Investigation of the role of miRNA variants in neurodegenerative brain diseases

Alexandros Frydas ^1,2* Rita Cacace ^1,2 Julie van der Zee ^1,2 Christine Van Broeckhoven ^1,2 Eline Wauters ^1,2

• ¹ VIB Center for Molecular Neurology, Antwerp, Antwerp, Belgium
• ² Department of Biomedical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Antwerp, Belgium

miRNAs are small noncoding elements known to regulate different molecular processes, including developmental and executive functions in the brain. Dysregulation of miRNAs could contribute to brain neurodegeneration, as suggested by miRNA profiling studies of individuals suffering from neurodegenerative brain diseases (NBDs). Here, we report rare miRNA variants in patients with Alzheimer's dementia (AD) and frontotemporal dementia (FTD). We used whole exome sequencing data in a subset of FTD patients (n=209) from Flanders-Belgium and identified rare seed variants in MIR656, MIR423, MIR122 and MIR885. We then performed targeted resequencing of these miRNAs in another subset of FTD patients (n=126) and control individuals (n=426). After sequencing of the MIR885 locus in a Flanders-Belgian AD cohort (n=947), we initially observed a significant association for MIR885 variants with AD (SKAT-O, p-value = 0.026). Genetic association was not maintained when we included sex and APOE status as covariates. Using the miRVaS prediction tool, variants rs897551430 and rs993255773 appeared to evoke significant structural changes in the primary miRNA. These variants are also predicted to strongly downregulate mature miR885 levels, in line with what is reported for MIR885 in the context of AD. We believe that the genetic evidence presented here suggests a role for MIR885 in molecular mechanisms involved in AD and warrants genetic follow-up in larger cohorts to explore this hypothesis.