Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

Vivianna M. Van Deerlin; Patrick M.A. Sleiman; Maria Martinez-Lage; Alice Chen-Plotkin; Li San Wang; Neill R. Graff-Radford; Dennis W. Dickson; Rosa Rademakers; Bradley F. Boeve; Murray Grossman; Steven E. Arnold; David M.A. Mann; Stuart M. Pickering-Brown; Harro Seelaar; Peter Heutink; John C. Van Swieten; Jill R. Murrell; Bernardino Ghetti; Salvatore Spina; Jordan Grafman; John Hodges; Maria Grazia Spillantini; Sid Gilman; Andrew P. Lieberman; Jeffrey A. Kaye; Randall L. Woltjer; Eileen H. Bigio; Marsel Mesulam; Safa Al-Sarraj; Claire Troakes; Roger N. Rosenberg; Charles L. White; Isidro Ferrer; Albert Lladó; Manuela Neumann; Hans A. Kretzschmar; Christine Marie Hulette; Kathleen A. Welsh-Bohmer; Bruce L. Miller; Ainhoa Alzualde; Adolfo Lopez De Munain; Ann C. McKee; Marla Gearing; Allan I. Levey; James J. Lah; John Hardy; Jonathan D. Rohrer; Tammaryn Lashley; Ian R.A. MacKenzie; Howard H. Feldman; Ronald L. Hamilton; Steven T. Dekosky; Julie Van Der Zee; Samir Kumar-Singh; Christine Van Broeckhoven; Richard Mayeux; Jean Paul G. Vonsattel; Juan C. Troncoso; Jillian J. Kril; John B.J. Kwok; Glenda M. Halliday; Thomas D. Bird; Paul G. Ince; Pamela J. Shaw; Nigel J. Cairns; John C. Morris; Catriona Ann McLean; Charles Decarli; William G. Ellis; Stefanie H. Freeman; Matthew P. Frosch; John H. Growdon; Daniel P. Perl; Mary Sano; David A. Bennett; Julie A. Schneider; Thomas G. Beach; Eric M. Reiman; Bryan K. Woodruff; Jeffrey Cummings; Harry V. Vinters; Carol A. Miller; Helena C. Chui; Irina Alafuzoff; Päivi Hartikainen; Danielle Seilhean; Douglas Galasko; Eliezer Masliah; Carl W. Cotman; M. Teresa Tũón; M. Cristina Caballero Martínez; David G. Munoz; Steven L. Carroll; Daniel Marson; Peter F. Riederer; Nenad Bogdanovic; Gerard D. Schellenberg; Hakon Hakonarson; John Q. Trojanowski; Virginia M.Y. Lee

doi:10.1038/ng.536

Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

Vivianna M. Van Deerlin, Patrick M.A. Sleiman, Maria Martinez-Lage, Alice Chen-Plotkin, Li San Wang, Neill R. Graff-Radford, Dennis W. Dickson, Rosa Rademakers, Bradley F. Boeve, Murray Grossman, Steven E. Arnold, David M.A. Mann, Stuart M. Pickering-Brown, Harro Seelaar, Peter Heutink, John C. Van Swieten, Jill R. Murrell, Bernardino Ghetti, Salvatore Spina, Jordan GrafmanJohn Hodges, Maria Grazia Spillantini, Sid Gilman, Andrew P. Lieberman, Jeffrey A. Kaye, Randall L. Woltjer, Eileen H. Bigio, Marsel Mesulam, Safa Al-Sarraj, Claire Troakes, Roger N. Rosenberg, Charles L. White, Isidro Ferrer, Albert Lladó, Manuela Neumann, Hans A. Kretzschmar, Christine Marie Hulette, Kathleen A. Welsh-Bohmer, Bruce L. Miller, Ainhoa Alzualde, Adolfo Lopez De Munain, Ann C. McKee, Marla Gearing, Allan I. Levey, James J. Lah, John Hardy, Jonathan D. Rohrer, Tammaryn Lashley, Ian R.A. MacKenzie, Howard H. Feldman, Ronald L. Hamilton, Steven T. Dekosky, Julie Van Der Zee, Samir Kumar-Singh, Christine Van Broeckhoven, Richard Mayeux, Jean Paul G. Vonsattel, Juan C. Troncoso, Jillian J. Kril, John B.J. Kwok, Glenda M. Halliday, Thomas D. Bird, Paul G. Ince, Pamela J. Shaw, Nigel J. Cairns, John C. Morris, Catriona Ann McLean, Charles Decarli, William G. Ellis, Stefanie H. Freeman, Matthew P. Frosch, John H. Growdon, Daniel P. Perl, Mary Sano, David A. Bennett, Julie A. Schneider, Thomas G. Beach, Eric M. Reiman, Bryan K. Woodruff, Jeffrey Cummings, Harry V. Vinters, Carol A. Miller, Helena C. Chui, Irina Alafuzoff, Päivi Hartikainen, Danielle Seilhean, Douglas Galasko, Eliezer Masliah, Carl W. Cotman, M. Teresa Tũón, M. Cristina Caballero Martínez, David G. Munoz, Steven L. Carroll, Daniel Marson, Peter F. Riederer, Nenad Bogdanovic, Gerard D. Schellenberg, Hakon Hakonarson, John Q. Trojanowski, Virginia M.Y. Lee

