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.
Highlights
Late-onset Alzheimer’s disease (LOAD) is a neurodegenerative disease responsible for most dementia cases worldwide in the elderly population (Lane et al, 2018)
Linkage Disequilibrium Since many of the variants found associated in a Genome-wide association studies (GWAS) are not responsible for the disease and probably act as tag single-nucleotide polymorphisms (SNPs), we performed the linkage disequilibrium (LD) analysis for the variants that remained associated after correction for independent variables and false discovery rate (FDR)
Expression and Splicing Quantitative Trait Loci For SNPs associated in this study and all variants in LD with them, we evaluated their possible role as eQTL or sQTL in brain tissue and/or whole blood (GTEx and Braineac)
Summary
Late-onset Alzheimer’s disease (LOAD) is a neurodegenerative disease responsible for most dementia cases worldwide in the elderly population (Lane et al, 2018). Over 90 GWAS have been performed with LOAD (GWAS Catalog) They led to the identification of different polymorphisms, mostly in intronic or intergenic regions, possibly modulating the susceptibility to disease in the populations where they were analyzed, but most were not investigated nor replicated yet in Latin American populations (Kretzschmar et al, 2020). In this context, our study sought to replicate in the South Brazilian population some of the single-nucleotide polymorphism (SNP) alleles found associated with LOAD in GWAS performed in European-derived populations, as well as to evaluate possible functional explanations for these associations
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