Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Günter U. Höglinger; Nadine M. Melhem; Dennis W. Dickson; Patrick M.A. Sleiman; Li San Wang; Lambertus Klei; Rosa Rademakers; Rohan De Silva; Irene Litvan; David E. Riley; John C. Van Swieten; Peter Heutink; Zbigniew K. Wszolek; Ryan J. Uitti; Jana Vandrovcova; Howard I. Hurtig; Rachel G. Gross; Walter Maetzler; Stefano Goldwurm; Eduardo Tolosa; Barbara Borroni; Pau Pastor; Laura B. Cantwell; Mi Ryung Han; Allissa Dillman; Marcel P. Van Der Brug; J. Raphael Gibbs; Mark R. Cookson; Dena G. Hernandez; Andrew B. Singleton; Matthew J. Farrer; Chang En Yu; Lawrence I. Golbe; Tamas Revesz; John Hardy; Andrew J. Lees; Bernie Devlin; Hakon Hakonarson; Ulrich Müller; Gerard D. Schellenberg; Roger L. Albin; Elena Alonso; Angelo Antonini; Manuela Apfelbacher; Steven E. Arnold; Jesus Avila; Thomas G. Beach; Sherry Beecher; Daniela Berg; Thomas D. Bird; Nenad Bogdanovic; Agnita J.W. Boon; Yvette Bordelon; Alexis Brice; Herbert Budka; Margherita Canesi; Wang Zheng Chiu; Roberto Cilia; Carlo Colosimo; Peter P. De Deyn; Justo Garcãa De Yebenes; Laura Donker Kaat; Ranjan Duara; Alexandra Durr; Sebastiaan Engelborghs; Giovanni Fabbrini; Nicole A. Finch; Robyn Flook; Matthew P. Frosch; Carles Gaig; Douglas R. Galasko; Thomas Gasser; Marla Gearing; Evan T. Geller; Bernardino Ghetti; Neill R. Graff-Radford; Murray Grossman; Deborah A. Hall; Lili Naz Hazrati; Matthias Höllerhage; Joseph Jankovic; Jorge L. Juncos; Anna Karydas; Hans A. Kretzschmar; Isabelle Leber; Virginia M. Lee; Andrew P. Lieberman; Kelly E. Lyons; Claudio Mariani; Eliezer Masliah; Luke A. Massey; Catriona A. McLean; Nicoletta Meucci; Bruce L. Miller; Brit Mollenhauer; Jens C. Möller; Huw R. Morris; Chris Morris; Sean S. O'Sullivan; Wolfgang H. Oertel; Donatella Ottaviani; Alessandro Padovani; Rajesh Pahwa; Gianni Pezzoli; Stuart Pickering-Brown; Werner Poewe; Alberto Rabano; Alex Rajput; Stephen G. Reich; Gesine Respondek; Sigrun Roeber; Jonathan D. Rohrer; Owen A. Ross; Martin N. Rossor; Giorgio Sacilotto; William W. Seeley; Klaus Seppi; Laura Silveira-Moriyama; Salvatore Spina; Karin Srulijes; Peter St. George-Hyslop; Maria Stamelou; David G. Standaert; Silvana Tesei; Wallace W. Tourtellotte; Claudia Trenkwalder; Claire Troakes; John Q. Trojanowski; Juan C. Troncoso; Vivianna M. Van Deerlin; Jean Paul G. Vonsattel; Gregor K. Wenning; Charles L. White; Pia Winter; Chris Zarow; Anna L. Zecchinelli

