Frontotemporal dementia and its subtypes: a genome-wide association study

Raffaele Ferrari; Dena Hernandez; Michael Nalls; Jonathan Rohrer; Adaikalavan Ramasamy; John Kwok; Carol Dobson-Stone; William Brooks; Peter Schofield; Glenda Halliday; John Hodges; Olivier Piguet; Lauren Bartley; Elizabeth Thompson; Eric Haan; Isabel Hernandez; Agustin Ruiz; Merce Boada; Barbara Borroni; Alessandro Padovani; Carlos Cruchaga; Nigel Cairns; L Benussi; Giuliano Binetti; Roberta Ghidoni; Gianluigi Forloni; Daniela Galimberti; Chiara Fenoglio; Maria Serpente; Elio Scarpini; Jordi Clarimon; Alberto Lleo; Rafael Blesa; Maria Waldo; K Nilsson; Christer Nilsson; Ian Mackenzie; Ging-Yuek Hsiung; David Mann; Jordan Grafman; Christopher Morris; Johannes Attems; Timothy Griffiths; Ian McKeith; Alan Thomas; P Pietrini; Edward Huey; Eric Wassermann; Atik Baborie; Evelyn Jaros; Michael 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; James Rowe; Johannes Schlachetzki; James Uphill; John Collinge; Simon Mead; Adrian Danek; Vivianna van Deerlin; Murray Grossman; John Trojanowski; Julie van der Zee; William Deschamps; Tim Van Langenhove; Marc Cruts; Christine Van Broeckhoven; Stefano Cappa; Isabelle Le Ber; Didier Hannequin; Veronique Golfier; Martine Vercelletto; Alexis Brice; Benedetta Nacmias; Sandro Sorbi; Silvia Bagnoli; Irene Piaceri; Jorgen Nielsen; Lena Hjermind; Matthias Riemenschneider; Manuel Mayhaus; Bernd Ibach; Gilles Gasparoni; Sabrina Pichler; Wei Gu; Martin Rossor; Nick Fox; Jason Warren; Maria Spillantini; Huw Morris; Patrizia Rizzu; Peter Heutink; Julie Snowden; Sara Rollinson; Anna Richardson; Alexander Gerhard; Amalia Bruni; Raffaele Maletta; Francesca Frangipane; Chiara Cupidi; Livia Bernardi; Maria Anfossi; Maura Gallo; Maria Conidi; Nicoletta Smirne; Rosa Rademakers; Matt Baker; Dennis Dickson; Neil Graff-Radford; Ronald Petersen; David Knopman; Keith Josephs; Bradley Boeve; Joseph Parisi; William Seeley; Bruce Miller; Anna Karydas; Howard Rosen; John van Swieten; Elise Dopper; Harro Seelaar; Yolande Pijnenburg; Philip Scheltens; Giancarlo Logroscino; Rosa Capozzo; Valeria Novelli; Annibale 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 Singleton; John Hardy; Parastoo Momeni

doi:10.1016/S1474-4422(14)70065-1

Frontotemporal dementia and its subtypes: a genome-wide association study

Raffaele Ferrari, Dena Hernandez, Michael Nalls, Jonathan Rohrer, Adaikalavan Ramasamy, John Kwok, Carol Dobson-Stone, William Brooks, Peter Schofield, Glenda Halliday, John Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernandez, Agustin Ruiz, Merce Boada, Barbara Borroni, Alessandro PadovaniCarlos Cruchaga, Nigel Cairns, L Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimon, Alberto Lleo, Rafael Blesa, Maria Waldo, K Nilsson, Christer Nilsson, Ian Mackenzie, Ging-Yuek Hsiung, David Mann, Jordan Grafman, Christopher Morris, Johannes Attems, Timothy Griffiths, Ian McKeith, Alan Thomas, P Pietrini, Edward Huey, Eric Wassermann, Atik Baborie, Evelyn Jaros, Michael 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, James Rowe, Johannes Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna van Deerlin, Murray Grossman, John Trojanowski, Julie van der Zee, William Deschamps, Tim Van Langenhove, Marc Cruts, Christine Van Broeckhoven, Stefano Cappa, Isabelle Le Ber, Didier Hannequin, Veronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jorgen Nielsen, Lena Hjermind, Matthias Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin Rossor, Nick Fox, Jason Warren, Maria Spillantini, Huw Morris, Patrizia Rizzu, Peter Heutink, Julie Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, Amalia Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis Dickson, Neil Graff-Radford, Ronald Petersen, David Knopman, Keith Josephs, Bradley Boeve, Joseph Parisi, William Seeley, Bruce Miller, Anna Karydas, Howard Rosen, John van Swieten, Elise Dopper, Harro Seelaar, Yolande Pijnenburg, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale 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 Singleton, John Hardy, Parastoo Momeni

Research output: Contribution to journal › Article › peer-review

214 Citations (Scopus)

Abstract

Background: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10 ^-8 ) single-nucleotide polymorphisms. Findings: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10 ^-8 ). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10 ^-8 ; odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10 ^-9 ; 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10 ^-8 , 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10 ^-7 ; 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding: The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.

