New Tools Facilitate Analysis of Alzheimer's Disease Genetics and Genomics Data
Key findings
- Researchers at Massachusetts General Hospital have developed a suite of tools for analyzing Alzheimer's disease (AD) gene expression data in combination with data from genome-wide association studies
- The tools include a clinical-neuropathological score for defining AD, gene expression maps of the brain and network visualizations for studying the impact of polymorphisms in AD pathways
- As an example of the utility of these tools, the researchers documented changes in the calcium signaling pathway that are consistent with AD-related calcium dysregulation
- They also identified synaptic genes related to downregulation of the calcium-/calmodulin-activated calcineurin pathway in neurons
Alzheimer's disease (AD) is notoriously complex with regard to genotypes, phenotypes and the course of the illness. Largely because of this variation, there are still no disease-modifying therapies despite decades of effort.
Researchers are using multiomics—genomics, epigenomics and proteomics data—as one approach to understand the heterogeneity of Alzheimer's disease. The largest such effort is the Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD), a public–private open science initiative. This multi-institution consortium has gathered data on more than 2,000 human brain samples and made them publicly available.
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Sudeshna Das, PhD, director of the Biomedical Informatics Core, and Bradley T. Hyman, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease, and colleagues have developed a suite of tools for processing AMP-AD data, combining it with the results of genome-wide association studies (GWAS) and visualizing it in various ways. They describe their methods, and an example of its use, in Alzheimer's & Dementia.
Clinical–Neuropathology Score
The team obtained 27 sets of AMP-AD gene expression data that spanned 19 brain regions and included both microarrays and RNA sequences. They devised a score to analyze the data that combines the Braak method of staging Alzheimer's disease with the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) method for neuropathologic assessment. The composite score was used to define subjects as having normal cognition, AD, preclinical AD or dementia other than AD. Scripts for this work are available free online.
Differential Gene Expression Analysis
Using the four AMP-AD data sets with the highest numbers of differentially expressed genes, the researchers evaluated the Braak method, CERAD method, clinical diagnosis, Mini–Mental State Exam and clinical–neuropathology score for their ability to distinguish AD patients from controls. The clinical–neuropathology score was superior.
The team created a brain expression map for a set of these genes, with examples given in a supplement to the journal.
Integration of GWAS and Gene Expression Data
Based on the clinical–neuropathology score, the researchers identified 4,044 genes to explore further. They combined that list with 828 genes found to be significant in previous GWAS, according to a meta-analysis conducted by the International Genomics of Alzheimer's Project.
For each gene, the team selected the single-nucleotide polymorphism with the lowest P-value within ±1 Mbp of the gene loci start and end. The calcium signaling pathway proved to be the most significant pathway in this set of genes.
Calcium Homeostasis Dysregulation in AD
The researchers tested the hypothesis that the calcium signaling pathway has a pathogenic role in AD, which with previously available approaches could be evaluated only in animal models.
They confirmed a series of changes that are consistent with AD-related calcium dysregulation, including downregulation of the calcium-/calmodulin-activated calcineurin pathway in neurons, which could lead to abnormal neuronal function. These results closely matched predictions based on mouse data.
Visualization Tools
The team made their observations partly by creating bubble charts of the calcium signaling pathway that give gene expression and GWAS information. These maps and the other visual tools the researchers created—scatter plots and force-directed visualizations—are interactive, allowing the user to look up information or navigate to areas of further interest. The code is available free online.
Toward the Future
The new tools will be useful for a variety of investigations, the researchers predict, such as the study of neuroinflammation, interferon signaling pathways, pathological aging, mitochondrial stress, autophagy, protein degradation and microglial signatures.
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