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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 ; Costa, Beatrice ; Saba, Valentina LU orcid ; Jabbari, Edwin ; Tan, Manuela MX ; Albani, Diego and Alvarez, Victoria , et al. (2024) In American Journal of Human Genetics 111(7). p.1316-1329
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Human Genetics
volume
111
issue
7
pages
14 pages
publisher
Cell Press
external identifiers
  • pmid:38889728
  • scopus:85197544348
ISSN
0002-9297
DOI
10.1016/j.ajhg.2024.05.017
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2024 The Author(s)
id
c85863e6-3c3b-4645-80f8-238c58f493f6
date added to LUP
2024-07-21 11:33:42
date last changed
2024-07-23 03:00:39
@article{c85863e6-3c3b-4645-80f8-238c58f493f6,
  abstract     = {{<p>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<sup>−12</sup>, OR = 1.27) and APOE (rs6857; p = 1.31 × 10<sup>−12</sup>, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10<sup>−8</sup>, 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.</p>}},
  author       = {{Manzoni, Claudia and Kia, Demis A. and Ferrari, Raffaele and Leonenko, Ganna and Costa, Beatrice and Saba, Valentina and Jabbari, Edwin and Tan, Manuela MX and Albani, Diego and Alvarez, Victoria and Alvarez, Ignacio and Andreassen, Ole A. and Angiolillo, Antonella and Arighi, Andrea and Baker, Matt and Benussi, Luisa and Bessi, Valentina and Binetti, Giuliano and Blackburn, Daniel J. and Boada, Merce and Boeve, Bradley F. and Borrego-Ecija, Sergi and Borroni, Barbara and Bråthen, Geir and Brooks, William S. and Bruni, Amalia C. and Caroppo, Paola and Bandres-Ciga, Sara and Clarimon, Jordi and Colao, Rosanna and Cruchaga, Carlos and Danek, Adrian and de Boer, Sterre CM and de Rojas, Itziar and di Costanzo, Alfonso and Dickson, Dennis W. and Diehl-Schmid, Janine and Dobson-Stone, Carol and Dols-Icardo, Oriol and Donizetti, Aldo and Dopper, Elise and Durante, Elisabetta and Ferrari, Camilla and Forloni, Gianluigi and Frangipane, Francesca and Fratiglioni, Laura and Kramberger, Milica G. and Galimberti, Daniela and Gallucci, Maurizio and García-González, Pablo and Ghidoni, Roberta and Giaccone, Giorgio and Graff, Caroline and Graff-Radford, Neill R. and Grafman, Jordan and Halliday, Glenda M. and Hernandez, Dena G. and Hjermind, Lena E. and Hodges, John R. and Holloway, Guy and Huey, Edward D. and Illán-Gala, Ignacio and Josephs, Keith A. and Knopman, David S. and Kristiansen, Mark and Kwok, John B. and Leber, Isabelle and Leonard, Hampton L. and Libri, Ilenia and Lleo, Alberto and Mackenzie, Ian R. and Madhan, Gaganjit K. and Maletta, Raffaele and Marquié, Marta and Maver, Ales and Menendez-Gonzalez, Manuel and Milan, Graziella and Miller, Bruce L. and Morris, Christopher M. and Morris, Huw R. and Nacmias, Benedetta and Newton, Judith and Nielsen, Jørgen E. and Nilsson, Christer and Novelli, Valeria and Padovani, Alessandro and Pal, Suvankar and Pasquier, Florence and Pastor, Pau and Perneczky, Robert and Peterlin, Borut and Petersen, Ronald C. and Piguet, Olivier and Pijnenburg, Yolande AL and Puca, Annibale A. and Rademakers, Rosa and Rainero, Innocenzo and Reus, Lianne M. and Richardson, Anna MT and Riemenschneider, Matthias and Rogaeva, Ekaterina and Rogelj, Boris and Rollinson, Sara and Rosen, Howard and Rossi, Giacomina and Rowe, James B. and Rubino, Elisa and Ruiz, Agustin and Salvi, Erika and Sanchez-Valle, Raquel and Sando, Sigrid Botne and Santillo, Alexander F. and Saxon, Jennifer A. and Schlachetzki, Johannes CM and Scholz, Sonja W. and Seelaar, Harro and Seeley, William W. and Serpente, Maria and Sorbi, Sandro and Sordon, Sabrina and St George-Hyslop, Peter and Thompson, Jennifer C. and Van Broeckhoven, Christine and Van Deerlin, Vivianna M. and Van der Lee, Sven J. and Van Swieten, John and Tagliavini, Fabrizio and van der Zee, Julie and Veronesi, Arianna and Vitale, Emilia and Waldo, Maria Landqvist and Yokoyama, Jennifer S. and Nalls, Mike A. and Momeni, Parastoo and Singleton, Andrew B. and Hardy, John and Escott-Price, Valentina}},
  issn         = {{0002-9297}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{7}},
  pages        = {{1316--1329}},
  publisher    = {{Cell Press}},
  series       = {{American Journal of Human Genetics}},
  title        = {{Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia}},
  url          = {{http://dx.doi.org/10.1016/j.ajhg.2024.05.017}},
  doi          = {{10.1016/j.ajhg.2024.05.017}},
  volume       = {{111}},
  year         = {{2024}},
}