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.
ABSTRACT
Circulating cell-free microRNAs (miRNAs) are stable in many biological fluids and their expression profiles can suffer changes under different physiological and pathological conditions. In the last few years, miRNAs have been proposed as putative noninvasive biomarkers in diagnosis, prognosis and response to treatment for several diseases, including neurodegenerative disorders as Alzheimer's disease (AD) and Parkinson's disease (PD). Cognitive and/or motor impairments are usually considered for establishing clinical diagnosis, and at this stage, the majority of the neurons may already be lost making difficult attempts of novel therapies. In this review, we intend to survey the circulating cell-free miRNAs found as dysregulated in cerebrospinal fluid, serum and plasma samples in AD and PD patients, and show how those miRNAs can be useful for early and differential diagnosis. Beyond that, we highlighted the miRNAs that are possibly related to common molecular mechanisms in the neurodegeneration process, as well those miRNAs related to specific disease pathways.