doi:10.1038/ng.859

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Günter U. Höglinger, Nadine M. Melhem, Dennis W. Dickson, Patrick M.A. Sleiman, Li San Wang, Lambertus Klei, Rosa Rademakers, Rohan De Silva, Irene Litvan, David E. Riley, John C. Van Swieten, Peter Heutink, Zbigniew K. Wszolek, Ryan J. Uitti, Jana Vandrovcova, Howard I. Hurtig, Rachel G. Gross, Walter Maetzler, Stefano Goldwurm, Eduardo TolosaBarbara Borroni, Pau Pastor, Laura B. Cantwell, Mi Ryung Han, Allissa Dillman, Marcel P. Van Der Brug, J. Raphael Gibbs, Mark R. Cookson, Dena G. Hernandez, Andrew B. Singleton, Matthew J. Farrer, Chang En Yu, Lawrence I. Golbe, Tamas Revesz, John Hardy, Andrew J. Lees, Bernie Devlin, Hakon Hakonarson, Ulrich Müller, Gerard D. Schellenberg, Roger L. Albin, Elena Alonso, Angelo Antonini, Manuela Apfelbacher, Steven E. Arnold, Jesus Avila, Thomas G. Beach, Sherry Beecher, Daniela Berg, Thomas D. Bird, Nenad Bogdanovic, Agnita J.W. Boon, Yvette Bordelon, Alexis Brice, Herbert Budka, Margherita Canesi, Wang Zheng Chiu, Roberto Cilia, Carlo Colosimo, Peter P. De Deyn, Justo Garcãa De Yebenes, Laura Donker Kaat, Ranjan Duara, Alexandra Durr, Sebastiaan Engelborghs, Giovanni Fabbrini, Nicole A. Finch, Robyn Flook, Matthew P. Frosch, Carles Gaig, Douglas R. Galasko, Thomas Gasser, Marla Gearing, Evan T. Geller, Bernardino Ghetti, Neill R. Graff-Radford, Murray Grossman, Deborah A. Hall, Lili Naz Hazrati, Matthias Höllerhage, Joseph Jankovic, Jorge L. Juncos, Anna Karydas, Hans A. Kretzschmar, Isabelle Leber, Virginia M. Lee, Andrew P. Lieberman, Kelly E. Lyons, Claudio Mariani, Eliezer Masliah, Luke A. Massey, Catriona A. McLean, Nicoletta Meucci, Bruce L. Miller, Brit Mollenhauer, Jens C. Möller, Huw R. Morris, Chris Morris, Sean S. O'Sullivan, Wolfgang H. Oertel, Donatella Ottaviani, Alessandro Padovani, Rajesh Pahwa, Gianni Pezzoli, Stuart Pickering-Brown, Werner Poewe, Alberto Rabano, Alex Rajput, Stephen G. Reich, Gesine Respondek, Sigrun Roeber, Jonathan D. Rohrer, Owen A. Ross, Martin N. Rossor, Giorgio Sacilotto, William W. Seeley, Klaus Seppi, Laura Silveira-Moriyama, Salvatore Spina, Karin Srulijes, Peter St. George-Hyslop, Maria Stamelou, David G. Standaert, Silvana Tesei, Wallace W. Tourtellotte, Claudia Trenkwalder, Claire Troakes, John Q. Trojanowski, Juan C. Troncoso, Vivianna M. Van Deerlin, Jean Paul G. Vonsattel, Gregor K. Wenning, Charles L. White, Pia Winter, Chris Zarow, Anna L. Zecchinelli

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

325 Scopus citations

Abstract

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10^-3. We found significant previously unidentified signals (P < 5 × 10^-8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

Original language	English (US)
Pages (from-to)	699-705
Number of pages	7
Journal	Nature Genetics
Volume	43
Issue number	7
DOIs	https://doi.org/10.1038/ng.859
State	Published - Jul 2011

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/ng.859

Cite this

Höglinger, G. U., Melhem, N. M., Dickson, D. W., Sleiman, P. M. A., Wang, L. S., Klei, L., Rademakers, R., De Silva, R., Litvan, I., Riley, D. E., Van Swieten, J. C., Heutink, P., Wszolek, Z. K., Uitti, R. J., Vandrovcova, J., Hurtig, H. I., Gross, R. G., Maetzler, W., Goldwurm, S., ... Zecchinelli, A. L. (2011). Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nature Genetics, 43(7), 699-705. https://doi.org/10.1038/ng.859

