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Review
, 124 (11), 1455-1471

Genome-wide Significant, Replicated and Functional Risk Variants for Alzheimer's Disease

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Review

Genome-wide Significant, Replicated and Functional Risk Variants for Alzheimer's Disease

Xiaoyun Guo et al. J Neural Transm (Vienna).

Abstract

Genome-wide association studies (GWASs) have reported numerous associations between risk variants and Alzheimer's disease (AD). However, these associations do not necessarily indicate a causal relationship. If the risk variants can be demonstrated to be biologically functional, the possibility of a causal relationship would be increased. In this article, we reviewed all of the published GWASs to extract the genome-wide significant (p < 5×10-8) and replicated associations between risk variants and AD or AD-biomarkers. The regulatory effects of these risk variants on the expression of a novel class of non-coding RNAs (piRNAs) and protein-coding RNAs (mRNAs), the alteration of proteins caused by these variants, the associations between AD and these variants in our own sample, the expression of piRNAs, mRNAs and proteins in human brains targeted by these variants, the expression correlations between the risk genes and APOE, the pathways and networks that the risk genes belonged to, and the possible long non-coding RNAs (LncRNAs) that might regulate the risk genes were analyzed, to investigate the potential biological functions of the risk variants and explore the potential mechanisms underlying the SNP-AD associations. We found replicated and significant associations for AD or AD-biomarkers, surprisingly, only at 17 SNPs located in 11 genes/snRNAs/LncRNAs in eight genomic regions. Most of these 17 SNPs enriched some AD-related pathways or networks, and were potentially functional in regulating piRNAs and mRNAs; some SNPs were associated with AD in our sample, and some SNPs altered protein structures. Most of the protein-coding genes regulated by the risk SNPs were expressed in human brain and correlated with APOE expression. We conclude that these variants were most robust risk markers for AD, and their contributions to AD risk was likely to be causal. As expected, APOE and the lipoprotein metabolism pathway possess the highest weight among these contributions.

Keywords: APOE; Alzheimer’s disease; GWAS; Gene expression; Genome-wide significant; Replicated; Risk variant.

Conflict of interest statement

Conflict of Interest: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Illustration for the pathways underlying SNP-AD association
[Solid lines: Directly evidenced by our study; Dash lines: Indirectly evidenced by literatures. &#x02776; LncRNA expression is regulated by the SNPs (by eQTL analysis); &#x02777; LncRNAs regulate the expression of the nearest protein-coding genes by sequence complementarity; &#x02778; mRNA expression of the risk genes is correlated to APOE mRNA expression (by correlation analysis); &#x02779; mRNA of APOE encodes APOE protein, and both mRNA and protein of APOE are expressed in brain and related to AD; &#x0277A; RNAs/proteins expressed in brain are assumed to have potential brain functions; &#x0277B; many brain functions are assumed to be related to the development of AD; &#x0277C; piRNA expression is regulated by the risk SNPs (by transcriptome-wide eQTL analysis); &#x0277D; piRNAs regulate the expression of the nearest protein-coding genes by sequence complementarity; &#x0277E; mRNAs encode proteins; &#x0277F; proteins are expressed in brains (by mass spectrometry-based proteomics microarray analyses); &#x024EB; mRNA expression is regulated by the risk SNPs (by cis-eQTL analysis and bioinformatic analysis); &#x024EC; protein structures are altered by SNPs (by bioinformatics analysis); &#x024ED; mRNA expression of risk genes is detected in brains (by RNA-Seq or RNA microarray analyses); &#x024EE; SNPs are associated with AD (by our study or published GWASs); &#x024EF; piRNAs are detected in brains (by microarray)]
Figure 2
Figure 2. The significantly enriched network Lipid Metabolism, Molecular Transport, Small Molecule Biochemistry
[This figure was generated from a Core Analysis in IPA for the risk genes (green-colored) and their relationship to AD (red-colored)]

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