SYSTEMATIC REVIEW OF GENOME-WIDE STUDIES IN ALZHEIMER’S DISEASE AND PRIORITIZATION OF CANDIDATE PATHWAYS USING AN INTEGRATIVE SYSTEMS BIOLOGY APPROACH

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease with complex pathophysiology and multifactorial etiology. Here, we aim to systematically review genome-wide studies in AD and prioritize AD associated pathways. We extracted articles from Pubmed, AlzGene database, Google Scholar using keywords alone or in combination and their cross references to identify genome-wide linkage (GWL), genome-wide expression (GWE), genome-wide association (GWA) and epigenome-wide studies (EWAS) followed by identification of genes and pathways using genomic convergence approach for AD risk. We identified 16 GWL, 31 GWE, 34 GWA and 3 EWAS studies which were systematically reviewed. Although, these studies have identified large number of additional loci as being potentially involved in AD, only few of the implicated genes have been found in multiple independently conducted studies and none of the newly identified genes either alone or in combination have been found to be suitable for use as diagnostic marker or for development of new drugs. We therefore used a novel integrative approach to identify AD biomarker candidate genes and pathways involving integration of three different AD datasets - GWE, GWL and GWA. Genes identified in each dataset were used for pathway enrichment analysis and the pathways in each datasets were ranked using our previously published novel cumulative rank score (SR) based method (Talwar et al., BMC Genomics, 2014). SR for each pathway is calculated by addition of rank assigned to individual pathway based on the p value in three datasets. This analysis yielded 261 plausible AD associated pathways. The top three ranked pathways were glypican, TNF-related apoptosis-inducing ligand (TRAIL) signalling and vascular endothelial growth factor (VEGF)-VEGFR signalling. Further, EGFR-dependent Endothelin signalling events also showed in the top 15 which substantiated our previous finding of EGFR as one the most significant candidate genes for AD risk. The findings provide evidence on the multifactorial etiology of AD (Talwar et al., Mol Neurobiol, 2015) and apart from identification of significant pathways paralleling AD patho-physiological process.