Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus
Abstract Background Insulin 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...
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-023-01589-4 |
| _version_ | 1797647293603643392 |
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| author | Chloé Sarnowski Tianxiao Huan Yiyi Ma Roby Joehanes Alexa Beiser Charles S. DeCarli Nancy L. Heard-Costa Daniel Levy Honghuang Lin Ching-Ti Liu Chunyu Liu James B. Meigs Claudia L. Satizabal Jose C. Florez Marie-France Hivert Josée Dupuis Philip L. De Jager David A. Bennett Sudha Seshadri Alanna C. Morrison |
| author_facet | Chloé Sarnowski Tianxiao Huan Yiyi Ma Roby Joehanes Alexa Beiser Charles S. DeCarli Nancy L. Heard-Costa Daniel Levy Honghuang Lin Ching-Ti Liu Chunyu Liu James B. Meigs Claudia L. Satizabal Jose C. Florez Marie-France Hivert Josée Dupuis Philip L. De Jager David A. Bennett Sudha Seshadri Alanna C. Morrison |
| author_sort | Chloé Sarnowski |
| collection | DOAJ |
| description | Abstract Background Insulin 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. Methods We 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. Results We 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). Conclusions Our results suggest potentially distinct epigenetic regulatory mechanisms between peripheral blood and dorsolateral prefrontal cortex tissues underlying IR and AD at CPT1A locus. |
| first_indexed | 2024-03-11T15:15:12Z |
| format | Article |
| id | doaj.art-d9f552a1cc0842fc826edbb499f07475 |
| institution | Directory Open Access Journal |
| issn | 1868-7083 |
| language | English |
| last_indexed | 2024-03-11T15:15:12Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj.art-d9f552a1cc0842fc826edbb499f074752023-10-29T12:27:38ZengBMCClinical Epigenetics1868-70832023-10-0115111710.1186/s13148-023-01589-4Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locusChloé Sarnowski0Tianxiao Huan1Yiyi Ma2Roby Joehanes3Alexa Beiser4Charles S. DeCarli5Nancy L. Heard-Costa6Daniel Levy7Honghuang Lin8Ching-Ti Liu9Chunyu Liu10James B. Meigs11Claudia L. Satizabal12Jose C. Florez13Marie-France Hivert14Josée Dupuis15Philip L. De Jager16David A. Bennett17Sudha Seshadri18Alanna C. Morrison19Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at HoustonPopulation Sciences Branch, National Heart, Lung and Blood Institutes of HealthCenter for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical CenterPopulation Sciences Branch, National Heart, Lung and Blood Institutes of HealthThe Framingham Heart StudyDepartment of Neurology, University of CaliforniaThe Framingham Heart StudyCenter for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical CenterDepartment of Medicine, University of Massachusetts Chan Medical SchoolDepartment of Biostatistics, School of Public Health, Boston UniversityDepartment of Biostatistics, School of Public Health, Boston UniversityDivision of General Internal Medicine, Massachusetts General HospitalThe Framingham Heart StudyDepartment of Medicine, Harvard Medical SchoolDepartment of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Harvard UniversityDepartment of Biostatistics, School of Public Health, Boston UniversityCenter for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical CenterRush Alzheimer’s Disease Center, Rush University Medical CenterThe Framingham Heart StudyHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at HoustonAbstract Background Insulin 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. Methods We 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. Results We 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). Conclusions Our results suggest potentially distinct epigenetic regulatory mechanisms between peripheral blood and dorsolateral prefrontal cortex tissues underlying IR and AD at CPT1A locus.https://doi.org/10.1186/s13148-023-01589-4EpigeneticsInsulin resistanceAlzheimer’s diseaseFHSROSMAPDNA methylation |
| spellingShingle | Chloé Sarnowski Tianxiao Huan Yiyi Ma Roby Joehanes Alexa Beiser Charles S. DeCarli Nancy L. Heard-Costa Daniel Levy Honghuang Lin Ching-Ti Liu Chunyu Liu James B. Meigs Claudia L. Satizabal Jose C. Florez Marie-France Hivert Josée Dupuis Philip L. De Jager David A. Bennett Sudha Seshadri Alanna C. Morrison Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus Clinical Epigenetics Epigenetics Insulin resistance Alzheimer’s disease FHS ROSMAP DNA methylation |
| title | Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus |
| title_full | Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus |
| title_fullStr | Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus |
| title_full_unstemmed | Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus |
| title_short | Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus |
| title_sort | multi tissue epigenetic analysis identifies distinct associations underlying insulin resistance and alzheimer s disease at cpt1a locus |
| topic | Epigenetics Insulin resistance Alzheimer’s disease FHS ROSMAP DNA methylation |
| url | https://doi.org/10.1186/s13148-023-01589-4 |
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