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01-11-2017 | Translational Neurosciences - Original Article

Genome-wide significant, replicated and functional risk variants for Alzheimer’s disease

Authors: Xiaoyun Guo, Wenying Qiu, Rolando Garcia-Milian, Xiandong Lin, Yong Zhang, Yuping Cao, Yunlong Tan, Zhiren Wang, Jing Shi, Jijun Wang, Dengtang Liu, Lisheng Song, Yifeng Xu, Xiaoping Wang, Na Liu, Tao Sun, Jianming Zheng, Justine Luo, Huihao Zhang, Jianying Xu, Longli Kang, Chao Ma, Kesheng Wang, Xingguang Luo

Published in: Journal of Neural Transmission | Issue 11/2017

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.

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Title: Genome-wide significant, replicated and functional risk variants for Alzheimer’s disease
Authors: Xiaoyun Guo
Wenying Qiu
Rolando Garcia-Milian
Xiandong Lin
Yong Zhang
Yuping Cao
Yunlong Tan
Zhiren Wang
Jing Shi
Jijun Wang
Dengtang Liu
Lisheng Song
Yifeng Xu
Xiaoping Wang
Na Liu
Tao Sun
Jianming Zheng
Justine Luo
Huihao Zhang
Jianying Xu
Longli Kang
Chao Ma
Kesheng Wang
Xingguang Luo
Publication date: 01-11-2017
Publisher: Springer Vienna
Published in: Journal of Neural Transmission / Issue 11/2017
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-017-1773-0

At a glance: The STEP trials

Springer Medicine

Genome-wide significant, replicated and functional risk variants for Alzheimer’s disease

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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