Original language	English
Pages (from-to)	686-699
Number of pages	14
Journal	Lancet Neurology
Volume	13
Issue number	7
DOIs	https://doi.org/10.1016/S1474-4422(14)70065-1
Publication status	Published - Jul 2014

Access to Document

10.1016/S1474-4422(14)70065-1

Cite this

Ferrari, R., Hernandez, D., Nalls, M., Rohrer, J., Ramasamy, A., Kwok, J., Dobson-Stone, C., Brooks, W., Schofield, P., Halliday, G., Hodges, J., Piguet, O., Bartley, L., Thompson, E., Haan, E., Hernandez, I., Ruiz, A., Boada, M., Borroni, B., ... Momeni, P. (2014). Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurology, 13(7), 686-699. https://doi.org/10.1016/S1474-4422(14)70065-1

@article{fe3651a4f32b4b948f6290a2398f4843,

title = "Frontotemporal dementia and its subtypes: a genome-wide association study",

abstract = " Background: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10 -8 ) single-nucleotide polymorphisms. Findings: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10 -8 ). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10 -8 ; odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10 -9 ; 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10 -8 , 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10 -7 ; 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding: The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.",

author = "Raffaele Ferrari and Dena Hernandez and Michael Nalls and Jonathan Rohrer and Adaikalavan Ramasamy and John Kwok and Carol Dobson-Stone and William Brooks and Peter Schofield and Glenda Halliday and John Hodges and Olivier Piguet and Lauren Bartley and Elizabeth Thompson and Eric Haan and Isabel Hernandez and Agustin Ruiz and Merce Boada and Barbara Borroni and Alessandro Padovani and Carlos Cruchaga and Nigel Cairns and L Benussi and Giuliano Binetti and Roberta Ghidoni and Gianluigi Forloni and Daniela Galimberti and Chiara Fenoglio and Maria Serpente and Elio Scarpini and Jordi Clarimon and Alberto Lleo and Rafael Blesa and Maria Waldo and K Nilsson and Christer Nilsson and Ian Mackenzie and Ging-Yuek Hsiung and David Mann and Jordan Grafman and Christopher Morris and Johannes Attems and Timothy Griffiths and Ian McKeith and Alan Thomas and P Pietrini and Edward Huey and Eric Wassermann and Atik Baborie and Evelyn Jaros and Michael Tierney and Pau Pastor and Cristina Razquin and Sara Ortega-Cubero and Elena Alonso and Robert Perneczky and Janine Diehl-Schmid and Panagiotis Alexopoulos and Alexander Kurz and Innocenzo Rainero and Elisa Rubino and Lorenzo Pinessi and Ekaterina Rogaeva and {St George-Hyslop}, Peter and Giacomina Rossi and Fabrizio Tagliavini and Giorgio Giaccone and James Rowe and Johannes Schlachetzki and James Uphill and John Collinge and Simon Mead and Adrian Danek and {van Deerlin}, Vivianna and Murray Grossman and John Trojanowski and {van der Zee}, Julie and William Deschamps and {Van Langenhove}, Tim and Marc Cruts and {Van Broeckhoven}, Christine and Stefano Cappa and {Le Ber}, Isabelle and Didier Hannequin and Veronique Golfier and Martine Vercelletto and Alexis Brice and Benedetta Nacmias and Sandro Sorbi and Silvia Bagnoli and Irene Piaceri and Jorgen Nielsen and Lena Hjermind and Matthias Riemenschneider and Manuel Mayhaus and Bernd Ibach and Gilles Gasparoni and Sabrina Pichler and Wei Gu and Martin Rossor and Nick Fox and Jason Warren and Maria Spillantini and Huw Morris and Patrizia Rizzu and Peter Heutink and Julie Snowden and Sara Rollinson and Anna Richardson and Alexander Gerhard and Amalia Bruni and Raffaele Maletta and Francesca Frangipane and Chiara Cupidi and Livia Bernardi and Maria Anfossi and Maura Gallo and Maria Conidi and Nicoletta Smirne and Rosa Rademakers and Matt Baker and Dennis Dickson and Neil Graff-Radford and Ronald Petersen and David Knopman and Keith Josephs and Bradley Boeve and Joseph Parisi and William Seeley and Bruce Miller and Anna Karydas and Howard Rosen and {van Swieten}, John and Elise Dopper and Harro Seelaar and Yolande Pijnenburg and Philip Scheltens and Giancarlo Logroscino and Rosa Capozzo and Valeria Novelli and Annibale Puca and Massimo Franceschi and Alfredo Postiglione and Graziella Milan and Paolo Sorrentino and Mark Kristiansen and Huei-Hsin Chiang and Caroline Graff and Florence Pasquier and Adeline Rollin and Vincent Deramecourt and Florence Lebert and Dimitrios Kapogiannis and Luigi Ferrucci and Stuart Pickering-Brown and Andrew Singleton and John Hardy and Parastoo Momeni",

