Dataset Information

Association between DNA methylation levels in brain tissue and late-life depression in community-based participants.

ABSTRACT:

Objective

Major depressive disorder (MDD) arises from a combination of genetic and environmental risk factors and DNA methylation is one of the molecular mechanisms through which these factors can manifest. However, little is known about the epigenetic signature of MDD in brain tissue. This study aimed to investigate associations between brain tissue-based DNA methylation and late-life MDD.

Methods

We performed a brain epigenome-wide association study (EWAS) of late-life MDD in 608 participants from the Religious Order Study and the Rush Memory and Aging Project (ROS/MAP) using DNA methylation profiles of the dorsal lateral prefrontal cortex generated using the Illumina HumanMethylation450 Beadchip array. We also conducted an EWAS of MDD in each sex separately.

Results

We found epigenome-wide significant associations between brain tissue-based DNA methylation and late-life MDD. The most significant and robust association was found with altered methylation levels in the YOD1 locus (cg25594636, p value = 2.55 × 10^-11; cg03899372, p value = 3.12 × 10^-09; cg12796440, p value = 1.51 × 10^-08, cg23982678, p value = 7.94 × 10^-08). Analysis of differentially methylated regions (p value = 5.06 × 10^-10) further confirmed this locus. Other significant loci include UGT8 (cg18921206, p value = 1.75 × 10^-08), FNDC3B (cg20367479, p value = 4.97 × 10^-08) and SLIT2 (cg10946669, p value = 8.01 × 10^-08). Notably, brain tissue-based methylation levels were strongly associated with late-life MDD in men more than in women.

Conclusions

We identified altered methylation in the YOD1, UGT8, FNDC3B, and SLIT2 loci as new epigenetic factors associated with late-life MDD. Furthermore, our study highlights the sex-specific molecular heterogeneity of MDD.

SUBMITTER: Huls A

PROVIDER: S-EPMC7393126 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

Association between DNA methylation levels in brain tissue and late-life depression in community-based participants.

Hüls Anke A Robins Chloe C Conneely Karen N KN De Jager Philip L PL Bennett David A DA Epstein Michael P MP Wingo Thomas S TS Wingo Aliza P AP

Translational psychiatry 20200730 1

<h4>Objective</h4>Major depressive disorder (MDD) arises from a combination of genetic and environmental risk factors and DNA methylation is one of the molecular mechanisms through which these factors can manifest. However, little is known about the epigenetic signature of MDD in brain tissue. This study aimed to investigate associations between brain tissue-based DNA methylation and late-life MDD.<h4>Methods</h4>We performed a brain epigenome-wide association study (EWAS) of late-life MDD in 60 ...[more]

PMID: 32733030

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Project description:BackgroundMajor depressive disorders rank in the top ten causes of ill health in all but four countries worldwide and are the leading cause of years lived with disability in Europe (WHO). Recent research suggests that neurodegenerative pathology may contribute to the development of late-life depression (LLD) in a sub-group of patients and represent a target for prevention and early diagnosis. In parallel, electroconvulsive therapy (ECT), which is the most effective treatment for severe LLD, has been associated with significant brain structural changes. In both LLD and ECT hippocampal volume change plays a central role; however, the neurobiological mechanism underlying it and its relevance for clinical outcomes remain unresolved.MethodsThis is a monocentric, clinical cohort study with a cross-sectional arm evaluating PET-MR imaging and behavioural measures in 64 patients with LLD compared to 64 healthy controls, and a longitudinal arm evaluating the same imaging and behavioural measures after 10 ECT sessions in 20 patients receiving ECT as part of their normal clinical management. Triple tracer PET-MRI data will be used to measure: hippocampal volume (high resolution MRI), synaptic density using [11C]UCB-J, which targets the Synaptic Vesicle Glycoprotein 2A receptor, tau pathology using [18F]MK-6240, and cerebral amyloid using [18F]-Flutemetamol, which targets beta-amyloid neuritic plaques in the brain. Additional MRI measures and ultrasound will assess cerebral vascular structure and brain connectivity. Formal clinical and neuropsychological assessments will be conducted alongside experience sampling and physiological monitoring to assess mood, stress, cognition and psychomotor function.DiscussionThe main aim of the study is to identify the origin and consequences of hippocampal volume differences in LLD by investigating how biomarkers of pathological ageing contribute to medial temporal lobe pathology. Studying how synaptic density, tau, amyloid and vascular pathology relate to neuropsychological, psychomotor function, stress and ECT, will increase our pathophysiological understanding of the in vivo molecular, structural and functional alterations occurring in depression and what effect this has on clinical outcome. It may also lead to improvements in the differential diagnosis of depression and dementia yielding earlier, more optimal, cost-effective clinical management. Finally, it will improve our understanding of the neurobiological mechanism of ECT.Trial registrationClinicalTrials.gov Identifier: NCT03849417 , 21/2/2019.

Dataset Information

Association between DNA methylation levels in brain tissue and late-life depression in community-based participants.

Objective

Methods

Results

Conclusions

Publications

Association between DNA methylation levels in brain tissue and late-life depression in community-based participants.

Similar Datasets

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