Functional annotation of Alzheimer's disease associated loci revealed by GWASs

<div><p>Genome-wide association studies (GWASs) discovered a number of SNPs and genes associated with Alzheimer's disease (AD). However, how these SNPs and genes influence the liability to AD is not fully understood. We deployed computational approaches to explore the function and action mechanisms of AD -related SNPs and genes identified by GWASs, including the effects of 195 GWAS lead SNPs and 338 proxy SNPs on miRNAs binding and protein phosphorylation, their RegulomeDB and 3DSNP scores, and gene ontology, pathway enrichment and protein-protein interaction network of 126 AD-associated genes. Our computational analysis identified 6 lead SNPs (rs10119, rs1048699, rs148763909, rs610932, rs6857 and rs714948) and 2 proxy SNPs (rs12539172 and rs2847655) that potentially impacted the miRNA binding. Lead SNP rs2296160 and proxy SNPs rs679620 and rs2228145 were identified as PhosSNPs potentially influencing protein phosphorylation. AD-associated genes showed enrichment of “regulation of beta-amyloid formation”, “regulation of neurofibrillary tangle assembly”, “leukocyte mediated immunity” and “protein-lipid complex assembly” signaling pathway. Protein-protein interaction network and functional module analyses identified highly-interconnected “hub” genes (<i>APOE</i>, <i>PICALM</i>, <i>BIN1</i>, <i>ABCA7</i>, <i>CD2AP</i>, <i>CLU</i>, <i>CR1</i>, <i>MS4A4E</i> and <i>MS4A6A</i>) and bottleneck genes (<i>APOE</i>, <i>TOMM40</i>, <i>NME8</i>, <i>PICALM</i>, <i>CD2AP</i>, <i>ZCWPW1</i>, <i>FAM180B</i>, <i>GAB2</i> and <i>PTK2B</i>) that created three tight subnetworks. Our results provided the targets for further experimental assessment and further insight on AD pathophysiology.</p></div

RegulomeDB score and related functional annotation.

<p>RegulomeDB score and related functional annotation.</p

Workflow for Alzheimer’s disease -associated loci derived from genome-wide association studies.

<p>Workflow for Alzheimer’s disease -associated loci derived from genome-wide association studies.</p

Modules in the protein–protein interaction network.

<p>There are 19, 9 and 4 nodes in Modules 1 (a), 2 (b) and 3 (c), respectively. Yellow nodes represent hub genes, blue nodes represent bottleneck genes, green nodes represent neither hub nor bottleneck genes, and red nodes represent both types of genes.</p

Significantly enriched pathways of Alzheimer’s disease-associated genes.

<p>Significantly enriched pathways of Alzheimer’s disease-associated genes.</p

(a) The molecular function, (b) cellular component and (c) biological process of Alzheimer’s disease-associated genes identified by genome-wide association studies.

<p>(a) The molecular function, (b) cellular component and (c) biological process of Alzheimer’s disease-associated genes identified by genome-wide association studies.</p

SNPs predicted to potentially affect miRNA binding.

<p>SNPs predicted to potentially affect miRNA binding.</p

Hub and bottleneck genes in the protein–protein interaction network.

<p>Hub and bottleneck genes in the protein–protein interaction network.</p

Protein–protein interaction network of Alzheimer’s disease-associated genes.

<p>The nodes and edges represent the proteins (genes) and their interactions, respectively. Yellow nodes represent the hub genes, blue nodes represent bottleneck genes, and red nodes represent both types of genes.</p

Hub genes associated with Alzheimer’s disease and their interactions.

<p>Hub genes associated with Alzheimer’s disease and their interactions.</p