year = "2014",

month = jul,

doi = "10.1016/S1474-4422(14)70065-1",

language = "English",

volume = "13",

pages = "686--699",

journal = "Lancet Neurology",

issn = "1474-4422",

number = "7",

}

Ferrari, R, Hernandez, D, Nalls, M, Rohrer, J, Ramasamy, A, Kwok, J, Dobson-Stone, C, Brooks, W, Schofield, P, Halliday, G, Hodges, J, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernandez, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, N, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimon, J, Lleo, A, Blesa, R, Waldo, M, Nilsson, K, Nilsson, C, Mackenzie, I, Hsiung, G-Y, Mann, D, Grafman, J, Morris, C, Attems, J, Griffiths, T, McKeith, I, Thomas, A, Pietrini, P, Huey, E, Wassermann, E, Baborie, A, Jaros, E, Tierney, M, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, J, Schlachetzki, J, Uphill, J, Collinge, J, Mead, S, Danek, A, van Deerlin, V, Grossman, M, Trojanowski, J, van der Zee, J, Deschamps, W, Van Langenhove, T, Cruts, M, Van Broeckhoven, C, Cappa, S, Le Ber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, J, Hjermind, L, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, M, Fox, N, Warren, J, Spillantini, M, Morris, H, Rizzu, P, Heutink, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, A, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, M, Smirne, N, Rademakers, R, Baker, M, Dickson, D, Graff-Radford, N, Petersen, R, Knopman, D, Josephs, K, Boeve, B, Parisi, J, Seeley, W, Miller, B, Karydas, A, Rosen, H, van Swieten, J, Dopper, E, Seelaar, H, Pijnenburg, Y, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, A, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, H-H, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebert, F, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, A, Hardy, J & Momeni, P 2014, 'Frontotemporal dementia and its subtypes: a genome-wide association study', Lancet Neurology, vol. 13, no. 7, pp. 686-699. https://doi.org/10.1016/S1474-4422(14)70065-1

