DataSheet1_GWAS-Top Polymorphisms Associated With Late-Onset Alzheimer Disease in Brazil: Pointing Out Possible New Culprits Among Non-Coding RNAs.XLSX

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.

多项全基因组关联研究（GWAS）已针对晚发性阿尔茨海默病（LOAD）进行，主要在欧洲和亚洲人群中开展。不同的多态性与之相关联，但其中一些缺乏功能性的解释。GWAS对于识别与疾病相关的位点至关重要，尽管它们通常并不指向因果多态性。在这种意义上，功能研究是发现因果关系的根本工具，尽管这种验证的失败并不一定意味着非因果关系。此外，与关联的遗传变异的等位基因频率可能在不同人群中广泛变化，需要在这些其他族群中重复验证这些关联。在此意义上，我们的研究旨在在巴西南部150名阿尔茨海默病患者和114名老年对照者中复制欧洲GWAS中发现的与阿尔茨海默病相关的18个单核苷酸多态性（SNPs），并进一步使用生物信息学工具对相关SNPs进行功能研究。在研究的18个SNPs中，只有四个与我们的群体相关：rs769449（APOE）、rs10838725（CELF1）、rs6733839和rs744373（BIN1–CYP27C1）。我们发现了与关联SNPs连锁不平衡（LD）的54个变异，其中大部分作为表达或剪接数量性状位点（eQTLs/sQTLs）在先前与阿尔茨海默病或可能具有疾病功能作用的基因中发挥作用，例如CELF1、MADD、MYBPC3、NR1H3、NUP160、SPI1和TOMM40。有趣的是，其中八个变异位于尚未就阿尔茨海默病进行研究的长非编码RNA（lncRNA）基因内。这些多态性中的一些可能导致这些lncRNA的二级结构发生变化，从而引起微RNA（miRNA）结合位点的丧失或获得，从而扰乱下游通路。我们的开创性工作不仅复制了在巴西人群中尚未关联的LOAD多态性与关联，还识别了六个可能干扰LOAD发展的可能长非编码RNA。这些结果使我们强调，在大型关联研究中发现的关联在不同人群中的功能探索的重要性，以在未来基于个性化包容性医学。