Höglinger, GU, Melhem, NM, Dickson, DW, Sleiman, PMA, Wang, LS, Klei, L, Rademakers, R, De Silva, R, Litvan, I, Riley, DE, Van Swieten, JC, Heutink, P, Wszolek, ZK, Uitti, RJ, Vandrovcova, J, Hurtig, HI, Gross, RG, Maetzler, W, Goldwurm, S, Tolosa, E, Borroni, B, Pastor, P, Cantwell, LB, Han, MR, Dillman, A, Van Der Brug, MP, Gibbs, JR, Cookson, MR, Hernandez, DG, Singleton, AB, Farrer, MJ, Yu, CE, Golbe, LI, Revesz, T, Hardy, J, Lees, AJ, Devlin, B, Hakonarson, H, Müller, U, Schellenberg, GD, Albin, RL, Alonso, E, Antonini, A, Apfelbacher, M, Arnold, SE, Avila, J, Beach, TG, Beecher, S, Berg, D, Bird, TD, Bogdanovic, N, Boon, AJW, Bordelon, Y, Brice, A, Budka, H, Canesi, M, Chiu, WZ, Cilia, R, Colosimo, C, De Deyn, PP, De Yebenes, JG, Kaat, LD, Duara, R, Durr, A, Engelborghs, S, Fabbrini, G, Finch, NA, Flook, R, Frosch, MP, Gaig, C, Galasko, DR, Gasser, T, Gearing, M, Geller, ET, Ghetti, B, Graff-Radford, NR, Grossman, M, Hall, DA, Hazrati, LN, Höllerhage, M, Jankovic, J, Juncos, JL, Karydas, A, Kretzschmar, HA, Leber, I, Lee, VM, Lieberman, AP, Lyons, KE, Mariani, C, Masliah, E, Massey, LA, McLean, CA, Meucci, N, Miller, BL, Mollenhauer, B, Möller, JC, Morris, HR, Morris, C, O'Sullivan, SS, Oertel, WH, Ottaviani, D, Padovani, A, Pahwa, R, Pezzoli, G, Pickering-Brown, S, Poewe, W, Rabano, A, Rajput, A, Reich, SG, Respondek, G, Roeber, S, Rohrer, JD, Ross, OA, Rossor, MN, Sacilotto, G, Seeley, WW, Seppi, K, Silveira-Moriyama, L, Spina, S, Srulijes, K, St. George-Hyslop, P, Stamelou, M, Standaert, DG, Tesei, S, Tourtellotte, WW, Trenkwalder, C, Troakes, C, Trojanowski, JQ, Troncoso, JC, Van Deerlin, VM, Vonsattel, JPG, Wenning, GK, White, CL, Winter, P, Zarow, C & Zecchinelli, AL 2011, 'Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy', Nature Genetics, vol. 43, no. 7, pp. 699-705. https://doi.org/10.1038/ng.859

@article{279e0e8919c84b1298dde84dcb8d79ca,

title = "Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy",

abstract = "Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10-3. We found significant previously unidentified signals (P < 5 × 10-8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.",

