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

  • 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
Translational Neurosciences - Original Article

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

Alzheimer’s disease GWAS Genome-wide significant Replicated Risk variant Gene expression APOE 

Supplementary material

702_2017_1773_MOESM1_ESM.doc (125 kb)
Supplementary material 1 (DOC 125 kb)

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Copyright information

© Springer-Verlag GmbH Austria 2017

Authors and Affiliations

  • Xiaoyun Guo
    • 1
    • 2
  • Wenying Qiu
    • 3
  • Rolando Garcia-Milian
    • 4
  • Xiandong Lin
    • 5
  • Yong Zhang
    • 6
  • Yuping Cao
    • 7
  • Yunlong Tan
    • 8
  • Zhiren Wang
    • 8
  • Jing Shi
    • 8
  • Jijun Wang
    • 1
  • Dengtang Liu
    • 1
  • Lisheng Song
    • 1
  • Yifeng Xu
    • 1
  • Xiaoping Wang
    • 9
  • Na Liu
    • 10
  • Tao Sun
    • 11
  • Jianming Zheng
    • 11
  • Justine Luo
    • 2
  • Huihao Zhang
    • 12
  • Jianying Xu
    • 13
  • Longli Kang
    • 14
  • Chao Ma
    • 3
  • Kesheng Wang
    • 15
  • Xingguang Luo
    • 2
    • 8
  1. 1.Shanghai Mental Health CenterShanghaiChina
  2. 2.Department of PsychiatryYale University School of MedicineNew HavenUSA
  3. 3.Department of Human Anatomy, Histology and Embryology, Institute of Basic Medical Sciences, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic MedicinePeking Union Medical CollegeBeijingChina
  4. 4.Curriculum and Research Support Department, Cushing/Whitney Medical LibraryYale University School of MedicineNew HavenUSA
  5. 5.Department of Pathology, Fujian Provincial Cancer HospitalThe Teaching Hospital of Fujian Medical UniversityFuzhouChina
  6. 6.Tianjin Mental Health CenterTianjinChina
  7. 7.Department of Psychiatry, Second Xiangya HospitalCentral South UniversityChangshaChina
  8. 8.Biological Psychiatry Research CenterBeijing Huilongguan HospitalBeijingChina
  9. 9.Department of Neurology, Shanghai Tongren HospitalShanghai Jiao Tong UniversityShanghaiChina
  10. 10.Nanjing Brain HospitalNanjing Medical UniversityNanjingChina
  11. 11.Huashan HospitalFudan University School of MedicineShanghaiChina
  12. 12.The First Affiliated HospitalFujian Medical UniversityFuzhouChina
  13. 13.Zhuhai Municipal Maternal and Children’s Health HospitalZhuhaiChina
  14. 14.Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Diseases of Tibet Autonomous RegionXizang Minzu University School of MedicineXiangyangChina
  15. 15.Department of Biostatistics and Epidemiology, College of Public HealthEast Tennessee State UniversityJohnson CityUSA

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