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

Raffaele Ferrari; Dena G Hernandez; Michael A Nalls; Jonathan D Rohrer; Adaikalavan Ramasamy; John B J Kwok; Carol Dobson-Stone; William S Brooks; Peter R Schofield; Glenda M Halliday; John R Hodges; Olivier Piguet; Lauren Bartley; Elizabeth Thompson; Eric Haan; 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; P 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; James B Rowe; 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; William Deschamps; Tim Van Langenhove; Marc Cruts; 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; Jørgen E Nielsen; 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

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

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

Raffaele Ferrari, Dena G Hernandez, Michael A Nalls, Jonathan D Rohrer, Adaikalavan Ramasamy, John B J Kwok, Carol Dobson-Stone, William S Brooks, Peter R Schofield, Glenda M Halliday, John R Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernández, Agustín Ruiz, Mercè Boada, Barbara Borroni, Alessandro PadovaniCarlos 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, P 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, James B Rowe, 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, William Deschamps, Tim Van Langenhove, Marc Cruts, 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, Jørgen E Nielsen, 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

Medical Genetics Program

157 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
Journal	Lancet Neurology
Volume	13
Issue number	7
Pages (from-to)	686-99
Number of pages	14
ISSN	1474-4422
DOIs	https://doi.org/10.1016/S1474-4422(14)70065-1
Publication status	Published - Jul 2014

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Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Brooks, W. S., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Haan, E., Hernández, I., Ruiz, A., Boada, M., Borroni, B., ... Momeni, P. (2014). Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurology, 13(7), 686-99. https://doi.org/10.1016/S1474-4422(14)70065-1

Ferrari, R, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Brooks, WS, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, ML, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, G-YR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, 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, JB, Schlachetzki, JCM, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, VM, Grossman, M, Trojanowski, JQ, van der Zee, J, Deschamps, W, Van Langenhove, T, Cruts, M, Van Broeckhoven, C, Cappa, SF, Le Ber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, JE, Hjermind, LE, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, MN, Fox, NC, Warren, JD, Spillantini, MG, Morris, HR, Rizzu, P, Heutink, P, Snowden, JS, Rollinson, S, Richardson, A, Gerhard, A, Bruni, AC, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, ME, Smirne, N, Rademakers, R, Baker, M, Dickson, DW, Graff-Radford, NR, Petersen, RC, Knopman, D, Josephs, KA, Boeve, BF, Parisi, JE, Seeley, WW, Miller, BL, Karydas, AM, Rosen, H, van Swieten, JC, Dopper, EGP, Seelaar, H, Pijnenburg, YAL, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, AA, 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, AB, Hardy, J & Momeni, P 2014, 'Frontotemporal dementia and its subtypes: a genome-wide association study', Lancet Neurology, vol. 13, no. 7, pp. 686-99. https://doi.org/10.1016/S1474-4422(14)70065-1

@article{d8e853b6ddcd4d0f954adc45236dcae9,

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 Hernandez, {Dena G} and Nalls, {Michael A} and Rohrer, {Jonathan D} and Adaikalavan Ramasamy and Kwok, {John B J} and Carol Dobson-Stone and Brooks, {William S} and Schofield, {Peter R} and Halliday, {Glenda M} and Hodges, {John R} and Olivier Piguet and Lauren Bartley and Elizabeth Thompson and Eric Haan and Isabel Hern{\'a}ndez and Agust{\'i}n Ruiz and Merc{\`e} Boada and Barbara Borroni and Alessandro Padovani and Carlos Cruchaga and Cairns, {Nigel J} and Luisa Benussi and Giuliano Binetti and Roberta Ghidoni and Gianluigi Forloni and Daniela Galimberti and Chiara Fenoglio and Maria Serpente and Elio Scarpini and Jordi Clarim{\'o}n and Alberto Lle{\'o} and Rafael Blesa and Wald{\"o}, {Maria Landqvist} and Karin Nilsson and Christer Nilsson and Mackenzie, {Ian R A} and Hsiung, {Ging-Yuek R} and Mann, {David M A} and Jordan Grafman and Morris, {Christopher M} and Johannes Attems and Griffiths, {Timothy D} and McKeith, {Ian G} and Thomas, {Alan J} and P Pietrini and Huey, {Edward D} and Wassermann, {Eric M} and Atik Baborie and Evelyn Jaros and Tierney, {Michael C} 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 Rowe, {James B} and Schlachetzki, {Johannes C M} and James Uphill and John Collinge and Simon Mead and Adrian Danek and {Van Deerlin}, {Vivianna M} and Murray Grossman and Trojanowski, {John Q} and {van der Zee}, Julie and William Deschamps and {Van Langenhove}, Tim and Marc Cruts and {Van Broeckhoven}, Christine and Cappa, {Stefano F} and {Le Ber}, Isabelle and Didier Hannequin and V{\'e}ronique Golfier and Martine Vercelletto and Alexis Brice and Benedetta Nacmias and Sandro Sorbi and Silvia Bagnoli and Irene Piaceri and Nielsen, {J{\o}rgen E} and Hjermind, {Lena E} and Matthias Riemenschneider and Manuel Mayhaus and Bernd Ibach and Gilles Gasparoni and Sabrina Pichler and Wei Gu and Rossor, {Martin N} and Fox, {Nick C} and Warren, {Jason D} and Spillantini, {Maria Grazia} and Morris, {Huw R} and Patrizia Rizzu and Peter Heutink and Snowden, {Julie S} and Sara Rollinson and Anna Richardson and Alexander Gerhard and Bruni, {Amalia C} and Raffaele Maletta and Francesca Frangipane and Chiara Cupidi and Livia Bernardi and Maria Anfossi and Maura Gallo and Conidi, {Maria Elena} and Nicoletta Smirne and Rosa Rademakers and Matt Baker and Dickson, {Dennis W} and Graff-Radford, {Neill R} and Petersen, {Ronald C} and David Knopman and Josephs, {Keith A} and Boeve, {Bradley F} and Parisi, {Joseph E} and Seeley, {William W} and Miller, {Bruce L} and Karydas, {Anna M} and Howard Rosen and {van Swieten}, {John C} and Dopper, {Elise G P} and Harro Seelaar and Pijnenburg, {Yolande A L} and Philip Scheltens and Giancarlo Logroscino and Rosa Capozzo and Valeria Novelli and Puca, {Annibale A} 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 Singleton, {Andrew B} and John Hardy and Parastoo Momeni",

