Dataset Information

Integrative analysis of DNA methylation and gene expression identifies genes associated with biological aging in Alzheimer's disease.

ABSTRACT:

Introduction

The acceleration of biological aging is a risk factor for Alzheimer's disease (AD). Here, we performed weighted gene co-expression network analysis (WGCNA) to identify modules and dysregulated genesinvolved in biological aging in AD.

Methods

We performed WGCNA to identify modules associated with biological clocks and hub genes of the module with the highest module significance. In addition, we performed differential expression analysis and association analysis with AD biomarkers.

Results

WGCNA identified five modules associated with biological clocks, with the module designated as "purple" showing the strongest association. Functional enrichment analysis revealed that the purple module was related to cell migration and death. Ten genes were identified as hub genes in purple modules, of which CX3CR1 was downregulated in AD and low levels of CX3CR1 expression were associated with AD biomarkers.

Conclusion

Network analysis identified genes associated with biological clocks, which suggests the genetic architecture underlying biological aging in AD.

Highlights

Examine links between Alzheimer's disease (AD) peripheral transcriptome and biological aging changes.Weighted gene co-expression network analysis (WGCNA) found five modules related to biological aging.Among the hub genes of the module, CX3CR1 was downregulated in AD.The CX3CR1 expression level was associated with cognitive performance and brain atrophy.

SUBMITTER: Kim BH

PROVIDER: S-EPMC9489162 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Integrative analysis of DNA methylation and gene expression identifies genes associated with biological aging in Alzheimer's disease.

Kim Bo-Hyun BH Vasanthakumar Aparna A Li Qingqin S QS Nudelman Kelly N H KNH Risacher Shannon L SL Davis Justin W JW Idler Kenneth K Lee Jong-Min JM Seo Sang Won SW Waring Jeffrey F JF Saykin Andrew J AJ Nho Kwangsik K

Alzheimer's & dementia (Amsterdam, Netherlands) 20220920 1

<h4>Introduction</h4>The acceleration of biological aging is a risk factor for Alzheimer's disease (AD). Here, we performed weighted gene co-expression network analysis (WGCNA) to identify modules and dysregulated genesinvolved in biological aging in AD.<h4>Methods</h4>We performed WGCNA to identify modules associated with biological clocks and hub genes of the module with the highest module significance. In addition, we performed differential expression analysis and association analysis with AD ...[more]

PMID: 36187194

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Project description:Alzheimer's disease (AD) is a neurodegenerative disorder contributing to rapid decline in cognitive function and ultimately dementia. Most cases of AD occur in elderly and later years. There is a growing need for understanding the relationship between aging and AD to identify shared and unique hallmarks associated with the disease in a region and cell-type specific manner. Although genomic studies on AD have been performed extensively, the molecular mechanism of disease progression is still not clear. The major objective of our study is to obtain a higher-order network-level understanding of aging and AD, and their relationship using the hippocampal gene expression profiles of young (20-50 years), aging (70-99 years), and AD (70-99 years). The hippocampus is vulnerable to damage at early stages of AD and altered neurogenesis in the hippocampus is linked to the onset of AD. We combined the weighted gene co-expression network and weighted protein-protein interaction network-level approaches to study the transition from young to aging to AD. The network analysis revealed the organization of co-expression network into functional modules that are cell-type specific in aging and AD. We found that modules associated with astrocytes, endothelial cells and microglial cells are upregulated and significantly correlate with both aging and AD. The modules associated with neurons, mitochondria and endoplasmic reticulum are downregulated and significantly correlate with AD than aging. The oligodendrocytes module does not show significant correlation with neither aging nor disease. Further, we identified aging- and AD-specific interactions/subnetworks by integrating the gene expression with a human protein-protein interaction network. We found dysregulation of genes encoding protein kinases (FYN, SYK, SRC, PKC, MAPK1, ephrin receptors) and transcription factors (FOS, STAT3, CEBPB, MYC, NFKβ, and EGR1) in AD. Further, we found genes that encode proteins with neuroprotective function (14-3-3 proteins, PIN1, ATXN1, BDNF, VEGFA) to be part of the downregulated AD subnetwork. Our study highlights that simultaneously analyzing aging and AD will help to understand the pre-clinical and clinical phase of AD and aid in developing the treatment strategies.

Project description:ObjectiveTo evaluate the association between promoter DNA methylation and discoidin domain receptor 1 (DDR1) gene expression in men with nonobstructive azoospermia (NOA).DesignComparing fibroblasts cultured from testicular biopsies using a high resolution Infinium 450K methylation array.SettingBasic research laboratory.Patient(s)Men with NOA (n = 16) and with normal spermatogenesis (n = 5).Intervention(s)None.Main outcome measure(s)Bisulfite clonal sequencing for validation and quantification of CpG methylation of DDR1; gene expression analysis of DDR1 with quantitative polymerase chain reaction and immunohistochemistry to validate the array results at mRNA and protein levels.Result(s)We validated promoter methylation, mRNA and protein levels of the CpG sites identified from array results. Differentially methylated CpG sites (∼20K) were identified using an F-test in the NOA samples. We identified 20 genes with >30% difference in DNA methylation within the promoter region of men with NOA and fertile controls. Of the aberrantly methylated genes, 10 were hypomethylated and 10 were hypermethylated genes. From the top 10 hypermethylated genes, six genes (MRI1, DCAF12L1, TMEM95, CECR2, DDR1, and NPHS2) were selected for validation because they were shown to be expressed in the testis. Of the six genes expressed in the fibroblasts cultured from testis, DDR1 showed an abnormal gene expression pattern. Three patients (19%) out of the 16 men with NOA for whom gene expression data were available had lower DDR1 expression levels (1.8x fold decrease) than the fertile men, whereas four (25%) men had higher expression levels (2x fold increase) of DDR1 compared with the levels in fertile men. Quantitative analysis by bisulfite clonal sequencing showed that one of the CpG sites (cg13329862) of DDR1 promoter was hypermethylated in NOA patients compared with fertile controls (53% vs. 15%). Immunohistochemical analysis suggests presence of DDR1 within cytoplasm of germ cells and peritubular connective tissue (in men with hypospermatogenesis) and decreased expression of the protein in men with Sertoli-cell only syndrome.Conclusion(s)Abnormal gene expression of DDR1 is associated with NOA. The functional relevance of aberrant methylation of DDR1 to expression of DDR1 in men with NOA warrants further investigation.

Dataset Information

Integrative analysis of DNA methylation and gene expression identifies genes associated with biological aging in Alzheimer's disease.

Introduction

Methods

Results

Conclusion

Highlights

Publications

Integrative analysis of DNA methylation and gene expression identifies genes associated with biological aging in Alzheimer's disease.

Similar Datasets

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