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

被引：29

作者：

Ghanbari, Mohsen ^{[1
,2
]}

Munshi, Shashini T. ^{[3
]}

Ma, Buyun ^{[4
]}

Lendemeijer, Bas ^{[3
]}

Bansal, Sakshi ^{[3
]}

Adams, Hieab H. ^{[1
,5
,6
]}

Wang, Wenshi ^{[4
]}

Goth, Kerstin ^{[7
]}

Slump, Denise E. ^{[3
]}

van den Hout, Mirjam C. G. N. ^{[8
]}

van IJcken, Wilfred F. J. ^{[8
]}

Bellusci, Saverio ^{[7
]}

Pan, Qiuwei ^{[4
]}

Erkeland, Stefan J. ^{[9
]}

de Vrij, Femke M. S. ^{[3
]}

Kushner, Steven A. ^{[3
]}

Ikram, M. Arfan ^{[1
]}

机构：

[1] Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands

[2] Mashhad Univ Med Sci, Sch Med, Dept Genet, Mashhad, Razavi Khorasan, Iran

[3] Univ Med Ctr Rotterdam, Dept Psychiat, Erasmus MC, Rotterdam, Netherlands

[4] Univ Med Ctr Rotterdam, Dept Gastroenterol, Erasmus MC, Rotterdam, Netherlands

[5] Univ Med Ctr Rotterdam, Dept Clin Genet, Erasmus MC, Rotterdam, Netherlands

[6] Univ Med Ctr Rotterdam, Dept Radiol & Nucl Med, Erasmus MC, Rotterdam, Netherlands

[7] Univ Justus Liebig Giessen, Dept Lung Matrix Remodeling, ECCPS, Giessen, Germany

[8] Univ Med Ctr Rotterdam, Ctr Biom, Dept Cell Biol, Erasmus MC, Rotterdam, Netherlands

[9] Univ Med Ctr Rotterdam, Dept Immunol, Erasmus MC, Rotterdam, Netherlands

来源：

HUMAN MUTATION | 2019年 / 40卷 / 11期

关键词：

Alzheimer disease; lncRNAs; miR-142; miRNAs; noncoding RNAs; PICALM; TGFBR1; GENOME-WIDE ASSOCIATION; CEREBRAL-CORTEX; UP-REGULATION; GENETIC-LOCI; BETA; MICRORNA-142; RNA; NEURODEGENERATION; DIFFERENTIATION; HOMEOSTASIS;

D O I：

10.1002/humu.23872

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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.

引用

页码：2131 / 2145

页数：15

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