Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes.
17q21.31 inversion region
Dorsolateral prefrontal cortex
Expression quantitative trait loci (eQTL)
Frontotemporal dementia
SEC22B
Transcriptome-wide association study
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
15 04 2021
15 04 2021
Historique:
received:
06
07
2020
revised:
01
12
2020
accepted:
29
12
2020
pubmed:
28
2
2021
medline:
24
4
2021
entrez:
27
2
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33637304
pii: S0006-3223(21)00032-9
doi: 10.1016/j.biopsych.2020.12.023
pmc: PMC8415425
mid: NIHMS1734323
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
825-835Subventions
Organisme : Medical Research Council
ID : MC_UU_00024/9
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : R01 MH120794
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00024/1
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : T32 HG002536
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG019724
Pays : United States
Organisme : Medical Research Council
ID : G0301152
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : R01 HG009120
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG062268
Pays : United States
Investigateurs
Raffaele Ferrari
(R)
Dena G Hernandez
(DG)
Michael A Nalls
(MA)
Jonathan D Rohrer
(JD)
Adaikalavan Ramasamy
(A)
John B J Kwok
(JBJ)
Carol Dobson-Stone
(C)
William S Brooks
(WS)
Peter R Schofield
(PR)
Glenda M Halliday
(GM)
John R Hodges
(JR)
Olivier Piguet
(O)
Lauren Bartley
(L)
Elizabeth Thompson
(E)
Isabel Hernández
(I)
Agustín Ruiz
(A)
Mercè Boada
(M)
Barbara Borroni
(B)
Alessandro Padovani
(A)
Carlos Cruchaga
(C)
Nigel J Cairns
(NJ)
Luisa Benussi
(L)
Giuliano Binetti
(G)
Roberta Ghidoni
(R)
Gianluigi Forloni
(G)
Daniela Galimberti
(D)
Chiara Fenoglio
(C)
Maria Serpente
(M)
Elio Scarpini
(E)
Jordi Clarimón
(J)
Alberto Lleó
(A)
Rafael Blesa
(R)
Maria Landqvist Waldö
(ML)
Karin Nilsson
(K)
Christer Nilsson
(C)
Ian R A Mackenzie
(IRA)
Ging-Yuek R Hsiung
(GR)
David M A Mann
(DMA)
Jordan Grafman
(J)
Christopher M Morris
(CM)
Johannes Attems
(J)
Timothy D Griffiths
(TD)
Ian G McKeith
(IG)
Alan J Thomas
(AJ)
Pietro Pietrini
(P)
Edward D Huey
(ED)
Eric M Wassermann
(EM)
Atik Baborie
(A)
Evelyn Jaros
(E)
Michael C Tierney
(MC)
Pau Pastor
(P)
Cristina Razquin
(C)
Sara Ortega-Cubero
(S)
Elena Alonso
(E)
Robert Perneczky
(R)
Janine Diehl-Schmid
(J)
Panagiotis Alexopoulos
(P)
Alexander Kurz
(A)
Innocenzo Rainero
(I)
Elisa Rubino
(E)
Lorenzo Pinessi
(L)
Ekaterina Rogaeva
(E)
Peter St George-Hyslop
(P)
Giacomina Rossi
(G)
Fabrizio Tagliavini
(F)
Giorgio Giaccone
(G)
James B Rowe
(JB)
Johannes C M Schlachetzki
(JCM)
James Uphill
(J)
John Collinge
(J)
Simon Mead
