Copy Number Variants in miR-138 as a Potential Risk Factor for Early-Onset Alzheimer’s Disease

Article type: Research Article

Authors: Boscher, Emmanuelle^{a; b} | Husson, Thomas^c | Quenez, Olivier^c | Laquerrière, Annie^d | Marguet, Florent^d | Cassinari, Kevin^c | Wallon, David^e | Martinaud, Olivier^f | Charbonnier, Camille^c | Nicolas, Gaël^c | Deleuze, Jean-François^g | Boland, Anne^g | Lathrop, Mark^h | Frébourg, Thierry^c | FREX Consortiumⁱ | Campion, Dominique^c | Hébert, Sébastien S.^{a; b; 1; *} | Rovelet-Lecrux, Anne^{c; 1}

Affiliations: [a] Centre de recherche du CHU de Québec-Université Laval, CHUL, Axe Neurosciences, Québec, Canada | [b] Faculté de médecine, Département de psychiatrie et de neurosciences, Université Laval, Québec, Canada | [c] Department of Genetics and CNR-MAJ, Normandie Univ, UNIROUEN, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, Rouen, France | [d] Department of Pathology, Normandie Univ, UNIROUEN, Rouen University Hospital, Rouen, France | [e] Department of Neurology and CNR-MAJ, Normandie Univ, UNIROUEN, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, Rouen, France | [f] Normandie Univ, UNICAEN, EPHE, INSERM, U1077, CHU de Caen, Neuropsychologie et Imagerie de la Mémoire Humaine, Caen, France | [g] Centre National de recherche en Génomique Humaine, Institut de Génomique, CEA, Evry, France | [h] McGill University and Génome Québec Innovation Centre, Montréal, Canada | [i] The FREX consortium members are listed in the Supplementary Material

Correspondence: [*] Correspondence to: Dr. Sébastien S. Hébert, Centre de recherche du CHU de Québec-UL, CHUL, Axe Neurosciences, 2705 boul. Laurier, P-09800, Québec G1V 4G2, Canada. Tel.: +1 418 525 4444/ Ext. 49233; E-mail: [email protected].

Note: [1] These senior authors contributed equally to this work.

Abstract: Early-onset Alzheimer’s disease (EOAD) accounts for 5-10% of all AD cases, with a heritability ranging between 92% to 100%. With the exception of rare mutations in APP, PSEN1, and PSEN2 genes causing autosomal dominant EOAD, little is known about the genetic factors underlying most of the EOAD cases. In this study, we hypothesized that copy number variations (CNVs) in microRNA (miR) genes could contribute to risk for EOAD. miRs are short non-coding RNAs previously implicated in the regulation of AD-related genes and phenotypes. Using whole exome sequencing, we screened a series of 546 EOAD patients negative for autosomal dominant EOAD mutations and 597 controls. We identified 86 CNVs in miR genes of which 31 were exclusive to EOAD cases, including a duplication of the MIR138-2 locus. In functional studies in human cultured cells, we could demonstrate that miR-138 overexpression leads to higher Aβ production as well as tau phosphorylation, both implicated in AD pathophysiology. These changes were mediated in part by GSK-3β and FERMT2, a potential risk factor for AD. Additional disease-related genes were also prone to miR-138 regulation including APP and BACE1. This study suggests that increased gene dosage of MIR138-2 could contribute to risk for EOAD by regulating different biological pathways implicated in amyloid and tau metabolism. Additional studies are now required to better understand the role of miR-CNVs in EOAD.

Keywords: Copy number variants, early-onset Alzheimer’s disease, microRNA, miR-138

DOI: 10.3233/JAD-180940

Journal: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1243-1255, 2019