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Cited by 119Bioinformatics and Genomic NetworksAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

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Variations in the transcriptome of Alzheimer's disease reveal molecular networks involved in cardiovascular diseases

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Ray, Monika, Ruan, Jianhua, Zhang, Weixiong·2008·Genome Biology
DOI 10.1186/gb-2008-9-10-r148PMC PMC2760875
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Abstract

Background: Because of its polygenic nature, Alzheimer's disease is believed to be caused not by defects in single genes, but rather by variations in a large number of genes and their complex interactions. A systems biology approach, such as the generation of a network of co-expressed genes and the identification of functional modules and cis-regulatory elements, to extract insights and knowledge from microarray data will lead to a better understanding of complex diseases such as Alzheimer's disease. In this study, we perform a series of analyses using co-expression networks, cis-regulatory elements, and functions of co-expressed gene modules to analyze single-cell gene expression data from normal and Alzheimer's disease-affected subjects. Results: We identified six co-expressed gene modules, each of which represented a biological process perturbed in Alzheimer's disease. Alzheimer's disease-related genes, such as APOE, A2M, PON2 and MAP4, and cardiovascular disease-associated genes, including COMT, CBS and WNK1, all congregated in a single module. Some of the disease-related genes were hub genes while many of them were directly connected to one or more hub genes. Further investigation of this disease-associated module revealed cis-regulatory elements that match to the binding sites of transcription factors involved in Alzheimer's disease and cardiovascular disease. Conclusion: Our results show the extensive links between Alzheimer's disease and cardiovascular disease at the co-expression and co-regulation levels, providing further evidence for the hypothesis that cardiovascular disease and Alzheimer's disease are linked. Our results support the notion that diseases in which the same set of biochemical pathways are affected may tend to co-occur with each other.

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Figure 1 Steps taken to analyze Alzheimer's disease using laser capture microdissected microarray data. Sequence of steps taken to analyze incipient Alzheimer's disease from single cell expression data. We apply co-expression network analysis, EASE and WordSpy (motif finding method) in an integrated manner to study Alzheimer's disease and reveal connections to other conditions such as cardiovascular diseases and diabetes.
Figure 1 Steps taken to analyze Alzheimer's disease using laser capture microdissected microarray data. Sequence of steps taken to analyze incipient Alzheimer's disease from single cell expression data. We apply co-expression network analysis, EASE and WordSpy (motif finding method) in an integrated manner to study Alzheimer's disease and reveal connections to other conditions such as cardiovascular diseases and diabetes.CC BY · PubMed Central
Figure 2 Unsupervised classification by principal component analysis. Principal component analysis was used to classify the 33 samples. The blue spheres refer to controls and the red correspond to affected subjects. This demonstrated that the samples were distinguishable based on the expression profiles of 1,663 differentially expressed genes.
Figure 2 Unsupervised classification by principal component analysis. Principal component analysis was used to classify the 33 samples. The blue spheres refer to controls and the red correspond to affected subjects. This demonstrated that the samples were distinguishable based on the expression profiles of 1,663 differentially expressed genes.CC BY · PubMed Central
Figure 3 Adjacency matrix of co-expression network. The adjacency matrix representation of the co-expression network. Modules are labeled c1, c2, c3, c4, c5 and c6. The dots refer to the intra- and inter-module edges between the genes. The graphical representation of this matrix is in Additional data file 4.
Figure 3 Adjacency matrix of co-expression network. The adjacency matrix representation of the co-expression network. Modules are labeled c1, c2, c3, c4, c5 and c6. The dots refer to the intra- and inter-module edges between the genes. The graphical representation of this matrix is in Additional data file 4.CC BY · PubMed Central
Figure 4 Pearson correlation coefficient between 1,663 genes. This figure shows the strength of correlation between pairs of genes. The genes are organized by modules - c1, c2, c3, c4, c5 and c6. The top leftmost red block on the diagonal corresponds to module c1 and the bottom rightmost red block on the same diagonal refers to module c6. Modules c1 and c2 contain upregulated genes and modules c3 through c6 comprise downregulated genes.
Figure 4 Pearson correlation coefficient between 1,663 genes. This figure shows the strength of correlation between pairs of genes. The genes are organized by modules - c1, c2, c3, c4, c5 and c6. The top leftmost red block on the diagonal corresponds to module c1 and the bottom rightmost red block on the same diagonal refers to module c6. Modules c1 and c2 contain upregulated genes and modules c3 through c6 comprise downregulated genes.CC BY · PubMed Central
Figure 5 Sub-network in module 1 illustrating the 18 disease associated genes and their connections. This sub-network shows the 18 disease associated genes (colored yellow) and the genes that they are connected to within module 1. The hub genes are represented as triangle nodes. Disease genes MAP4, PON2 and ATP1A2 were also hub genes. Only the hub genes that connect to disease genes are shown here. Module 1 consists of 22 hub genes in total.
Figure 5 Sub-network in module 1 illustrating the 18 disease associated genes and their connections. This sub-network shows the 18 disease associated genes (colored yellow) and the genes that they are connected to within module 1. The hub genes are represented as triangle nodes. Disease genes MAP4, PON2 and ATP1A2 were also hub genes. Only the hub genes that connect to disease genes are shown here. Module 1 consists of 22 hub genes in total.CC BY · PubMed Central

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Metadata

Authors
Ray, M., Ruan, J., & Zhang, W.
Affiliations
  • Washington University in St. Louis (US)
  • The University of Texas at San Antonio (US)
Corresponding author
Zhang, Weixiong
ORCID
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2008-10-08
Volume
9
Issue
10
Pages
R148-R148
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/gb-2008-9-10-r148
PMC
PMC2760875
OpenAlex
W2125698969
Cited by
119
References
86
Citations by year
2026: 1 · 2025: 4 · 2024: 7 · 2023: 6 · 2022: 3 · 2021: 3 · 2020: 10 · 2019: 1 · 2018: 3 · 2017: 6 · 2016: 12 · 2015: 11 · 2014: 13 · 2013: 13 · 2012: 11
FWCI
2.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, other-oa)
Funders
  • National Science Foundation (0535257, 0743797)
  • Alzheimer's Association
  • University of Texas at San Antonio
  • University of California, Los Angeles
  • National Heart, Lung, and Blood Institute (R01HL091028)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, cardiovascular disease, transcriptome, co-expression network, gene modules, cis-regulatory elements, transcription factor binding sites, hub genes, apolipoprotein E, catechol-O-methyltransferase, WNK1, disease co-occurrence, single-cell gene expression
MeSH terms
Aged, 80 and over, Alzheimer Disease, Cardiovascular Diseases, Humans, Genetic Variation, Brain-Derived Neurotrophic Factor, Gene Expression Profiling, Systems Biology, Gene Regulatory Networks

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