(S)
Adrian Danek
(A)
Vivianna M Van Deerlin
(VM)
Murray Grossman
(M)
John Q Trojanowski
(JQ)
Julie van der Zee
(J)
Christine Van Broeckhoven
(C)
Stefano F Cappa
(SF)
Isabelle Le Ber
(I)
Didier Hannequin
(D)
Véronique Golfier
(V)
Martine Vercelletto
(M)
Alexis Brice
(A)
Benedetta Nacmias
(B)
Sandro Sorbi
(S)
Silvia Bagnoli
(S)
Irene Piaceri
(I)
Jørgen E Nielsen
(JE)
Lena E Hjermind
(LE)
Matthias Riemenschneider
(M)
Manuel Mayhaus
(M)
Bernd Ibach
(B)
Gilles Gasparoni
(G)
Sabrina Pichler
(S)
Wei Gu
(W)
Martin N Rossor
(MN)
Nick C Fox
(NC)
Jason D Warren
(JD)
Maria Grazia Spillantini
(MG)
Huw R Morris
(HR)
Patrizia Rizzu
(P)
Peter Heutink
(P)
Julie S Snowden
(JS)
Sara Rollinson
(S)
Anna Richardson
(A)
Alexander Gerhard
(A)
Amalia C Bruni
(AC)
Raffaele Maletta
(R)
Francesca Frangipane
(F)
Chiara Cupidi
(C)
Livia Bernardi
(L)
Maria Anfossi
(M)
Maura Gallo
(M)
Maria Elena Conidi
(ME)
Nicoletta Smirne
(N)
Rosa Rademakers
(R)
Matt Baker
(M)
Dennis W Dickson
(DW)
Neill R Graff-Radford
(NR)
Ronald C Petersen
(RC)
David Knopman
(D)
Keith A Josephs
(KA)
Bradley F Boeve
(BF)
Joseph E Parisi
(JE)
William W Seeley
(WW)
Bruce L Miller
(BL)
Anna M Karydas
(AM)
Howard Rosen
(H)
John C van Swieten
(JC)
Elise G P Dopper
(EGP)
Harro Seelaar
(H)
Yolande A L Pijnenburg
(YAL)
Philip Scheltens
(P)
Giancarlo Logroscino
(G)
Rosa Capozzo
(R)
Valeria Novelli
(V)
Annibale A Puca
(AA)
Massimo Franceschi
(M)
Alfredo Postiglione
(A)
Graziella Milan
(G)
Paolo Sorrentino
(P)
Mark Kristiansen
(M)
Huei-Hsin Chiang
(HH)
Caroline Graff
(C)
Florence Pasquier
(F)
Adeline Rollin
(A)
Vincent Deramecourt
(V)
Florence Lebert
(F)
Dimitrios Kapogiannis
(D)
Luigi Ferrucci
(L)
Stuart Pickering-Brown
(S)
Andrew B Singleton
(AB)
John Hardy
(J)
Parastoo Momeni
(P)
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Society of Biological Psychiatry. All rights reserved.
Références
Nat Genet. 2016 May;48(5):481-7
pubmed: 27019110
Neurobiol Aging. 2013 Jun;34(6):1653-61
pubmed: 23273601
J Neurol. 2019 Aug;266(8):2075-2086
pubmed: 31119452
Ann Neurol. 2014 Jul;76(1):120-33
pubmed: 24931836
Nature. 2017 Oct 11;550(7675):204-213
pubmed: 29022597
Nat Genet. 2018 Apr;50(4):538-548
pubmed: 29632383
Biochem Soc Trans. 2001 Nov;29(Pt 6):717-22
pubmed: 11709062
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
Nat Genet. 2014 May;46(5):430-7
pubmed: 24728292
Science. 2015 May 8;348(6235):648-60
pubmed: 25954001
PLoS Genet. 2010 Apr 01;6(4):e1000888
pubmed: 20369019
Biochim Biophys Acta. 2005 Jan 17;1703(2):135-40
pubmed: 15680221
Neuron. 2011 Oct 20;72(2):257-68
pubmed: 21944779
Arch Neurol. 2008 Nov;65(11):1473-8
pubmed: 19001166
Nat Genet. 2016 Mar;48(3):245-52
pubmed: 26854917