TY - JOUR

T1 - Frontotemporal dementia and its subtypes: a genome-wide association study

AU - Ferrari, Raffaele

AU - Hernandez, Dena

AU - Nalls, Michael

AU - Rohrer, Jonathan

AU - Ramasamy, Adaikalavan

AU - Kwok, John

AU - Dobson-Stone, Carol

AU - Brooks, William

AU - Schofield, Peter

AU - Halliday, Glenda

AU - Hodges, John

AU - Piguet, Olivier

AU - Bartley, Lauren

AU - Thompson, Elizabeth

AU - Haan, Eric

AU - Hernandez, Isabel

AU - Ruiz, Agustin

AU - Boada, Merce

AU - Borroni, Barbara

AU - Padovani, Alessandro

AU - Cruchaga, Carlos

AU - Cairns, Nigel

AU - Benussi, L

AU - Binetti, Giuliano

AU - Ghidoni, Roberta

AU - Forloni, Gianluigi

AU - Galimberti, Daniela

AU - Fenoglio, Chiara

AU - Serpente, Maria

AU - Scarpini, Elio

AU - Clarimon, Jordi

AU - Lleo, Alberto

AU - Blesa, Rafael

AU - Waldo, Maria

AU - Nilsson, K

AU - Nilsson, Christer

AU - Mackenzie, Ian

AU - Hsiung, Ging-Yuek

AU - Mann, David

AU - Grafman, Jordan

AU - Morris, Christopher

AU - Attems, Johannes

AU - Griffiths, Timothy

AU - McKeith, Ian

AU - Thomas, Alan

AU - Pietrini, P

AU - Huey, Edward

AU - Wassermann, Eric

AU - Baborie, Atik

AU - Jaros, Evelyn

AU - Tierney, Michael

AU - Pastor, Pau

AU - Razquin, Cristina

AU - Ortega-Cubero, Sara

AU - Alonso, Elena

AU - Perneczky, Robert

AU - Diehl-Schmid, Janine

AU - Alexopoulos, Panagiotis

AU - Kurz, Alexander

AU - Rainero, Innocenzo

AU - Rubino, Elisa

AU - Pinessi, Lorenzo

AU - Rogaeva, Ekaterina

AU - St George-Hyslop, Peter

AU - Rossi, Giacomina

AU - Tagliavini, Fabrizio

AU - Giaccone, Giorgio

AU - Rowe, James

AU - Schlachetzki, Johannes

AU - Uphill, James

AU - Collinge, John

AU - Mead, Simon

AU - Danek, Adrian

AU - van Deerlin, Vivianna

AU - Grossman, Murray

AU - Trojanowski, John

AU - van der Zee, Julie

AU - Deschamps, William

AU - Van Langenhove, Tim

AU - Cruts, Marc

AU - Van Broeckhoven, Christine

AU - Cappa, Stefano

AU - Le Ber, Isabelle

AU - Hannequin, Didier

AU - Golfier, Veronique

AU - Vercelletto, Martine

AU - Brice, Alexis

AU - Nacmias, Benedetta

AU - Sorbi, Sandro

AU - Bagnoli, Silvia

AU - Piaceri, Irene

AU - Nielsen, Jorgen

AU - Hjermind, Lena

AU - Riemenschneider, Matthias

AU - Mayhaus, Manuel

AU - Ibach, Bernd

AU - Gasparoni, Gilles

AU - Pichler, Sabrina

AU - Gu, Wei

AU - Rossor, Martin

AU - Fox, Nick

AU - Warren, Jason

AU - Spillantini, Maria

AU - Morris, Huw

AU - Rizzu, Patrizia

AU - Heutink, Peter

AU - Snowden, Julie

AU - Rollinson, Sara

AU - Richardson, Anna

AU - Gerhard, Alexander

AU - Bruni, Amalia

AU - Maletta, Raffaele

AU - Frangipane, Francesca

AU - Cupidi, Chiara

AU - Bernardi, Livia

AU - Anfossi, Maria

AU - Gallo, Maura

AU - Conidi, Maria

AU - Smirne, Nicoletta

AU - Rademakers, Rosa

AU - Baker, Matt

AU - Dickson, Dennis

AU - Graff-Radford, Neil

AU - Petersen, Ronald

AU - Knopman, David

AU - Josephs, Keith

AU - Boeve, Bradley

AU - Parisi, Joseph

AU - Seeley, William

AU - Miller, Bruce

AU - Karydas, Anna

AU - Rosen, Howard

AU - van Swieten, John

AU - Dopper, Elise

AU - Seelaar, Harro

AU - Pijnenburg, Yolande

AU - Scheltens, Philip

AU - Logroscino, Giancarlo

AU - Capozzo, Rosa

AU - Novelli, Valeria

AU - Puca, Annibale

AU - Franceschi, Massimo

AU - Postiglione, Alfredo

AU - Milan, Graziella

AU - Sorrentino, Paolo

AU - Kristiansen, Mark

AU - Chiang, Huei-Hsin

AU - Graff, Caroline

AU - Pasquier, Florence

AU - Rollin, Adeline

AU - Deramecourt, Vincent

AU - Lebert, Florence

AU - Kapogiannis, Dimitrios

AU - Ferrucci, Luigi

AU - Pickering-Brown, Stuart

AU - Singleton, Andrew

AU - Hardy, John

AU - Momeni, Parastoo

PY - 2014/7

Y1 - 2014/7

N2 - Background: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10 -8 ) single-nucleotide polymorphisms. Findings: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10 -8 ). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10 -8 ; odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10 -9 ; 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10 -8 , 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10 -7 ; 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding: The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.

AB - Background: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10 -8 ) single-nucleotide polymorphisms. Findings: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10 -8 ). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10 -8 ; odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10 -9 ; 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10 -8 , 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10 -7 ; 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding: The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.

UR - http://www.scopus.com/inward/record.url?scp=84902509590&partnerID=8YFLogxK

U2 - 10.1016/S1474-4422(14)70065-1

DO - 10.1016/S1474-4422(14)70065-1

M3 - Article

SN - 1474-4422

VL - 13

SP - 686

EP - 699

JO - Lancet Neurology

JF - Lancet Neurology

IS - 7

ER -

Frontotemporal dementia and its subtypes: a genome-wide association study

Abstract

Access to Document

Other files and links

Fingerprint

Cite this