Novel methods for integration and visualization of genomics and genetics data in Alzheimer's disease

Abstract

Introduction: Numerous omics studies have been conducted to understand the molecular networks involved in Alzheimer's disease (AD), but the pathophysiology is still not completely understood; new approaches that enable neuroscientists to better interpret the results of omics analysis are required.

Methods: We have developed advanced methods to analyze and visualize publicly-available genomics and genetics data. The tools include a composite clinical-neuropathological score for defining AD, gene expression maps in the brain, and networks integrating omics data to understand the impact of polymorphisms on AD pathways.

Results: We have analyzed over 50 public human gene expression data sets, spanning 19 different brain regions and encompassing three separate cohorts. We integrated genome-wide association studies with expression data to identify important genes in the pathophysiology of AD, which provides further insight into the calcium signaling and calcineurin pathways.

Discussion: Biologists can use these freely-available tools to obtain a comprehensive, information-rich view of the pathways in AD.

Keywords: Alzheimer's disease; Calcineurin; Calcium signaling pathway; Data visualization; Genomics; PTK2B; TOMM40.

Fig. 1.

Defining analysis groups. (A) Braak scores were divided into high, medium, and low scores. (B) Combined neuropathological score was developed using Braak and CERAD. (C) Composite diagnosis score (CpDx) combines clinical and neuropathological measures. Comprehensive scoring CpDxAll applies to all categories with a neuropathological threshold NP score > 2. Low-scoring CpDxLow applies to low NP score values 1–2 and extreme value 4; cases with transitional NP score = 3 are ignored. Strict scoring CpDxStrict applies to extreme NP score values 1 and 4 only, and cases with transitional NP score values 2–3 are ignored. AD, Alzheimer’s disease; CDR, clinical dementiarating; CERAD, Consortiumto EstablishaRegistry forAlzheimer’sDisease; PCAD, preclinicalAD; DNAD, dementia not AD.

Fig. 2.

KEGG AD pathway. Differentially expressed genes are colored. AD, Alzheimer’s disease; KEGG, Kyoto Encyclopedia of Genes and Genomes; AICD, amyloid precursor protein intracellular domain; sAPP, soluble amyloid precursor protein; APP, amyloid precursor protein; ROS, reactive oxygen species; ATP, adenosine triphosphate; NAC, non-Aβ component.

Fig.3.

Plot of fold change in AD versus control of ROSMAP PFC using CpDxLow composite score vs. significance of SNP in IGAP meta-analysis that is within 61 Mbp of gene. All differentially expressed genes in the ROSMAP PFC data set that has IGAP data are shown. Each dot represents a gene and is colored by whether it is significant in the IGAP study, Mayo eQTL study, both, or none. GWAS, genome-wide association studies; AD, Alzheimer’s disease; IGAP, International Genomics of Alzheimer’s Project; ROSMAP, Religious Orders Study and Memory and Aging Project; PFC, prefrontal cortex.

Fig.4.

Network visualization of the calcium signaling pathway with expression and GWAS information. Each bubble is a gene and is colored by its fold change in differential expression analysis of AD versus normal defined using the composite clinical and neuropathological scores (CpDxLow) in the ROSMAP dorsolateral prefrontal cortex RNA-Seq data; the size indicates significance. Edges are protein or pathway interactions. The black text labels indicate significance of the locus computed using GWiS from the IGAP meta-analysis; the size indicates the magnitude of the significance log10 (P value). The blue labels are differentially expressed genes without significant GWiS results. GWAS, genome-wide association studies; AD, Alzheimer’s disease; IGAP, International Genomics of Alzheimer’s Project; ROSMAP, Religious Orders Study and Memory and Aging Project; GWiS, Gene-Wide Significance.

Fig.5.

Network visualization of the synapse genes of the calcineurin pathway with expression and GWAS information. Each bubble is a gene and is colored by direction in differential expression analysis of AD versus normal defined using the composite clinical and neuropathological scores (CpDxLow) in the ROSMAP dorsolateral prefrontal cortex RNA-Seq data; the size indicates significance (-log10 P value). Edges are protein or pathway interactions. The black text labels indicate significance of the locus computed using GWiS from the IGAP meta-analysis; the size indicates the magnitude of the significance. The blue labels are differentially expressed genes without significant GWiS results. GWAS, genome-wide association studies; GWiS, Gene-Wide Significance; AD, Alzheimer’s disease; IGAP, International Genomics of Alzheimer’s Project; ROSMAP, Religious Orders Study and Memory and Aging Project.