1. A functional variant in the miR‐142 promoter modulating its expression and conferring risk of Alzheimer disease
- Author
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Wenshi Wang, Saverio Bellusci, Stefan J. Erkeland, Bas Lendemeijer, Steven A. Kushner, Shashini T. Munshi, Kerstin Goth, Femke M.S. de Vrij, M. Arfan Ikram, Buyun Ma, Mohsen Ghanbari, Wilfred F. J. van IJcken, Denise E. Slump, Hieab H.H. Adams, Sakshi Bansal, Mirjam C G N van den Hout, Qiuwei Pan, Epidemiology, Psychiatry, Gastroenterology & Hepatology, Clinical Genetics, Radiology & Nuclear Medicine, Cell biology, and Immunology
- Subjects
RNA, Untranslated ,Induced Pluripotent Stem Cells ,Locus (genetics) ,Biology ,Hippocampus ,Models, Biological ,Polymorphism, Single Nucleotide ,Cell Line ,PICALM ,Mice ,03 medical and health sciences ,Neural Stem Cells ,Alzheimer Disease ,microRNA ,Genetics ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Promoter Regions, Genetic ,Gene ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,Derepression ,030304 developmental biology ,Mice, Knockout ,Regulation of gene expression ,0303 health sciences ,030305 genetics & heredity ,Chromosome Mapping ,Computational Biology ,Genetic Variation ,medicine.disease ,Disease Models, Animal ,MicroRNAs ,Gene Expression Regulation ,Knockout mouse ,RNA Interference ,Alzheimer's disease ,Genome-Wide Association Study - 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 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.
- Published
- 2019