TY - JOUR
T1 - Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus
AU - Sarnowski, Chloé
AU - Huan, Tianxiao
AU - Ma, Yiyi
AU - Joehanes, Roby
AU - Beiser, Alexa
AU - DeCarli, Charles S.
AU - Heard-Costa, Nancy L.
AU - Levy, Daniel
AU - Lin, Honghuang
AU - Liu, Ching Ti
AU - Liu, Chunyu
AU - Meigs, James B.
AU - Satizabal, Claudia L.
AU - Florez, Jose C.
AU - Hivert, Marie France
AU - Dupuis, Josée
AU - De Jager, Philip L.
AU - Bennett, David A.
AU - Seshadri, Sudha
AU - Morrison, Alanna C.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - DNA methylation
KW - Epigenetics
KW - FHS
KW - Insulin resistance
KW - ROSMAP
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U2 - 10.1186/s13148-023-01589-4
DO - 10.1186/s13148-023-01589-4
M3 - Article
C2 - 37891690
AN - SCOPUS:85174905143
SN - 1868-7075
VL - 15
JO - Clinical Epigenetics
JF - Clinical Epigenetics
IS - 1
M1 - 173
ER -