author = "H{\"o}glinger, {G{\"u}nter U.} and Melhem, {Nadine M.} and Dickson, {Dennis W.} and Sleiman, {Patrick M.A.} and Wang, {Li San} and Lambertus Klei and Rosa Rademakers and {De Silva}, Rohan and Irene Litvan and Riley, {David E.} and {Van Swieten}, {John C.} and Peter Heutink and Wszolek, {Zbigniew K.} and Uitti, {Ryan J.} and Jana Vandrovcova and Hurtig, {Howard I.} and Gross, {Rachel G.} and Walter Maetzler and Stefano Goldwurm and Eduardo Tolosa and Barbara Borroni and Pau Pastor and Cantwell, {Laura B.} and Han, {Mi Ryung} and Allissa Dillman and {Van Der Brug}, {Marcel P.} and Gibbs, {J. Raphael} and Cookson, {Mark R.} and Hernandez, {Dena G.} and Singleton, {Andrew B.} and Farrer, {Matthew J.} and Yu, {Chang En} and Golbe, {Lawrence I.} and Tamas Revesz and John Hardy and Lees, {Andrew J.} and Bernie Devlin and Hakon Hakonarson and Ulrich M{\"u}ller and Schellenberg, {Gerard D.} and Albin, {Roger L.} and Elena Alonso and Angelo Antonini and Manuela Apfelbacher and Arnold, {Steven E.} and Jesus Avila and Beach, {Thomas G.} and Sherry Beecher and Daniela Berg and Bird, {Thomas D.} and Nenad Bogdanovic and Boon, {Agnita J.W.} and Yvette Bordelon and Alexis Brice and Herbert Budka and Margherita Canesi and Chiu, {Wang Zheng} and Roberto Cilia and Carlo Colosimo and {De Deyn}, {Peter P.} and {De Yebenes}, {Justo Garc{\~a}a} and Kaat, {Laura Donker} and Ranjan Duara and Alexandra Durr and Sebastiaan Engelborghs and Giovanni Fabbrini and Finch, {Nicole A.} and Robyn Flook and Frosch, {Matthew P.} and Carles Gaig and Galasko, {Douglas R.} and Thomas Gasser and Marla Gearing and Geller, {Evan T.} and Bernardino Ghetti and Graff-Radford, {Neill R.} and Murray Grossman and Hall, {Deborah A.} and Hazrati, {Lili Naz} and Matthias H{\"o}llerhage and Joseph Jankovic and Juncos, {Jorge L.} and Anna Karydas and Kretzschmar, {Hans A.} and Isabelle Leber and Lee, {Virginia M.} and Lieberman, {Andrew P.} and Lyons, {Kelly E.} and Claudio Mariani and Eliezer Masliah and Massey, {Luke A.} and McLean, {Catriona A.} and Nicoletta Meucci and Miller, {Bruce L.} and Brit Mollenhauer and M{\"o}ller, {Jens C.} and Morris, {Huw R.} and Chris Morris and O'Sullivan, {Sean S.} and Oertel, {Wolfgang H.} and Donatella Ottaviani and Alessandro Padovani and Rajesh Pahwa and Gianni Pezzoli and Stuart Pickering-Brown and Werner Poewe and Alberto Rabano and Alex Rajput and Reich, {Stephen G.} and Gesine Respondek and Sigrun Roeber and Rohrer, {Jonathan D.} and Ross, {Owen A.} and Rossor, {Martin N.} and Giorgio Sacilotto and Seeley, {William W.} and Klaus Seppi and Laura Silveira-Moriyama and Salvatore Spina and Karin Srulijes and {St. George-Hyslop}, Peter and Maria Stamelou and Standaert, {David G.} and Silvana Tesei and Tourtellotte, {Wallace W.} and Claudia Trenkwalder and Claire Troakes and Trojanowski, {John Q.} and Troncoso, {Juan C.} and {Van Deerlin}, {Vivianna M.} and Vonsattel, {Jean Paul G.} and Wenning, {Gregor K.} and White, {Charles L.} and Pia Winter and Chris Zarow and Zecchinelli, {Anna L.}",

note = "Funding Information: The datasets used for older controls were obtained from Database for Genotypes and Phenotypes (dbGap) at http://www.ncbi.nlm.nih.gov/gap/. Funding support for the {\textquoteleft}Genetic Consortium for Late Onset Alzheimer{\textquoteright}s Disease{\textquoteright} was provided through the Division of Neuroscience, NIA. The Genetic Consortium for Late Onset Alzheimer{\textquoteright}s Disease (study accession number: phs000168.v1.p1) includes a genomewide association study funded as part of the Division of Neuroscience, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Genetic Consortium for Late Onset Alzheimer{\textquoteright}s Disease. Funding support for the {\textquoteleft}CIDR Visceral Adiposity Study{\textquoteright} (study accession number: phs000169.v1.p1) was provided through the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. The CIDR Visceral Adiposity Study includes a genomewide association study funded as part of the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Heath ABC Study Investigators. Funding support for the Personalized Medicine Research Project (PMRP) was provided through a cooperative agreement (U01HG004608) with the National Human Genome Research Institute (NHGRI), with additional funding from the National Institute for General Medical Sciences Funding Information: We thank the subjects and their families that participated in this study. This work was funded by grants from the CurePSP Foundation, the Peebler PSP Research Foundation and US National Institutes of Health (NIH) grants R37 AG 11762, R01 PAS03092, P50 NS72187, P01 AG17216 (National Institute on Aging (NIA)/NIH), MH057881 and MH077930 (National Institute of Mental Health (NIMH)). Work was also supported in part by the NIA Intramural Research Program, the German National Genome Research Network (01GS081364) and the Deutsche Forschungsgemeinschaft (HO 2402/61), Prinses Beatrix Fonds (JCvS, 010128), the Reta Lila Weston Trust and the UK Medical Research Council (RdS: G0501560). The Newcastle Brain Tissue Resource provided tissue and is funded in part by a grant from the UK Medical Research Council (G0400074), by the Newcastle National Institute for Health Research (NIHR) Biomedical Research Centre in Ageing and Age Related Diseases to the Newcastle upon Tyne Hospitals National Health Service Foundation Trust and by a grant from the Alzheimer{\textquoteright}s Society and Alzheimer{\textquoteright}s Research Trust as part of the Brains for Dementia Research Project. We acknowledge the contribution of many tissue samples from the Harvard Brain Tissue Resource Center. We also acknowledge the {\textquoteleft}Human Genetic Bank of Patients affected by Parkinson Disease and Parkinsonism{\textquoteright} (http://www. parkinson.it/dnabank.html) of the Telethon Genetic Biobank Network, supported by TELETHON Italy (project no. GTB07001) and by Fondazione Grigioni per il Morbo di Parkinson. The University of Toronto sample collection was supported by grants from Wellcome Trust, Howard Hughes Medical Institute and the Canadian Institute of Health Research. BrainNetGermany is supported by the Federal Ministry of Education and Research (BMBF) (01GI0505). R.d.S., A.J.L. and J.A.H. are funded by the Reta Lila Weston Trust and the PSP (Europe) Association. R.d.S. is funded by the UK Medical Research Council (Grant G0501560) and Cure PSP+. Z.K.W. is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR programs (MCF #90052030 and MCF #90052030) and the gift from C.E. Bolch Jr. and S.B. Bolch (MCF #90052031/PAU #90052). The Mayo Clinic College of Medicine would like to acknowledge M. Baker, R. Crook, M. DeJesusHernandez and N. Rutherford for their preparation of samples. P.P. was supported by a grant from the Government of Navarra ({\textquoteleft}Ayudas para la Realizaci{\'o}n de Proyectos de Investigaci{\'o}n{\textquoteright} 2006–2007) and acknowledges the {\textquoteleft}Iberian Atypical Parkinsonism Study Group Researchers{\textquoteright}: M.A. Pastor, M.R. Luquin, M. Riverol, J.A. Obeso and M.C. RodriguezOroz (Department of Neurology, Cl{\'i}nica Universitaria de Navarra, University of Navarra, Pamplona, Spain), M. Blazquez (Neurology Department, Hospital Universitario Central de Asturias, Oviedo, Spain), A. Lopez de Munain, B. Indakoetxea, J. Olaskoaga, J. Ruiz, J. F{\'e}lix Mart{\'i} Mass{\'o} (Servicio de Neurolog{\'i}a, Hospital Donostia, San Sebasti{\'a}n, Spain), V. Alvarez (Genetics Department, Hospital Universitario Central de Asturias, Oviedo, Spain), T. Tu{\~n}on (Banco de Tejidos Neurologicos, CIBERNED, Hospital de Navarra, Navarra, Spain), F. Moreno (Servicio de Neurolog{\'i}a, Hospital Ntra. Sra. de la Antigua, Zumarraga, Gipuzkoa, Spain), A. Alzualde (Neurogen{\'e}tics Department, Hospital Donostia, San Sebasti{\'a}n, Spain). E.T. wishes to acknowledge the Banco de Tejidos Neurol{\'o}gicos de la Universidad de BarcelonaHospital Clinic, which provided many tissue samples for the project. We also acknowledge E. Loomis for providing technical support. Funding Information: (NIGMS). The samples used for PMRP analyses were obtained with funding from Marshfield Clinic, Health Resources Service Administration Office of Rural Health Policy grant number D1A RH00025 and Wisconsin Department of Commerce Technology Development Fund contract number TDF FYO10718. Funding support for genotyping, which was performed at Johns Hopkins University, was provided by the NIH (U01HG004438). Assistance with phenotype harmonization and genotype cleaning was provided by the eMERGE Administrative Coordinating Center (U01HG004603) and the National Center for Biotechnology Information (NCBI). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000170.v1.p1.",

