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

2024; Elsevier BV; Volume: 111; Issue: 7 Linguagem: Inglês

10.1016/j.ajhg.2024.05.017

1537-6605

Claudia Manzoni, Demis A. Kia, Raffaele Ferrari, Ganna Leonenko, Beatrice Costa, Valentina Saba, Edwin Jabbari, Manuela Tan, Diego Albani, Victoria Álvarez, Ignacio Álvarez, Ole A. Andreassen, Antonella Angiolillo, Andrea Arighi, Matt Baker, Luisa Benussi, Valentina Bessi, Giuliano Binetti, D. Blackburn, Merçé Boada, Bradley F. Boeve, Sergi Borrego‐Écija, Barbara Borroni, Geir Bråthen, William S. Brooks, Amalia C. Bruni, Paola Caroppo, Sara Bandrés‐Ciga, Jordi Clarimón, Rosanna Colao, Carlos Cruchaga, Adrian Danek, Sterre CM. de Boer, Itziar de Rojas, Alfonso Di Costanzo, Dennis W. Dickson, Janine Diehl‐Schmid, Carol Dobson‐Stone, Oriol Dols‐Icardo, Aldo Donizetti, Elise G.P. Dopper, Elisabetta Durante, Camilla Ferrari, Gianluigi Forloni, Francesca Frangipane, Laura Fratiglioni, Milica G. Kramberger, Daniela Galimberti, Maurizio Gallucci, Pablo García‐González, Roberta Ghidoni, Giorgio Giaccone, Caroline Graff, Neill R. Graff‐Radford, Jordan Grafman, Glenda M. Halliday, Dena Hernandez, Lena E. Hjermind, John R. Hodges, Guy Holloway, Edward D. Huey, Ignacio Illán‐Gala, Keith A. Josephs, David S. Knopman, Mark Kristiansen, John B. Kwok, Isabelle Leber, Hampton L. Leonard, Ilenia Libri, Alberto Lleó, Ian R. Mackenzie, Gaganjit K. Madhan, Raffaele Maletta, Marta Marquié, Aleš Maver, Manuel Menéndez‐González, Graziella Milan, Bruce L. Miller, Christopher M. Morris, Huw R. Morris, Benedetta Nacmias, Judith Newton, Jørgen E. Nielsen, Christer Nilsson, Valeria Novelli, Alessandro Padovani, Suvankar Pal, Florence Pasquier, Pau Pástor, Robert Perneczky, Borut Peterlin, Ronald C. Petersen, Olivier Piguet, Yolande A.L. Pijnenburg, Annibale Alessandro Puca, Rosa Rademakers, Innocenzo Rainero, Lianne M. Reus, Anna MT. Richardson, Markus J. Riemenschneider, Ekaterina Rogaeva, Boris Rogelj, Sara Rollinson, Howard Rosen, Giacomina Rossi, James B. Rowe, Elisa Rubino, Agustı́n Ruiz, Erika Salvi, Raquel Sánchez‐Valle, Sigrid Botne Sando, Alexander Santillo, Jennifer A. Saxon, Johannes C. M. Schlachetzki, Sonja W. Scholz, Harro Seelaar, William W. Seeley, María Serpente, Sandro Sorbi, Sabrina Sordon, Peter St George‐Hyslop, J. C. Thompson, Christine Van Broeckhoven, Vivianna M. Van Deerlin, Sven J Van Der Lee, John C. van Swieten, Fabrizio Tagliavini, Julie van der Zee, Arianna Veronesi, Emilia Vitale, María Landqvist Waldö, Jennifer S. Yokoyama, Mike A. Nalls, Parastoo Momeni, Andrew Singleton, John Hardy, Valentina Escott‐Price,

Prion Diseases and Protein Misfolding

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.