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

Mohsen Ghanbari, Shashini T. Munshi, Buyun Ma, Bas Lendemeijer, Sakshi Bansal, Hieab H. Adams, Wenshi Wang, Kerstin Goth, Denise E. Slump, Mirjam C.G.N. van den Hout, Wilfred F.J. van IJcken, Saverio Bellusci, Qiuwei Pan, Stefan J. Erkeland, Femke M.S. de Vrij, Steven A. Kushner, M. Arfan Ikram

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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.

Original languageEnglish
Pages (from-to)2131-2145
Number of pages15
JournalHuman Mutation
Issue number11
StatePublished - 1 Nov 2019
Externally publishedYes


  • Alzheimer disease
  • TGFBR1
  • lncRNAs
  • miR-142
  • miRNAs
  • noncoding RNAs


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