year = "2014",

month = jul,

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

language = "English",

volume = "13",

pages = "686--99",

journal = "The Lancet Neurology",

issn = "1474-4422",

publisher = "TheLancet Publishing Group",

number = "7",

}

TY - JOUR

T1 - Frontotemporal dementia and its subtypes

T2 - a genome-wide association study

AU - Ferrari, Raffaele

AU - Hernandez, Dena G

AU - Nalls, Michael A

AU - Rohrer, Jonathan D

AU - Ramasamy, Adaikalavan

AU - Kwok, John B J

AU - Dobson-Stone, Carol

AU - Brooks, William S

AU - Schofield, Peter R

AU - Halliday, Glenda M

AU - Hodges, John R

AU - Piguet, Olivier

AU - Bartley, Lauren

AU - Thompson, Elizabeth

AU - Haan, Eric

AU - Hernández, Isabel

AU - Ruiz, Agustín

AU - Boada, Mercè

AU - Borroni, Barbara

AU - Padovani, Alessandro

AU - Cruchaga, Carlos

AU - Cairns, Nigel J

AU - Benussi, Luisa

AU - Binetti, Giuliano

AU - Ghidoni, Roberta

AU - Forloni, Gianluigi

AU - Galimberti, Daniela

AU - Fenoglio, Chiara

AU - Serpente, Maria

AU - Scarpini, Elio

AU - Clarimón, Jordi

AU - Lleó, Alberto

AU - Blesa, Rafael

AU - Waldö, Maria Landqvist

AU - Nilsson, Karin

AU - Nilsson, Christer

AU - Mackenzie, Ian R A

AU - Hsiung, Ging-Yuek R

AU - Mann, David M A

AU - Grafman, Jordan

AU - Morris, Christopher M

AU - Attems, Johannes

AU - Griffiths, Timothy D

AU - McKeith, Ian G

AU - Thomas, Alan J

AU - Pietrini, P

AU - Huey, Edward D

AU - Wassermann, Eric M

AU - Baborie, Atik

AU - Jaros, Evelyn

AU - Tierney, Michael C

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 B

AU - Schlachetzki, Johannes C M

AU - Uphill, James

AU - Collinge, John

AU - Mead, Simon

AU - Danek, Adrian

AU - Van Deerlin, Vivianna M

AU - Grossman, Murray

AU - Trojanowski, John Q

AU - van der Zee, Julie

AU - Deschamps, William

AU - Van Langenhove, Tim

AU - Cruts, Marc

AU - Van Broeckhoven, Christine

AU - Cappa, Stefano F

AU - Le Ber, Isabelle

AU - Hannequin, Didier

AU - Golfier, Véronique

AU - Vercelletto, Martine

AU - Brice, Alexis

AU - Nacmias, Benedetta

AU - Sorbi, Sandro

AU - Bagnoli, Silvia

AU - Piaceri, Irene

AU - Nielsen, Jørgen E

AU - Hjermind, Lena E

AU - Riemenschneider, Matthias

AU - Mayhaus, Manuel

AU - Ibach, Bernd

AU - Gasparoni, Gilles

AU - Pichler, Sabrina

AU - Gu, Wei

AU - Rossor, Martin N

AU - Fox, Nick C

AU - Warren, Jason D

AU - Spillantini, Maria Grazia

AU - Morris, Huw R

AU - Rizzu, Patrizia

AU - Heutink, Peter

AU - Snowden, Julie S

AU - Rollinson, Sara

AU - Richardson, Anna

AU - Gerhard, Alexander

AU - Bruni, Amalia C

AU - Maletta, Raffaele

AU - Frangipane, Francesca

AU - Cupidi, Chiara

AU - Bernardi, Livia

AU - Anfossi, Maria

AU - Gallo, Maura

AU - Conidi, Maria Elena

AU - Smirne, Nicoletta

AU - Rademakers, Rosa

AU - Baker, Matt

AU - Dickson, Dennis W

AU - Graff-Radford, Neill R

AU - Petersen, Ronald C

AU - Knopman, David

AU - Josephs, Keith A

AU - Boeve, Bradley F

AU - Parisi, Joseph E

AU - Seeley, William W

AU - Miller, Bruce L

AU - Karydas, Anna M

AU - Rosen, Howard

AU - van Swieten, John C

AU - Dopper, Elise G P

AU - Seelaar, Harro

AU - Pijnenburg, Yolande A L

AU - Scheltens, Philip

AU - Logroscino, Giancarlo

AU - Capozzo, Rosa

AU - Novelli, Valeria

AU - Puca, Annibale A

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 B

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.

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

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

M3 - Journal article

C2 - 24943344

SN - 1474-4422

VL - 13

SP - 686

EP - 699

JO - The Lancet Neurology

JF - The Lancet Neurology

IS - 7

ER -

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

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