, Framingham, MA, USA;Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA;Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA;Department of Epidemiology, Biostatistics and Occupational Health, School of Population and Global Health, McGill University, Montreal, Canada;Department of Medicine, Harvard Medical School, Boston, MA, USA;Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA;Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA;Department of Neurology, University of California, Davis, CA, USA;Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Harvard University, Boston, MA, USA;Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA;Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada;Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA;Department of Medicine, Harvard Medical School, Boston, MA, USA;Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA;Population Sciences Branch, National Heart, Lung and Blood Institutes of Health, Bethesda, MD, USA;Population Sciences Branch, National Heart, Lung and Blood Institutes of Health, Bethesda, MD, USA;The Framingham Heart Study, Framingham, MA, USA;Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA;The Framingham Heart Study, Framingham, MA, USA;Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA;The Framingham Heart Study, Framingham, MA, USA;Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA;Department of Neurology, Boston University School of Medicine, Boston, MA, USA;The Framingham Heart Study, Framingham, MA, USA;Department of Neurology, Boston University School of Medicine, Boston, MA, USA;Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;The Framingham Heart Study, Framingham, MA, USA;Department of Neurology, Boston University School of Medicine, Boston, MA, USA;Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;Department of Population Health Sciences, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;

关键词: Epigenetics;    Insulin resistance;    Alzheimer’s disease;    FHS;    ROSMAP;    DNA methylation;   

DOI  :  10.1186/s13148-023-01589-4

 received in 2023-07-17, accepted in 2023-10-20,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundInsulin resistance (IR) is a major risk factor for Alzheimer’s disease (AD) dementia. The mechanisms by which IR predisposes to AD are not well-understood. Epigenetic studies may help identify molecular signatures of IR associated with AD, thus improving our understanding of the biological and regulatory mechanisms linking IR and AD.MethodsWe conducted an epigenome-wide association study of IR, quantified using the homeostatic model assessment of IR (HOMA-IR) and adjusted for body mass index, in 3,167 participants from the Framingham Heart Study (FHS) without type 2 diabetes at the time of blood draw used for methylation measurement. We identified DNA methylation markers associated with IR at the genome-wide level accounting for multiple testing (P < 1.1 × 10−7) and evaluated their association with neurological traits in participants from the FHS (N = 3040) and the Religious Orders Study/Memory and Aging Project (ROSMAP, N = 707). DNA methylation profiles were measured in blood (FHS) or dorsolateral prefrontal cortex (ROSMAP) using the Illumina HumanMethylation450 BeadChip. Linear regressions (ROSMAP) or mixed-effects models accounting for familial relatedness (FHS) adjusted for age, sex, cohort, self-reported race, batch, and cell type proportions were used to assess associations between DNA methylation and neurological traits accounting for multiple testing.ResultsWe confirmed the strong association of blood DNA methylation with IR at three loci (cg17901584–DHCR24, cg17058475–CPT1A, cg00574958–CPT1A, and cg06500161–ABCG1). In FHS, higher levels of blood DNA methylation at cg00574958 and cg17058475 were both associated with lower IR (P = 2.4 × 10−11 and P = 9.0 × 10–8), larger total brain volumes (P = 0.03 and P = 9.7 × 10−4), and smaller log lateral ventricular volumes (P = 0.07 and P = 0.03). In ROSMAP, higher levels of brain DNA methylation at the same two CPT1A markers were associated with greater risk of cognitive impairment (P = 0.005 and P = 0.02) and higher AD-related indices (CERAD score: P = 5 × 10−4 and 0.001; Braak stage: P = 0.004 and P = 0.01).ConclusionsOur results suggest potentially distinct epigenetic regulatory mechanisms between peripheral blood and dorsolateral prefrontal cortex tissues underlying IR and AD at CPT1A locus.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

Fig. 1