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

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

doi:10.1186/s13148-023-01589-4

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

Clin Epigenetics. 2023 Oct 27;15(1):173. doi: 10.1186/s13148-023-01589-4.

Authors

Chloé Sarnowski¹, Tianxiao Huan², Yiyi Ma³, Roby Joehanes^{2

4}, Alexa Beiser^{4

5

6}, Charles S DeCarli⁷, Nancy L Heard-Costa^{4

5}, Daniel Levy^{3

4}, Honghuang Lin⁸, Ching-Ti Liu⁵, Chunyu Liu⁵, James B Meigs^{9

10

11}, Claudia L Satizabal^{4

6

12

13}, Jose C Florez^{10

11

14}, Marie-France Hivert^{15

16

17}, Josée Dupuis^{5

18}, Philip L De Jager^{3

19}, David A Bennett²⁰, Sudha Seshadri^#^{4

6

12}, Alanna C Morrison^#²¹

Affiliations

¹ 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. Chloe.Sarnowski@uth.tmc.edu.
² Population Sciences Branch, National Heart, Lung and Blood Institutes of Health, Bethesda, MD, USA.
³ Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
⁴ The Framingham Heart Study, Framingham, MA, USA.
⁵ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
⁶ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁷ Department of Neurology, University of California, Davis, CA, USA.
⁸ Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁹ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹¹ Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹² Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
¹³ Department of Population Health Sciences, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
¹⁴ Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Harvard University, Boston, MA, USA.
¹⁶ Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.
¹⁸ Department of Epidemiology, Biostatistics and Occupational Health, School of Population and Global Health, McGill University, Montreal, Canada.
¹⁹ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
²⁰ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
²¹ 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.

^# Contributed equally.

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.

Keywords: Alzheimer’s disease; DNA methylation; Epigenetics; FHS; Insulin resistance; ROSMAP.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / genetics
DNA Methylation
Diabetes Mellitus, Type 2* / genetics
Epigenesis, Genetic
Genetic Markers
Genome-Wide Association Study / methods
Humans
Insulin Resistance* / genetics

Substances

Genetic Markers
CPT1A protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding