Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations

a genome-wide association study

Cyril Pottier, Xiaolai Zhou, Ralph B. Perkerson, Matt Baker, Gregory D. Jenkins, Daniel J. Serie, Roberta Ghidoni, Luisa Benussi, Giuliano Binetti, Adolfo López de Munain, Miren Zulaica, Fermin Moreno, Isabelle Le Ber, Florence Pasquier, Didier Hannequin, Raquel Sánchez-Valle, Anna Antonell, Albert Lladó, Tammee M. Parsons, Ni Cole A. Finch & 113 others Elizabeth C. Finger, Carol F. Lippa, Edward D. Huey, Manuela Neumann, Peter Heutink, Matthis Synofzik, Carlo Wilke, Robert A. Rissman, Jaroslaw Slawek, Emilia Sitek, Peter Johannsen, Jørgen E. Nielsen, Yingxue Ren, Marka van Blitterswijk, Mariely DeJesus-Hernandez, Elizabeth Christopher, Melissa E. Murray, Kevin F. Bieniek, Bret M. Evers, Camilla Ferrari, Sara Rollinson, Anna Richardson, Elio Scarpini, Giorgio G. Fumagalli, Alessandro Padovani, John Hardy, Parastoo Momeni, Raffaele Ferrari, Francesca Frangipane, Raffaele Maletta, Maria Anfossi, Maura Gallo, Leonard Petrucelli, Eun Ran Suh, Oscar L. Lopez, Tsz H. Wong, Jeroen G.J. van Rooij, Harro Seelaar, Simon Mead, Richard J. Caselli, Eric M. Reiman, Marwan Noel Sabbagh, Mads Kjolby, Anders Nykjaer, Anna M. Karydas, Adam L. Boxer, Lea T. Grinberg, Jordan Grafman, Salvatore Spina, Adrian Oblak, M. Marsel Mesulam, Sandra Weintraub, Changiz Geula, John R. Hodges, Olivier Piguet, William S. Brooks, David J. Irwin, John Q. Trojanowski, Edward B. Lee, Keith A. Josephs, Joseph E. Parisi, Nilüfer Ertekin-Taner, David S. Knopman, Benedetta Nacmias, Irene Piaceri, Silvia Bagnoli, Sandro Sorbi, Marla Gearing, Jonathan Glass, Thomas G. Beach, Sandra E. Black, Mario Masellis, Ekaterina Rogaeva, Jean Paul Vonsattel, Lawrence S. Honig, Julia Kofler, Amalia C. Bruni, Julie Snowden, David Mann, Stuart Pickering-Brown, Janine Diehl-Schmid, Juliane Winkelmann, Daniela Galimberti, Caroline Graff, Linn Öijerstedt, Claire Troakes, Safa Al-Sarraj, Carlos Cruchaga, Nigel J. Cairns, Jonathan D. Rohrer, Glenda M. Halliday, John B. Kwok, John C. van Swieten, Charles L. White, Bernardino Ghetti, Jill R. Murell, Ian R.A. Mackenzie, Ging Yuek R. Hsiung, Barbara Borroni, Giacomina Rossi, Fabrizio Tagliavini, Zbigniew K. Wszolek, Ronald C. Petersen, Eileen H. Bigio, Murray Grossman, Vivianna M. Van Deerlin, William W. Seeley, Bruce L. Miller, Neill R. Graff-Radford, Bradley F. Boeve, Dennis W. Dickson, Joanna M. Biernacka, Rosa Rademakers

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.

Original languageEnglish (US)
Pages (from-to)548-558
Number of pages11
JournalThe Lancet Neurology
Volume17
Issue number6
DOIs
StatePublished - Jun 1 2018

Fingerprint

Frontotemporal Lobar Degeneration
Inborn Genetic Diseases
Genome-Wide Association Study
Age of Onset
Meta-Analysis
Mutation
Neurodegenerative Diseases
Genome
Immunoprecipitation
Health
National Institute on Aging (U.S.)
Enzyme-Linked Immunosorbent Assay
Odds Ratio
Research
National Institute of Neurological Disorders and Stroke
Messenger RNA
Genetic Counseling
National Institutes of Health (U.S.)
DNA-Binding Proteins
Quality Control

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations : a genome-wide association study. / Pottier, Cyril; Zhou, Xiaolai; Perkerson, Ralph B.; Baker, Matt; Jenkins, Gregory D.; Serie, Daniel J.; Ghidoni, Roberta; Benussi, Luisa; Binetti, Giuliano; López de Munain, Adolfo; Zulaica, Miren; Moreno, Fermin; Le Ber, Isabelle; Pasquier, Florence; Hannequin, Didier; Sánchez-Valle, Raquel; Antonell, Anna; Lladó, Albert; Parsons, Tammee M.; Finch, Ni Cole A.; Finger, Elizabeth C.; Lippa, Carol F.; Huey, Edward D.; Neumann, Manuela; Heutink, Peter; Synofzik, Matthis; Wilke, Carlo; Rissman, Robert A.; Slawek, Jaroslaw; Sitek, Emilia; Johannsen, Peter; Nielsen, Jørgen E.; Ren, Yingxue; van Blitterswijk, Marka; DeJesus-Hernandez, Mariely; Christopher, Elizabeth; Murray, Melissa E.; Bieniek, Kevin F.; Evers, Bret M.; Ferrari, Camilla; Rollinson, Sara; Richardson, Anna; Scarpini, Elio; Fumagalli, Giorgio G.; Padovani, Alessandro; Hardy, John; Momeni, Parastoo; Ferrari, Raffaele; Frangipane, Francesca; Maletta, Raffaele; Anfossi, Maria; Gallo, Maura; Petrucelli, Leonard; Suh, Eun Ran; Lopez, Oscar L.; Wong, Tsz H.; van Rooij, Jeroen G.J.; Seelaar, Harro; Mead, Simon; Caselli, Richard J.; Reiman, Eric M.; Noel Sabbagh, Marwan; Kjolby, Mads; Nykjaer, Anders; Karydas, Anna M.; Boxer, Adam L.; Grinberg, Lea T.; Grafman, Jordan; Spina, Salvatore; Oblak, Adrian; Mesulam, M. Marsel; Weintraub, Sandra; Geula, Changiz; Hodges, John R.; Piguet, Olivier; Brooks, William S.; Irwin, David J.; Trojanowski, John Q.; Lee, Edward B.; Josephs, Keith A.; Parisi, Joseph E.; Ertekin-Taner, Nilüfer; Knopman, David S.; Nacmias, Benedetta; Piaceri, Irene; Bagnoli, Silvia; Sorbi, Sandro; Gearing, Marla; Glass, Jonathan; Beach, Thomas G.; Black, Sandra E.; Masellis, Mario; Rogaeva, Ekaterina; Vonsattel, Jean Paul; Honig, Lawrence S.; Kofler, Julia; Bruni, Amalia C.; Snowden, Julie; Mann, David; Pickering-Brown, Stuart; Diehl-Schmid, Janine; Winkelmann, Juliane; Galimberti, Daniela; Graff, Caroline; Öijerstedt, Linn; Troakes, Claire; Al-Sarraj, Safa; Cruchaga, Carlos; Cairns, Nigel J.; Rohrer, Jonathan D.; Halliday, Glenda M.; Kwok, John B.; van Swieten, John C.; White, Charles L.; Ghetti, Bernardino; Murell, Jill R.; Mackenzie, Ian R.A.; Hsiung, Ging Yuek R.; Borroni, Barbara; Rossi, Giacomina; Tagliavini, Fabrizio; Wszolek, Zbigniew K.; Petersen, Ronald C.; Bigio, Eileen H.; Grossman, Murray; Van Deerlin, Vivianna M.; Seeley, William W.; Miller, Bruce L.; Graff-Radford, Neill R.; Boeve, Bradley F.; Dickson, Dennis W.; Biernacka, Joanna M.; Rademakers, Rosa.

In: The Lancet Neurology, Vol. 17, No. 6, 01.06.2018, p. 548-558.

Research output: Contribution to journalArticle

Pottier, C, Zhou, X, Perkerson, RB, Baker, M, Jenkins, GD, Serie, DJ, Ghidoni, R, Benussi, L, Binetti, G, López de Munain, A, Zulaica, M, Moreno, F, Le Ber, I, Pasquier, F, Hannequin, D, Sánchez-Valle, R, Antonell, A, Lladó, A, Parsons, TM, Finch, NCA, Finger, EC, Lippa, CF, Huey, ED, Neumann, M, Heutink, P, Synofzik, M, Wilke, C, Rissman, RA, Slawek, J, Sitek, E, Johannsen, P, Nielsen, JE, Ren, Y, van Blitterswijk, M, DeJesus-Hernandez, M, Christopher, E, Murray, ME, Bieniek, KF, Evers, BM, Ferrari, C, Rollinson, S, Richardson, A, Scarpini, E, Fumagalli, GG, Padovani, A, Hardy, J, Momeni, P, Ferrari, R, Frangipane, F, Maletta, R, Anfossi, M, Gallo, M, Petrucelli, L, Suh, ER, Lopez, OL, Wong, TH, van Rooij, JGJ, Seelaar, H, Mead, S, Caselli, RJ, Reiman, EM, Noel Sabbagh, M, Kjolby, M, Nykjaer, A, Karydas, AM, Boxer, AL, Grinberg, LT, Grafman, J, Spina, S, Oblak, A, Mesulam, MM, Weintraub, S, Geula, C, Hodges, JR, Piguet, O, Brooks, WS, Irwin, DJ, Trojanowski, JQ, Lee, EB, Josephs, KA, Parisi, JE, Ertekin-Taner, N, Knopman, DS, Nacmias, B, Piaceri, I, Bagnoli, S, Sorbi, S, Gearing, M, Glass, J, Beach, TG, Black, SE, Masellis, M, Rogaeva, E, Vonsattel, JP, Honig, LS, Kofler, J, Bruni, AC, Snowden, J, Mann, D, Pickering-Brown, S, Diehl-Schmid, J, Winkelmann, J, Galimberti, D, Graff, C, Öijerstedt, L, Troakes, C, Al-Sarraj, S, Cruchaga, C, Cairns, NJ, Rohrer, JD, Halliday, GM, Kwok, JB, van Swieten, JC, White, CL, Ghetti, B, Murell, JR, Mackenzie, IRA, Hsiung, GYR, Borroni, B, Rossi, G, Tagliavini, F, Wszolek, ZK, Petersen, RC, Bigio, EH, Grossman, M, Van Deerlin, VM, Seeley, WW, Miller, BL, Graff-Radford, NR, Boeve, BF, Dickson, DW, Biernacka, JM & Rademakers, R 2018, 'Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study', The Lancet Neurology, vol. 17, no. 6, pp. 548-558. https://doi.org/10.1016/S1474-4422(18)30126-1
Pottier, Cyril ; Zhou, Xiaolai ; Perkerson, Ralph B. ; Baker, Matt ; Jenkins, Gregory D. ; Serie, Daniel J. ; Ghidoni, Roberta ; Benussi, Luisa ; Binetti, Giuliano ; López de Munain, Adolfo ; Zulaica, Miren ; Moreno, Fermin ; Le Ber, Isabelle ; Pasquier, Florence ; Hannequin, Didier ; Sánchez-Valle, Raquel ; Antonell, Anna ; Lladó, Albert ; Parsons, Tammee M. ; Finch, Ni Cole A. ; Finger, Elizabeth C. ; Lippa, Carol F. ; Huey, Edward D. ; Neumann, Manuela ; Heutink, Peter ; Synofzik, Matthis ; Wilke, Carlo ; Rissman, Robert A. ; Slawek, Jaroslaw ; Sitek, Emilia ; Johannsen, Peter ; Nielsen, Jørgen E. ; Ren, Yingxue ; van Blitterswijk, Marka ; DeJesus-Hernandez, Mariely ; Christopher, Elizabeth ; Murray, Melissa E. ; Bieniek, Kevin F. ; Evers, Bret M. ; Ferrari, Camilla ; Rollinson, Sara ; Richardson, Anna ; Scarpini, Elio ; Fumagalli, Giorgio G. ; Padovani, Alessandro ; Hardy, John ; Momeni, Parastoo ; Ferrari, Raffaele ; Frangipane, Francesca ; Maletta, Raffaele ; Anfossi, Maria ; Gallo, Maura ; Petrucelli, Leonard ; Suh, Eun Ran ; Lopez, Oscar L. ; Wong, Tsz H. ; van Rooij, Jeroen G.J. ; Seelaar, Harro ; Mead, Simon ; Caselli, Richard J. ; Reiman, Eric M. ; Noel Sabbagh, Marwan ; Kjolby, Mads ; Nykjaer, Anders ; Karydas, Anna M. ; Boxer, Adam L. ; Grinberg, Lea T. ; Grafman, Jordan ; Spina, Salvatore ; Oblak, Adrian ; Mesulam, M. Marsel ; Weintraub, Sandra ; Geula, Changiz ; Hodges, John R. ; Piguet, Olivier ; Brooks, William S. ; Irwin, David J. ; Trojanowski, John Q. ; Lee, Edward B. ; Josephs, Keith A. ; Parisi, Joseph E. ; Ertekin-Taner, Nilüfer ; Knopman, David S. ; Nacmias, Benedetta ; Piaceri, Irene ; Bagnoli, Silvia ; Sorbi, Sandro ; Gearing, Marla ; Glass, Jonathan ; Beach, Thomas G. ; Black, Sandra E. ; Masellis, Mario ; Rogaeva, Ekaterina ; Vonsattel, Jean Paul ; Honig, Lawrence S. ; Kofler, Julia ; Bruni, Amalia C. ; Snowden, Julie ; Mann, David ; Pickering-Brown, Stuart ; Diehl-Schmid, Janine ; Winkelmann, Juliane ; Galimberti, Daniela ; Graff, Caroline ; Öijerstedt, Linn ; Troakes, Claire ; Al-Sarraj, Safa ; Cruchaga, Carlos ; Cairns, Nigel J. ; Rohrer, Jonathan D. ; Halliday, Glenda M. ; Kwok, John B. ; van Swieten, John C. ; White, Charles L. ; Ghetti, Bernardino ; Murell, Jill R. ; Mackenzie, Ian R.A. ; Hsiung, Ging Yuek R. ; Borroni, Barbara ; Rossi, Giacomina ; Tagliavini, Fabrizio ; Wszolek, Zbigniew K. ; Petersen, Ronald C. ; Bigio, Eileen H. ; Grossman, Murray ; Van Deerlin, Vivianna M. ; Seeley, William W. ; Miller, Bruce L. ; Graff-Radford, Neill R. ; Boeve, Bradley F. ; Dickson, Dennis W. ; Biernacka, Joanna M. ; Rademakers, Rosa. / Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations : a genome-wide association study. In: The Lancet Neurology. 2018 ; Vol. 17, No. 6. pp. 548-558.
@article{d4484dd4d7f947229c3dc135385d951a,
title = "Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study",
abstract = "Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95{\%} CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95{\%} CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.",
author = "Cyril Pottier and Xiaolai Zhou and Perkerson, {Ralph B.} and Matt Baker and Jenkins, {Gregory D.} and Serie, {Daniel J.} and Roberta Ghidoni and Luisa Benussi and Giuliano Binetti and {L{\'o}pez de Munain}, Adolfo and Miren Zulaica and Fermin Moreno and {Le Ber}, Isabelle and Florence Pasquier and Didier Hannequin and Raquel S{\'a}nchez-Valle and Anna Antonell and Albert Llad{\'o} and Parsons, {Tammee M.} and Finch, {Ni Cole A.} and Finger, {Elizabeth C.} and Lippa, {Carol F.} and Huey, {Edward D.} and Manuela Neumann and Peter Heutink and Matthis Synofzik and Carlo Wilke and Rissman, {Robert A.} and Jaroslaw Slawek and Emilia Sitek and Peter Johannsen and Nielsen, {J{\o}rgen E.} and Yingxue Ren and {van Blitterswijk}, Marka and Mariely DeJesus-Hernandez and Elizabeth Christopher and Murray, {Melissa E.} and Bieniek, {Kevin F.} and Evers, {Bret M.} and Camilla Ferrari and Sara Rollinson and Anna Richardson and Elio Scarpini and Fumagalli, {Giorgio G.} and Alessandro Padovani and John Hardy and Parastoo Momeni and Raffaele Ferrari and Francesca Frangipane and Raffaele Maletta and Maria Anfossi and Maura Gallo and Leonard Petrucelli and Suh, {Eun Ran} and Lopez, {Oscar L.} and Wong, {Tsz H.} and {van Rooij}, {Jeroen G.J.} and Harro Seelaar and Simon Mead and Caselli, {Richard J.} and Reiman, {Eric M.} and {Noel Sabbagh}, Marwan and Mads Kjolby and Anders Nykjaer and Karydas, {Anna M.} and Boxer, {Adam L.} and Grinberg, {Lea T.} and Jordan Grafman and Salvatore Spina and Adrian Oblak and Mesulam, {M. Marsel} and Sandra Weintraub and Changiz Geula and Hodges, {John R.} and Olivier Piguet and Brooks, {William S.} and Irwin, {David J.} and Trojanowski, {John Q.} and Lee, {Edward B.} and Josephs, {Keith A.} and Parisi, {Joseph E.} and Nil{\"u}fer Ertekin-Taner and Knopman, {David S.} and Benedetta Nacmias and Irene Piaceri and Silvia Bagnoli and Sandro Sorbi and Marla Gearing and Jonathan Glass and Beach, {Thomas G.} and Black, {Sandra E.} and Mario Masellis and Ekaterina Rogaeva and Vonsattel, {Jean Paul} and Honig, {Lawrence S.} and Julia Kofler and Bruni, {Amalia C.} and Julie Snowden and David Mann and Stuart Pickering-Brown and Janine Diehl-Schmid and Juliane Winkelmann and Daniela Galimberti and Caroline Graff and Linn {\"O}ijerstedt and Claire Troakes and Safa Al-Sarraj and Carlos Cruchaga and Cairns, {Nigel J.} and Rohrer, {Jonathan D.} and Halliday, {Glenda M.} and Kwok, {John B.} and {van Swieten}, {John C.} and White, {Charles L.} and Bernardino Ghetti and Murell, {Jill R.} and Mackenzie, {Ian R.A.} and Hsiung, {Ging Yuek R.} and Barbara Borroni and Giacomina Rossi and Fabrizio Tagliavini and Wszolek, {Zbigniew K.} and Petersen, {Ronald C.} and Bigio, {Eileen H.} and Murray Grossman and {Van Deerlin}, {Vivianna M.} and Seeley, {William W.} and Miller, {Bruce L.} and Graff-Radford, {Neill R.} and Boeve, {Bradley F.} and Dickson, {Dennis W.} and Biernacka, {Joanna M.} and Rosa Rademakers",
year = "2018",
month = "6",
day = "1",
doi = "10.1016/S1474-4422(18)30126-1",
language = "English (US)",
volume = "17",
pages = "548--558",
journal = "The Lancet Neurology",
issn = "1474-4422",
publisher = "Lancet Publishing Group",
number = "6",

}

TY - JOUR

T1 - Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations

T2 - a genome-wide association study

AU - Pottier, Cyril

AU - Zhou, Xiaolai

AU - Perkerson, Ralph B.

AU - Baker, Matt

AU - Jenkins, Gregory D.

AU - Serie, Daniel J.

AU - Ghidoni, Roberta

AU - Benussi, Luisa

AU - Binetti, Giuliano

AU - López de Munain, Adolfo

AU - Zulaica, Miren

AU - Moreno, Fermin

AU - Le Ber, Isabelle

AU - Pasquier, Florence

AU - Hannequin, Didier

AU - Sánchez-Valle, Raquel

AU - Antonell, Anna

AU - Lladó, Albert

AU - Parsons, Tammee M.

AU - Finch, Ni Cole A.

AU - Finger, Elizabeth C.

AU - Lippa, Carol F.

AU - Huey, Edward D.

AU - Neumann, Manuela

AU - Heutink, Peter

AU - Synofzik, Matthis

AU - Wilke, Carlo

AU - Rissman, Robert A.

AU - Slawek, Jaroslaw

AU - Sitek, Emilia

AU - Johannsen, Peter

AU - Nielsen, Jørgen E.

AU - Ren, Yingxue

AU - van Blitterswijk, Marka

AU - DeJesus-Hernandez, Mariely

AU - Christopher, Elizabeth

AU - Murray, Melissa E.

AU - Bieniek, Kevin F.

AU - Evers, Bret M.

AU - Ferrari, Camilla

AU - Rollinson, Sara

AU - Richardson, Anna

AU - Scarpini, Elio

AU - Fumagalli, Giorgio G.

AU - Padovani, Alessandro

AU - Hardy, John

AU - Momeni, Parastoo

AU - Ferrari, Raffaele

AU - Frangipane, Francesca

AU - Maletta, Raffaele

AU - Anfossi, Maria

AU - Gallo, Maura

AU - Petrucelli, Leonard

AU - Suh, Eun Ran

AU - Lopez, Oscar L.

AU - Wong, Tsz H.

AU - van Rooij, Jeroen G.J.

AU - Seelaar, Harro

AU - Mead, Simon

AU - Caselli, Richard J.

AU - Reiman, Eric M.

AU - Noel Sabbagh, Marwan

AU - Kjolby, Mads

AU - Nykjaer, Anders

AU - Karydas, Anna M.

AU - Boxer, Adam L.

AU - Grinberg, Lea T.

AU - Grafman, Jordan

AU - Spina, Salvatore

AU - Oblak, Adrian

AU - Mesulam, M. Marsel

AU - Weintraub, Sandra

AU - Geula, Changiz

AU - Hodges, John R.

AU - Piguet, Olivier

AU - Brooks, William S.

AU - Irwin, David J.

AU - Trojanowski, John Q.

AU - Lee, Edward B.

AU - Josephs, Keith A.

AU - Parisi, Joseph E.

AU - Ertekin-Taner, Nilüfer

AU - Knopman, David S.

AU - Nacmias, Benedetta

AU - Piaceri, Irene

AU - Bagnoli, Silvia

AU - Sorbi, Sandro

AU - Gearing, Marla

AU - Glass, Jonathan

AU - Beach, Thomas G.

AU - Black, Sandra E.

AU - Masellis, Mario

AU - Rogaeva, Ekaterina

AU - Vonsattel, Jean Paul

AU - Honig, Lawrence S.

AU - Kofler, Julia

AU - Bruni, Amalia C.

AU - Snowden, Julie

AU - Mann, David

AU - Pickering-Brown, Stuart

AU - Diehl-Schmid, Janine

AU - Winkelmann, Juliane

AU - Galimberti, Daniela

AU - Graff, Caroline

AU - Öijerstedt, Linn

AU - Troakes, Claire

AU - Al-Sarraj, Safa

AU - Cruchaga, Carlos

AU - Cairns, Nigel J.

AU - Rohrer, Jonathan D.

AU - Halliday, Glenda M.

AU - Kwok, John B.

AU - van Swieten, John C.

AU - White, Charles L.

AU - Ghetti, Bernardino

AU - Murell, Jill R.

AU - Mackenzie, Ian R.A.

AU - Hsiung, Ging Yuek R.

AU - Borroni, Barbara

AU - Rossi, Giacomina

AU - Tagliavini, Fabrizio

AU - Wszolek, Zbigniew K.

AU - Petersen, Ronald C.

AU - Bigio, Eileen H.

AU - Grossman, Murray

AU - Van Deerlin, Vivianna M.

AU - Seeley, William W.

AU - Miller, Bruce L.

AU - Graff-Radford, Neill R.

AU - Boeve, Bradley F.

AU - Dickson, Dennis W.

AU - Biernacka, Joanna M.

AU - Rademakers, Rosa

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.

AB - Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.

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U2 - 10.1016/S1474-4422(18)30126-1

DO - 10.1016/S1474-4422(18)30126-1

M3 - Article

VL - 17

SP - 548

EP - 558

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

IS - 6

ER -