A functional polymorphism in miRNA-1229 influences the risk of Alzheimer’s disease
Mohsen Ghanbari1,2, M. Arfan Ikram1 , Hans W.J. de Looper3, Albert Hofman1, Stefan J. Erkeland3,
Oscar H. Franco1, Abbas Dehghan1.
1. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
2. Department of Genetics, School of medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
3. Department of Hematology, Erasmus University Medical Center, Cancer Institute, Rotterdam, the
Genome-wide association studies (GWAS) have enabled us to identify a large number of
genetic variants associated with Alzheimer’s disease (AD). However, the vast majority of the
identified variants are non-genic that their biological relevance to the disease remain to be
elucidated. MicroRNAs (miRNAs) serve as key post-transcriptional regulators of gene
expression and are involved in various biological processes. Genetic variation in miRNArelated sequences has been shown to interfere with miRNA gene regulation and subsequently
affect disease risk. Here, we investigated the extent to which variants fall in miRNAs and
miRNA-binding sites could constitute a part of the functional variants associated with AD.
Using data from the thus far largest GWAS on late-onset AD, we found that rs2291418
(Chr5;179798324:G>A) within the pre-miR-1229 sequence is associated with an increased
risk of AD (p-value=6.8×10-5 and β=0.18). In silico analysis showed that rs2291418 affect the
processing of pre-miR-1229 and in vitro assays demonstrated that the mutant allele enhance
the level of mature miR-1229-3p. Subsequently, we found a number of miR-1229-3p target
genes that may mediate the miRNA-effect on AD. Furthermore, we identified 11 variants in
the 3’UTR of 10 genes linked with AD that would potentially interfere with miRNAmediated regulation of the host genes by disrupting, creating or modifying miRNA binding
sites. With this approach, we further found two new genes, DMWD and HBEGF, that are
associated with AD. These findings may improve our understanding of the role of miRNAs in
the pathophysiology of AD and contribute to better annotation of GWAS findings.