Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

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  • Lianne M. Reus
  • Bogdan Pasaniuc
  • Danielle Posthuma
  • Toni Boltz
  • Raffaele Ferrari
  • Dena G. Hernandez
  • Michael A. Nalls
  • Jonathan D. Rohrer
  • Adaikalavan Ramasamy
  • John B.J. Kwok
  • Carol Dobson-Stone
  • William S. Brooks
  • Glenda M. Halliday
  • John R. Hodges
  • Olivier Piguet
  • Lauren Bartley
  • Elizabeth Thompson
  • Isabel Hernández
  • Agustín Ruiz
  • Mercè Boada
  • Barbara Borroni
  • Alessandro Padovani
  • Carlos Cruchaga
  • Nigel J. Cairns
  • Luisa Benussi
  • Giuliano Binetti
  • Roberta Ghidoni
  • Gianluigi Forloni
  • Daniela Galimberti
  • Chiara Fenoglio
  • Maria Serpente
  • Elio Scarpini
  • Jordi Clarimón
  • Alberto Lleó
  • Rafael Blesa
  • Maria Landqvist Waldö
  • Karin Nilsson
  • Christer Nilsson
  • Ian R.A. Mackenzie
  • Ging Yuek R. Hsiung
  • David M.A. Mann
  • Jordan Grafman
  • Christopher M. Morris
  • Johannes Attems
  • Timothy D. Griffiths
  • Ian G. McKeith
  • Alan J. Thomas
  • Pietro Pietrini
  • Edward D. Huey
  • Eric M. Wassermann
  • Atik Baborie
  • Evelyn Jaros
  • Michael C. Tierney
  • Pau Pastor
  • Cristina Razquin
  • Sara Ortega-Cubero
  • Elena Alonso
  • Robert Perneczky
  • Janine Diehl-Schmid
  • Panagiotis Alexopoulos
  • Alexander Kurz
  • Innocenzo Rainero
  • Elisa Rubino
  • Lorenzo Pinessi
  • Ekaterina Rogaeva
  • Peter St. George-Hyslop
  • Giacomina Rossi
  • Fabrizio Tagliavini
  • Giorgio Giaccone
  • Johannes C.M. Schlachetzki
  • James Uphill
  • John Collinge
  • Simon Mead
  • Adrian Danek
  • Vivianna M. Van Deerlin
  • Murray Grossman
  • John Q. Trojanowski
  • Julie van der Zee
  • Christine Van Broeckhoven
  • Stefano F. Cappa
  • Isabelle Le Ber
  • Didier Hannequin
  • Véronique Golfier
  • Martine Vercelletto
  • Alexis Brice
  • Benedetta Nacmias
  • Sandro Sorbi
  • Silvia Bagnoli
  • Irene Piaceri
  • Lena E. Hjermind
  • Matthias Riemenschneider
  • Manuel Mayhaus
  • Bernd Ibach
  • Gilles Gasparoni
  • Sabrina Pichler
  • Wei Gu
  • Martin N. Rossor
  • Nick C. Fox
  • Jason D. Warren
  • Maria Grazia Spillantini
  • Huw R. Morris
  • Patrizia Rizzu
  • Peter Heutink
  • Julie S. Snowden
  • Sara Rollinson
  • Anna Richardson
  • Alexander Gerhard
  • Amalia C. Bruni
  • Raffaele Maletta
  • Francesca Frangipane
  • Chiara Cupidi
  • Livia Bernardi
  • Maria Anfossi
  • Maura Gallo
  • Maria Elena Conidi
  • Nicoletta Smirne
  • Rosa Rademakers
  • Matt Baker
  • Dennis W. Dickson
  • Neill R. Graff-Radford
  • Ronald C. Petersen
  • David Knopman
  • Keith A. Josephs
  • Bradley F. Boeve
  • Joseph E. Parisi
  • William W. Seeley
  • Bruce L. Miller
  • Anna M. Karydas
  • Howard Rosen
  • John C. van Swieten
  • Elise G.P. Dopper
  • Harro Seelaar
  • Yolande A.L. Pijnenburg
  • Philip Scheltens
  • Giancarlo Logroscino
  • Rosa Capozzo
  • Valeria Novelli
  • Annibale A. Puca
  • Massimo Franceschi
  • Alfredo Postiglione
  • Graziella Milan
  • Paolo Sorrentino
  • Mark Kristiansen
  • Huei Hsin Chiang
  • Caroline Graff
  • Florence Pasquier
  • Adeline Rollin
  • Vincent Deramecourt
  • Florence Lebert
  • Dimitrios Kapogiannis
  • Luigi Ferrucci
  • Stuart Pickering-Brown
  • Andrew B. Singleton
  • John Hardy
  • Parastoo Momeni
  • Roel A. Ophoff
Background: The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach. Methods: FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold. Results: We identified 73 significant gene–tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed. Conclusions: We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.
OriginalsprogDansk
TidsskriftBiological Psychiatry
Vol/bind89
Udgave nummer8
Sider (fra-til)825-835
Antal sider11
ISSN0006-3223
DOI
StatusUdgivet - 2021

    Forskningsområder

  • 17q21.31 inversion region, Dorsolateral prefrontal cortex, Expression quantitative trait loci (eQTL), Frontotemporal dementia, SEC22B, Transcriptome-wide association study

ID: 291123380