Format

Send to

Choose Destination
J Neural Transm (Vienna). 2017 Nov;124(11):1455-1471. doi: 10.1007/s00702-017-1773-0. Epub 2017 Aug 2.

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

Author information

1
Shanghai Mental Health Center, Shanghai, 200030, China.
2
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06510, USA.
3
Department of Human Anatomy, Histology and Embryology, Institute of Basic Medical Sciences, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
4
Curriculum and Research Support Department, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, CT, 06510, USA.
5
Department of Pathology, Fujian Provincial Cancer Hospital, The Teaching Hospital of Fujian Medical University, Fuzhou, 350014, Fujian, China.
6
Tianjin Mental Health Center, Tianjin, 300222, China.
7
Department of Psychiatry, Second Xiangya Hospital, Central South University, Changsha, 410012, China.
8
Biological Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing, 100096, China.
9
Department of Neurology, Shanghai Tongren Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.
10
Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China.
11
Huashan Hospital, Fudan University School of Medicine, Shanghai, 200040, China.
12
The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350001, China.
13
Zhuhai Municipal Maternal and Children's Health Hospital, Zhuhai, 519000, Guangdong, China.
14
Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Diseases of Tibet Autonomous Region, Xizang Minzu University School of Medicine, Xiangyang, 712082, Shaanxi, China.
15
Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN, 37614, USA.
16
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06510, USA. Xingguang.Luo@yale.edu.
17
Biological Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing, 100096, China. Xingguang.Luo@yale.edu.

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

PMID:
28770390
PMCID:
PMC5654670
DOI:
10.1007/s00702-017-1773-0
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center