year = "2011",

month = jul,

doi = "10.1038/ng.859",

language = "English (US)",

volume = "43",

pages = "699--705",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "7",

}

TY - JOUR

T1 - Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

AU - Höglinger, Günter U.

AU - Melhem, Nadine M.

AU - Dickson, Dennis W.

AU - Sleiman, Patrick M.A.

AU - Wang, Li San

AU - Klei, Lambertus

AU - Rademakers, Rosa

AU - De Silva, Rohan

AU - Litvan, Irene

AU - Riley, David E.

AU - Van Swieten, John C.

AU - Heutink, Peter

AU - Wszolek, Zbigniew K.

AU - Uitti, Ryan J.

AU - Vandrovcova, Jana

AU - Hurtig, Howard I.

AU - Gross, Rachel G.

AU - Maetzler, Walter

AU - Goldwurm, Stefano

AU - Tolosa, Eduardo

AU - Borroni, Barbara

AU - Pastor, Pau

AU - Cantwell, Laura B.

AU - Han, Mi Ryung

AU - Dillman, Allissa

AU - Van Der Brug, Marcel P.

AU - Gibbs, J. Raphael

AU - Cookson, Mark R.

AU - Hernandez, Dena G.

AU - Singleton, Andrew B.

AU - Farrer, Matthew J.

AU - Yu, Chang En

AU - Golbe, Lawrence I.

AU - Revesz, Tamas

AU - Hardy, John

AU - Lees, Andrew J.

AU - Devlin, Bernie

AU - Hakonarson, Hakon

AU - Müller, Ulrich

AU - Schellenberg, Gerard D.

AU - Albin, Roger L.

AU - Alonso, Elena

AU - Antonini, Angelo

AU - Apfelbacher, Manuela

AU - Arnold, Steven E.

AU - Avila, Jesus

AU - Beach, Thomas G.

AU - Beecher, Sherry

AU - Berg, Daniela

AU - Bird, Thomas D.

AU - Bogdanovic, Nenad

AU - Boon, Agnita J.W.

AU - Bordelon, Yvette

AU - Brice, Alexis

AU - Budka, Herbert

AU - Canesi, Margherita

AU - Chiu, Wang Zheng

AU - Cilia, Roberto

AU - Colosimo, Carlo

AU - De Deyn, Peter P.

AU - De Yebenes, Justo Garcãa

AU - Kaat, Laura Donker

AU - Duara, Ranjan

AU - Durr, Alexandra

AU - Engelborghs, Sebastiaan

AU - Fabbrini, Giovanni

AU - Finch, Nicole A.

AU - Flook, Robyn

AU - Frosch, Matthew P.

AU - Gaig, Carles

AU - Galasko, Douglas R.

AU - Gasser, Thomas

AU - Gearing, Marla

AU - Geller, Evan T.

AU - Ghetti, Bernardino

AU - Graff-Radford, Neill R.

AU - Grossman, Murray

AU - Hall, Deborah A.

