A functional variant in the miR‐142 promoter modulating its expression and conferring risk of Alzheimer disease

Abstract

Noncoding RNAs have been widely recognized as essential mediators of gene regulation. However, in contrast to protein‐coding genes, much less is known about the influence of noncoding RNAs on human diseases. Here we examined the association of genetic variants located in primary microRNA sequences and long noncoding RNAs (lncRNAs) with Alzheimer disease (AD) by leveraging data from the largest genome‐wide association meta‐analysis of late‐onset AD. Variants annotated to 5 miRNAs and 10 lncRNAs (in seven distinct loci) exceeded the Bonferroni‐corrected significance threshold (p < 1.02 × 10−6). Among these, a leading variant (rs2526377:A>G) at the 17q22 locus annotated to two noncoding RNAs (MIR142 and BZRAP1‐AS) was significantly associated with a reduced risk of AD and fulfilled predefined criteria for being a functional variant. Our functional genomic analyses revealed that rs2526377 affects the promoter activity and decreases the expression of miR‐142. Moreover, differential expression analysis by RNA‐Seq in human iPSC‐derived neural progenitor cells and the hippocampus of miR‐142 knockout mice demonstrated multiple target genes of miR‐142 in the brain that are likely to be involved in the inflammatory and neurodegenerative manifestations of AD. These include TGFBR1 and PICALM, of which their derepression in the brain due to reduced expression levels of miR‐142‐3p may reduce the risk of AD.

Objectives, design and main findings until 2020 from the Rotterdam Study

“…Likewise, a systematic analysis integrating GWAS, gene expression and DNA methylation data indicated multiple long non-coding RNAs associated with cardiometabolic disorders [358]. Besides, functional genomics by integrating GWAS data and various experimental studies using human iPS-derived neuronal progenitor cells and miR-142 knockout mice demonstrated the role of miR-142 in the pathogenesis of Alzheimer's disease [359]. An independent study further identified that the clinical spectrum of early Alzheimer's disease pathology is explained by different biological pathways, in particular, the endocytosis, clathrin/AP2 adaptor complex, and immune response pathways, that are independent of apolipoprotein E (APOE) [360].…”

Genome-wide meta-analysis, fine-mapping, and integrative prioritization identify new Alzheimer’s disease risk genes

“…Column 'SNP prob' indicates the mean fine-mapping probability for the SNP; the SpliceAI score is the maximum splicing probability for donor gain/loss or acceptor gain/loss, with nonzero values highly enriched for splicing effects; the DeepSEA functional significance score represents the significance above expectation for chromatin feature changes, as well as evolutionary conservation, with lower values more significant. References for specific SNPs are shown 2,7,9,14,40,41,[60][61][62][63][64][65][66][67][68][69] . confidence variants also include a well-known missense SNP in PILRA 41 , and a splicealtering missense SNP in CD33 7 .…”

miR-142-3p regulates cortical oligodendrocyte gene co-expression networks associated with tauopathy

“…Variants of miR-142-3p have recently been associated with a reduced risk of Alzheimer's disease (49). Building on in vitro and in vivo data implicating miR-142-3p in the regulation of novel oligodendrocyte gene networks, we examined miR-142-null mice by WGCNA to directly assess whether our significant oligodendrocyte modules (M4, M8) or tauopathy modules (T4, T20, T25) were affected by absence of the miR (Fig.…”