Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

Manzoni, Claudia, Kia, Demis A., Ferrari, Raffaele, Leonenko, Ganna ORCID: https://orcid.org/0000-0001-8025-661X, Costa, Beatrice, Saba, Valentina, Jabbari, Edwin, Tan, Manuela M. X., Albani, Diego, Alvarez, Victoria, Alvarez, Ignacio, Andreassen, Ole A., Angiolillo, Antonella, Arighi, Andrea, Baker, Matt, Benussi, Luisa, Bessi, Valentina, Binetti, Giuliano, Blackburn, Daniel J., Boada, Merce, Boeve, Bradley F., Borrego-Ecija, Sergi, Borroni, Barbara, Bråthen, Geir, Brooks, William S., Bruni, Amalia C., Caroppo, Paola, Bandres-Ciga, Sara, Clarimon, Jordi, Colao, Rosanna, Cruchaga, Carlos, Danek, Adrian, de Boer, Sterre CM., de Rojas, Itziar, di Costanzo, Alfonso, Dickson, Dennis W., Diehl-Schmid, Janine, Dobson-Stone, Carol, Dols-Icardo, Oriol, Donizetti, Aldo, Dopper, Elise, Durante, Elisabetta, Ferrari, Camilla, Forloni, Gianluigi, Frangipane, Francesca, Fratiglioni, Laura, Kramberger, Milica G., Galimberti, Daniela, Gallucci, Maurizio, García-González, Pablo, Ghidoni, Roberta, Giaccone, Giorgio, Graff, Caroline, Graff-Radford, Neill R., Grafman, Jordan, Halliday, Glenda M., Hernandez, Dena G., Hjermind, Lena E., Hodges, John R., Holloway, Guy, Huey, Edward D., Illán-Gala, Ignacio, Josephs, Keith A., Knopman, David S., Kristiansen, Mark, Kwok, John B., Leber, Isabelle, Leonard, Hampton L., Libri, Ilenia, Lleo, Alberto, Mackenzie, Ian R., Madhan, Gaganjit K., Maletta, Raffaele, Marquié, Marta, Maver, Ales, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce L., Morris, Christopher M., Morris, Huw R., Nacmias, Benedetta, Newton, Judith, Nielsen, Jørgen E., Nilsson, Christer, Novelli, Valeria, Padovani, Alessandro, Pal, Suvankar, Pasquier, Florence, Pastor, Pau, Perneczky, Robert, Peterlin, Borut, Petersen, Ronald C., Piguet, Olivier, Pijnenburg, Yolande AL., Puca, Annibale A., Rademakers, Rosa, Rainero, Innocenzo, Reus, Lianne M., Richardson, Anna MT., Riemenschneider, Matthias, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rosen, Howard, Rossi, Giacomina, Rowe, James B., Rubino, Elisa, Ruiz, Agustin, Salvi, Erika, Sanchez-Valle, Raquel, Sando, Sigrid Botne, Santillo, Alexander F., Saxon, Jennifer A., Schlachetzki, Johannes CM., Scholz, Sonja W., Seelaar, Harro, Seeley, William W., Serpente, Maria, Sorbi, Sandro, Sordon, Sabrina, St George-Hyslop, Peter, Thompson, Jennifer C., Van Broeckhoven, Christine, Van Deerlin, Vivianna M., Van der Lee, Sven J., Van Swieten, John, Tagliavini, Fabrizio, van der Zee, Julie, Veronesi, Arianna, Vitale, Emilia, Waldo, Maria Landqvist, Yokoyama, Jennifer S., Nalls, Mike A., Momeni, Parastoo, Singleton, Andrew B., Hardy, John and Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483 2024. Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia. American Journal of Human Genetics 111 (7) , pp. 1316-1329. 10.1016/j.ajhg.2024.05.017

Preview

PDF - Published Version Available under License Creative Commons Attribution. Download (2MB) | Preview

Abstract

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	0002-9297
Date of First Compliant Deposit:	24 July 2024
Date of Acceptance:	17 May 2024
Last Modified:	24 Jul 2024 11:02
URI:	https://orca.cardiff.ac.uk/id/eprint/170889

Actions (repository staff only)

Edit Item