AU - Hazrati, Lili Naz

AU - Höllerhage, Matthias

AU - Jankovic, Joseph

AU - Juncos, Jorge L.

AU - Karydas, Anna

AU - Kretzschmar, Hans A.

AU - Leber, Isabelle

AU - Lee, Virginia M.

AU - Lieberman, Andrew P.

AU - Lyons, Kelly E.

AU - Mariani, Claudio

AU - Masliah, Eliezer

AU - Massey, Luke A.

AU - McLean, Catriona A.

AU - Meucci, Nicoletta

AU - Miller, Bruce L.

AU - Mollenhauer, Brit

AU - Möller, Jens C.

AU - Morris, Huw R.

AU - Morris, Chris

AU - O'Sullivan, Sean S.

AU - Oertel, Wolfgang H.

AU - Ottaviani, Donatella

AU - Padovani, Alessandro

AU - Pahwa, Rajesh

AU - Pezzoli, Gianni

AU - Pickering-Brown, Stuart

AU - Poewe, Werner

AU - Rabano, Alberto

AU - Rajput, Alex

AU - Reich, Stephen G.

AU - Respondek, Gesine

AU - Roeber, Sigrun

AU - Rohrer, Jonathan D.

AU - Ross, Owen A.

AU - Rossor, Martin N.

AU - Sacilotto, Giorgio

AU - Seeley, William W.

AU - Seppi, Klaus

AU - Silveira-Moriyama, Laura

AU - Spina, Salvatore

AU - Srulijes, Karin

AU - St. George-Hyslop, Peter

AU - Stamelou, Maria

AU - Standaert, David G.

AU - Tesei, Silvana

AU - Tourtellotte, Wallace W.

AU - Trenkwalder, Claudia

AU - Troakes, Claire

AU - Trojanowski, John Q.

AU - Troncoso, Juan C.

AU - Van Deerlin, Vivianna M.

AU - Vonsattel, Jean Paul G.

AU - Wenning, Gregor K.

AU - White, Charles L.

AU - Winter, Pia

AU - Zarow, Chris

AU - Zecchinelli, Anna L.

