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

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.

Quantitative Trait Module-Based Genetic Analysis of Alzheimer’s Disease

“…Indeed, APOE has been found to be associated with the atrophies of the hippocampus and amygdala [32]. NECTIN2 , APOC1 , and TOMM40 are neighbor genes of APOE on chromosome 19 [46,47]. In biology, these loci were involved in the deposition of β-amyloid protein and the abnormal phosphorylation of Tau protein [48].…”

Roles of glutamate receptors in a novel in vitro model of early, comorbid cerebrovascular, and Alzheimer’s diseases

“…2010;Gao, Tian, Gao, & Xu, 2013;Lu et al, 2015;Qiu et al, 2016;Zhai et al, 2016;Michalski, Hofmann, Pitsch, Grosche, & Hartig, 2017;Nguyen et al, 2018;Pimentel-Coelho, Michaud, & Rivest, 2013). However, those studies were designed as overt cerebrovascular insults applied to transgenic mice harboring genetic variants that represent, at most, 10% of the total AD cases [or 20% in the early onset form of Alzheimer's disease; Bekris, Yu, Bird, & Tsuang, 2010;Guo et al, 2017;Kim, 2018)]. Considering the numerous genetic risk factors for AD discovered in genome-wide association studies (Carmona, Hardy, & Guerreiro, 2018;Lambert et al, 2013) In rats subjected to endothelin-induced acute vasoconstriction in the striatum together with intra-cerebrovascular injection of the Aβ fragment 25-35 (Amtul et al, 2014), neurodegeneration markers were found at levels higher than caused by either insult alone (Amtul, Frias, Randhawa, Hill, & Arany, 2019;Amtul, Hill, Arany, & Cechetto, 2018;Amtul et al, 2014Amtul et al, , 2015.…”

Small Non-coding RNAs: New Class of Biomarkers and Potential Therapeutic Targets in Neurodegenerative Disease

“…Risk variants APOE (rs2075650) and RNU6-560P (rs10792835 + rs3851179) have been linked with AD through genome-wide association studies (GWAS). These risk variants were significantly correlated with nine (6 APOE and 3 RNU6-560P) different piRNAs, showing regulatory capabilities (Guo X. et al, 2017). PiRNA dysregulation may be integral to the development of AD through aberrant downstream signaling.…”