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

Mohsen Ghanbari,M Arfan Ikram,Oscar H Franco,Albert Hofman,Abbas Dehghan,Stefan J Erkeland,Hans W J De Looper

doi:10.1038/srep28387

Mohsen Ghanbari, M Arfan Ikram + Show 5 more

Open Access

https://doi.org/10.1038/srep28387

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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.

Highlights

Variants in genomic sequences encoding miRNAs or in the 3′UTRs of miRNA target genes that contribute to phenotypic variations and disease risk[18,19,20,21,22]
We investigated the association of all genetic variants located in miRNA genes as well as miRNA-binding sites in the 3′UTR of their target genes with risk of Alzheimer’s disease (AD) using data from the largest available GWAS on late-onset AD23
Out of 237 variants located in 206 miRNAs, we found rs2291418 (Chr5:179225324, A >G), a low-frequency variant (MAF = 0.02) in the pre-miR-1229 sequence, to be significantly associated with the risk of AD (p-value = 6.8 × 10−5 and OR = 1.2)

Summary

Introduction

Variants in genomic sequences encoding miRNAs or in the 3′UTRs of miRNA target genes that contribute to phenotypic variations and disease risk[18,19,20,21,22]. We hypothesized that miRNA-related variants could constitute a part of the functional genomic variants influencing the risk of AD. To test this hypothesis, we investigated the association of all genetic variants located in miRNA genes as well as miRNA-binding sites in the 3′UTR of their target genes with risk of AD using data from the largest available GWAS on late-onset AD23. We subsequently integrated our results with publicly available biological databases (such as miRNA and gene expression profiles) and performed experimental studies to provide evidence for the function of the identified variants in AD

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