N1 - Funding Information: The datasets used for older controls were obtained from Database for Genotypes and Phenotypes (dbGap) at http://www.ncbi.nlm.nih.gov/gap/. Funding support for the ‘Genetic Consortium for Late Onset Alzheimer’s Disease’ was provided through the Division of Neuroscience, NIA. The Genetic Consortium for Late Onset Alzheimer’s Disease (study accession number: phs000168.v1.p1) includes a genomewide association study funded as part of the Division of Neuroscience, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Genetic Consortium for Late Onset Alzheimer’s Disease. Funding support for the ‘CIDR Visceral Adiposity Study’ (study accession number: phs000169.v1.p1) was provided through the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. The CIDR Visceral Adiposity Study includes a genomewide association study funded as part of the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Heath ABC Study Investigators. Funding support for the Personalized Medicine Research Project (PMRP) was provided through a cooperative agreement (U01HG004608) with the National Human Genome Research Institute (NHGRI), with additional funding from the National Institute for General Medical Sciences Funding Information: We thank the subjects and their families that participated in this study. This work was funded by grants from the CurePSP Foundation, the Peebler PSP Research Foundation and US National Institutes of Health (NIH) grants R37 AG 11762, R01 PAS03092, P50 NS72187, P01 AG17216 (National Institute on Aging (NIA)/NIH), MH057881 and MH077930 (National Institute of Mental Health (NIMH)). Work was also supported in part by the NIA Intramural Research Program, the German National Genome Research Network (01GS081364) and the Deutsche Forschungsgemeinschaft (HO 2402/61), Prinses Beatrix Fonds (JCvS, 010128), the Reta Lila Weston Trust and the UK Medical Research Council (RdS: G0501560). The Newcastle Brain Tissue Resource provided tissue and is funded in part by a grant from the UK Medical Research Council (G0400074), by the Newcastle National Institute for Health Research (NIHR) Biomedical Research Centre in Ageing and Age Related Diseases to the Newcastle upon Tyne Hospitals National Health Service Foundation Trust and by a grant from the Alzheimer’s Society and Alzheimer’s Research Trust as part of the Brains for Dementia Research Project. We acknowledge the contribution of many tissue samples from the Harvard Brain Tissue Resource Center. We also acknowledge the ‘Human Genetic Bank of Patients affected by Parkinson Disease and Parkinsonism’ (http://www. parkinson.it/dnabank.html) of the Telethon Genetic Biobank Network, supported by TELETHON Italy (project no. GTB07001) and by Fondazione Grigioni per il Morbo di Parkinson. The University of Toronto sample collection was supported by grants from Wellcome Trust, Howard Hughes Medical Institute and the Canadian Institute of Health Research. BrainNetGermany is supported by the Federal Ministry of Education and Research (BMBF) (01GI0505). R.d.S., A.J.L. and J.A.H. are funded by the Reta Lila Weston Trust and the PSP (Europe) Association. R.d.S. is funded by the UK Medical Research Council (Grant G0501560) and Cure PSP+. Z.K.W. is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR programs (MCF #90052030 and MCF #90052030) and the gift from C.E. Bolch Jr. and S.B. Bolch (MCF #90052031/PAU #90052). The Mayo Clinic College of Medicine would like to acknowledge M. Baker, R. Crook, M. DeJesusHernandez and N. Rutherford for their preparation of samples. P.P. was supported by a grant from the Government of Navarra (‘Ayudas para la Realización de Proyectos de Investigación’ 2006–2007) and acknowledges the ‘Iberian Atypical Parkinsonism Study Group Researchers’: M.A. Pastor, M.R. Luquin, M. Riverol, J.A. Obeso and M.C. RodriguezOroz (Department of Neurology, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain), M. Blazquez (Neurology Department, Hospital Universitario Central de Asturias, Oviedo, Spain), A. Lopez de Munain, B. Indakoetxea, J. Olaskoaga, J. Ruiz, J. Félix Martí Massó (Servicio de Neurología, Hospital Donostia, San Sebastián, Spain), V. Alvarez (Genetics Department, Hospital Universitario Central de Asturias, Oviedo, Spain), T. Tuñon (Banco de Tejidos Neurologicos, CIBERNED, Hospital de Navarra, Navarra, Spain), F. Moreno (Servicio de Neurología, Hospital Ntra. Sra. de la Antigua, Zumarraga, Gipuzkoa, Spain), A. Alzualde (Neurogenétics Department, Hospital Donostia, San Sebastián, Spain). E.T. wishes to acknowledge the Banco de Tejidos Neurológicos de la Universidad de BarcelonaHospital Clinic, which provided many tissue samples for the project. We also acknowledge E. Loomis for providing technical support. Funding Information: (NIGMS). The samples used for PMRP analyses were obtained with funding from Marshfield Clinic, Health Resources Service Administration Office of Rural Health Policy grant number D1A RH00025 and Wisconsin Department of Commerce Technology Development Fund contract number TDF FYO10718. Funding support for genotyping, which was performed at Johns Hopkins University, was provided by the NIH (U01HG004438). Assistance with phenotype harmonization and genotype cleaning was provided by the eMERGE Administrative Coordinating Center (U01HG004603) and the National Center for Biotechnology Information (NCBI). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000170.v1.p1.

PY - 2011/7

Y1 - 2011/7

N2 - Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10-3. We found significant previously unidentified signals (P < 5 × 10-8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

AB - Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10-3. We found significant previously unidentified signals (P < 5 × 10-8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

UR - http://www.scopus.com/inward/record.url?scp=79959689333&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959689333&partnerID=8YFLogxK

U2 - 10.1038/ng.859

DO - 10.1038/ng.859

M3 - Article

C2 - 21685912

AN - SCOPUS:79959689333

SN - 1061-4036

VL - 43

SP - 699

EP - 705

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

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