Genome-wide identification of microRNA-related variants associated with risk of Alzheimer’s disease

Abstract

MicroRNAs (miRNAs) serve as key post-transcriptional regulators of gene expression. Genetic variation in miRNAs and miRNA-binding sites may affect miRNA function and contribute to disease risk. Here, we investigated the extent to which variants within miRNA-related sequences could constitute a part of the functional variants involved in developing Alzheimer’s disease (AD), using the largest available genome-wide association study of AD. First, among 237 variants in miRNAs, we found rs2291418 in the miR-1229 precursor to be significantly associated with AD (p-value = 6.8 × 10−5, OR = 1.2). Our in-silico analysis and in-vitro miRNA expression experiments demonstrated that the variant’s mutant allele enhances the production of miR-1229-3p. Next, we found miR-1229-3p target genes that are associated with AD and might mediate the miRNA function. We demonstrated that miR-1229-3p directly controls the expression of its top AD-associated target gene (SORL1) using luciferase reporter assays. Additionally, we showed that miR-1229-3p and SORL1 are both expressed in the human brain. Second, among 42,855 variants in miRNA-binding sites, we identified 10 variants (in the 3′ UTR of 9 genes) that are significantly associated with AD, including rs6857 that increases the miR-320e-mediated regulation of PVRL2. Collectively, this study shows that miRNA-related variants are associated with AD and suggests miRNA-dependent regulation of several AD genes.

Genetic analysis of α‐synuclein 3′ untranslated region and its corresponding microRNAs in relation to Parkinson's disease compared to dementia with Lewy bodies

“…Genetic variants in miRNAs or miRNA-binding sites could affect miRNA function and contribute to disease risk[32, 33]. Polymorphisms within the SNCA 3’UTR have been reported, and specifically associated with PD [34–38].…”

Cellular network perturbations by disease-associated variants

“…Recent studies have identified multiple disease-associated variants within miRNA gene regions and within miRNA binding sites in target mRNAs [11,59]. Differential binding of miRNA and RBPs to 3′UTR variants have also been modeled in silico [9,10].…”

Somatic mutations in miRNA genes in lung cancer – potential functional consequences of non-coding sequence variants

“…For example, the G>C substitution (SNP rs138166791) in the penultimate position of pre-miR-890, significantly lowers the cleavage efficiency by DROSHA and, consequently, decreases the levels of mature miR-890-5p and miR-890-3p (46). There is also evidence that some SNPs within miRNA genes may correlate with different diseases, including cancer (47)(48)(49)(50)(51)(52)(53). Finally, there are a few examples of Mendelian diseases caused by germline mutations in miRNA genes (54)(55)(56)(57).…”