Genome-wide analysis of long non-coding RNAs in Alzheimer’s disease reveals the causal variant at chr17q22 susceptibility locus within the miR-142 promoter region

Genome-wide association studies (GWAS) have identified multiple loci associated with Alzheimer’s disease (AD). However, the majority of AD-associated variants map to non-coding regions of the genome in which the biological consequences of candidate variants remain poorly understood. Here, we aimed to investigate the extent to which genetic associations with AD may act through long non-coding RNAs (lncRNAs). We retrieved genetic variants in lncRNAs from online databases and examined their association with AD risk by leveraging data from the available GWAS of AD. Genetic variants in five lncRNAs passed the significance threshold of p-value < 9.02×10-7. For the associated variants, we performed various in silico studies (e.g. functional mapping and annotation to regulatory features and eQTL analysis) to prioritize the potential functional variants. Of these, the leading candidate variant localized to chr17q22, a recently-identified susceptibility locus for AD, that overlaps with two lncRNAs (BZRAP1-AS1 and MIR142), was selected for further investigations. Our in vitro experiments (e.g. testing the impact of either alleles on the ncRNA expression level) provided evidence that the most likely casual variant in the locus occurs within the promoter region of miR-142. Furthermore, we used human induced pluripotent stem (iPS)-derived neural progenitor cells and miR-142 knock-out mice and found multiple putative miR-142 targets that may function to mediate the miRNA effect in relation to AD. Collectively, we confirm chr17q22 as a susceptibility locus for AD and suggest that the casual variant at this locus is located within the miR-142 promoter region, which functions by altering the miR-142 expression.

Keywords:

Alzheimer s disease , Non-coding RNAs , GWAS , MIR142