Neurosci Lett. 2000 Feb 4;279(3):129-32
pubmed: 10688046
J Neurol. 2017 May;264(5):882-890
pubmed: 28265751
Nature. 2020 Jun;582(7813):577-581
pubmed: 32499649
Biol Psychiatry. 2019 Aug 15;86(4):265-273
pubmed: 31230729
PLoS Comput Biol. 2015 Apr 17;11(4):e1004219
pubmed: 25885710
Lancet Neurol. 2014 Jul;13(7):686-99
pubmed: 24943344
Science. 2016 Apr 29;352(6285):600-4
pubmed: 27126046
Brain. 2011 Sep;134(Pt 9):2456-77
pubmed: 21810890
Neurology. 2007 Dec 11;69(24):2236-42
pubmed: 18071143
Brain. 2017 May 1;140(5):1437-1446
pubmed: 28387812
BMC Genomics. 2012 Sep 06;13:458
pubmed: 22950410
J Neurol Neurosurg Psychiatry. 2011 May;82(5):476-86
pubmed: 20971753
Nat Genet. 2015 Mar;47(3):291-5
pubmed: 25642630
PLoS One. 2017 Oct 11;12(10):e0185797
pubmed: 29020091
Lancet Neurol. 2016 Mar;15(3):332-42
pubmed: 26822748
Nat Genet. 2020 Jun;52(6):626-633
pubmed: 32424349
Hum Mol Genet. 2008 May 15;17(10):1349-62
pubmed: 18223198
Lancet. 2017 Nov 4;390(10107):2084-2098
pubmed: 28552366
Hum Mol Genet. 2005 Aug 15;14(16):2399-404
pubmed: 16000317
Acta Neuropathol. 2019 Jun;137(6):879-899
pubmed: 30739198
Am J Hum Genet. 2017 Mar 2;100(3):473-487
pubmed: 28238358
Nat Cell Biol. 2014 May;16(5):434-44
pubmed: 24705552
Neuron. 2011 Oct 20;72(2):245-56
pubmed: 21944778
Neurology. 2008 Sep 2;71(10):736-42
pubmed: 18765649
Diabetes Metab Res Rev. 2017 Oct;33(7):
pubmed: 28609607
Am J Alzheimers Dis Other Demen. 2016 Mar;31(2):163-8
pubmed: 26082458
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Biostatistics. 2009 Apr;10(2):327-34
pubmed: 19039033
Nat Genet. 2010 Mar;42(3):234-9
pubmed: 20154673
Nat Genet. 2019 Apr;51(4):592-599
pubmed: 30926968
Int J Mol Sci. 2019 Apr 22;20(8):
pubmed: 31013607
Genome Res. 2012 Sep;22(9):1790-7
pubmed: 22955989
Acta Neuropathol Commun. 2019 Mar 29;7(1):50
pubmed: 30922385
Nat Neurosci. 2016 Nov;19(11):1442-1453
pubmed: 27668389
Nat Commun. 2017 Nov 28;8(1):1826
pubmed: 29184056
Nature. 2016 Feb 11;530(7589):177-83
pubmed: 26814963
Int Rev Psychiatry. 2013 Apr;25(2):159-67
pubmed: 23611346
JAMA Neurol. 2018 Jul 1;75(7):860-875
pubmed: 29630712
J Lipid Res. 2017 Mar;58(3):481-493
pubmed: 28119442
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
Nat Methods. 2012 Feb 28;9(3):215-6
pubmed: 22373907
Nature. 2006 Aug 24;442(7105):916-9
pubmed: 16862116
PLoS Genet. 2014 Mar 06;10(3):e1004211
pubmed: 24603599
Science. 2012 Sep 7;337(6099):1190-5
pubmed: 22955828
Nature. 1998 Jun 18;393(6686):702-5
pubmed: 9641683
Acta Neuropathol. 2010 Jan;119(1):1-4
pubmed: 19924424
Nat Genet. 2019 Jun;51(6):933-940
pubmed: 31086352
Science. 2018 Dec 14;362(6420):
pubmed: 30545856
Nat Genet. 2015 Sep;47(9):1091-8
pubmed: 26258848