GWAS-Top Polymorphisms Associated With Late-Onset Alzheimer Disease in Brazil: Pointing Out Possible New Culprits Among Non-Coding RNAs

Abstract

Several genome-wide association studies (GWAS) have been carried out with late-onset Alzheimer’s disease (LOAD), mainly in European and Asian populations. Different polymorphisms were associated, but several of them without a functional explanation. GWAS are fundamental for identifying loci associated with diseases, although they often do not point to causal polymorphisms. In this sense, functional investigations are a fundamental tool for discovering causality, although the failure of this validation does not necessarily indicate a non-causality. Furthermore, the allele frequency of associated genetic variants may vary widely between populations, requiring replication of these associations in other ethnicities. In this sense, our study sought to replicate in 150 AD patients and 114 elderly controls from the South Brazilian population 18 single-nucleotide polymorphisms (SNPs) associated with AD in European GWAS, with further functional investigation using bioinformatic tools for the associated SNPs. Of the 18 SNPs investigated, only four were associated in our population: rs769449 (APOE), rs10838725 (CELF1), rs6733839, and rs744373 (BIN1–CYP27C1). We identified 54 variants in linkage disequilibrium (LD) with the associated SNPs, most of which act as expression or splicing quantitative trait loci (eQTLs/sQTLs) in genes previously associated with AD or with a possible functional role in the disease, such as CELF1, MADD, MYBPC3, NR1H3, NUP160, SPI1, and TOMM40. Interestingly, eight of these variants are located within long non-coding RNA (lncRNA) genes that have not been previously investigated regarding AD. Some of these polymorphisms can result in changes in these lncRNAs’ secondary structures, leading to either loss or gain of microRNA (miRNA)-binding sites, deregulating downstream pathways. Our pioneering work not only replicated LOAD association with polymorphisms not yet associated in the Brazilian population but also identified six possible lncRNAs that may interfere in LOAD development. The results lead us to emphasize the importance of functional exploration of associations found in large-scale association studies in different populations to base personalized and inclusive medicine in the future.

The Perspective of Dysregulated LncRNAs in Alzheimer's Disease: A Systematic Scoping Review

“…One study discovered eight variants in lncRNA genes that had never been studied before in AD. These polymorphisms can result in changes in lncRNA secondary structures, resulting in the loss or increase of microRNA binding sites (miRNAs) and downstream pathway regulation (Kretzschmar et al, 2021 ). According to the present study, the significant contribution of dysregulated LncRNAs in AD is assigned to Bace1-AS, NEAT1, MALAT1, SNHG1, 17A, and Rpph1 LncRNAs, respectively.…”

Missing lnc(RNAs) in Alzheimer’s Disease?

“…The occurrence and frequency of specific genetic variants might be reflected on the population ancestry making it essential to replicate GWAS data in different ethnicities [ 74 , 75 ]. A recent study investigated 18 SNPs associated with LOAD in European-based studies in 150 AD patients and 114 controls from the South Brazilian population [ 76 ]. Despite the limitation in sample size, four SNPs were found to overlap between both populations [ 76 ].…”

“…A recent study investigated 18 SNPs associated with LOAD in European-based studies in 150 AD patients and 114 controls from the South Brazilian population [ 76 ]. Despite the limitation in sample size, four SNPs were found to overlap between both populations [ 76 ]. Additionally, eight out of 54 variants found in linkage disequilibrium with the associated SNPs were located withing lncRNA genes; and six were found potentially involved in AD [ 76 ].…”

“…Despite the limitation in sample size, four SNPs were found to overlap between both populations [ 76 ]. Additionally, eight out of 54 variants found in linkage disequilibrium with the associated SNPs were located withing lncRNA genes; and six were found potentially involved in AD [ 76 ]. Of particular interest was the SNP allele rs769449*A, which was found in linkage disequilibrium with the APOE ε4 isoform rs429358*C allele and associated with LOAD susceptibility in the study’s cohort.…”

“…Another SNP, rs769449, localizes to two overlapping lncRNA genes ( NONHSAT179793.1 and NONHSAT066732.2 ). This latter SNP likely affects the secondary structure of NONHSAT066732.2, leading to changes in the interaction of this lncRNA with two miRNAs potentially involved in inflammatory responses [ 76 ].…”