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

454 Scopus citations

Abstract

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 × 10 11; odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 × 10 4). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

Original language	English
Pages (from-to)	234-239
Number of pages	6
Journal	Nature Genetics
Volume	42
Issue number	3
DOIs	https://doi.org/10.1038/ng.536
State	Published - Mar 2010

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Van Deerlin, V. M., Sleiman, P. M. A., Martinez-Lage, M., Chen-Plotkin, A., Wang, L. S., Graff-Radford, N. R., Dickson, D. W., Rademakers, R., Boeve, B. F., Grossman, M., Arnold, S. E., Mann, D. M. A., Pickering-Brown, S. M., Seelaar, H., Heutink, P., Van Swieten, J. C., Murrell, J. R., Ghetti, B., Spina, S., ... Lee, V. M. Y. (2010). Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nature Genetics, 42(3), 234-239. https://doi.org/10.1038/ng.536

@article{19589683d9524eb3a41c4b5b3e6ec5a0,

title = "Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions",

abstract = "Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 × 10 11; odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 × 10 4). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.",

author = "{Van Deerlin}, {Vivianna M.} and Sleiman, {Patrick M.A.} and Maria Martinez-Lage and Alice Chen-Plotkin and Wang, {Li San} and Graff-Radford, {Neill R.} and Dickson, {Dennis W.} and Rosa Rademakers and Boeve, {Bradley F.} and Murray Grossman and Arnold, {Steven E.} and Mann, {David M.A.} and Pickering-Brown, {Stuart M.} and Harro Seelaar and Peter Heutink and {Van Swieten}, {John C.} and Murrell, {Jill R.} and Bernardino Ghetti and Salvatore Spina and Jordan Grafman and John Hodges and Spillantini, {Maria Grazia} and Sid Gilman and Lieberman, {Andrew P.} and Kaye, {Jeffrey A.} and Woltjer, {Randall L.} and Bigio, {Eileen H.} and Marsel Mesulam and Safa Al-Sarraj and Claire Troakes and Rosenberg, {Roger N.} and White, {Charles L.} and Isidro Ferrer and Albert Llad{\'o} and Manuela Neumann and Kretzschmar, {Hans A.} and Hulette, {Christine Marie} and Welsh-Bohmer, {Kathleen A.} and Miller, {Bruce L.} and Ainhoa Alzualde and {De Munain}, {Adolfo Lopez} and McKee, {Ann C.} and Marla Gearing and Levey, {Allan I.} and Lah, {James J.} and John Hardy and Rohrer, {Jonathan D.} and Tammaryn Lashley and MacKenzie, {Ian R.A.} and Feldman, {Howard H.} and Hamilton, {Ronald L.} and Dekosky, {Steven T.} and {Van Der Zee}, Julie and Samir Kumar-Singh and {Van Broeckhoven}, Christine and Richard Mayeux and Vonsattel, {Jean Paul G.} and Troncoso, {Juan C.} and Kril, {Jillian J.} and Kwok, {John B.J.} and Halliday, {Glenda M.} and Bird, {Thomas D.} and Ince, {Paul G.} and Shaw, {Pamela J.} and Cairns, {Nigel J.} and Morris, {John C.} and McLean, {Catriona Ann} and Charles Decarli and Ellis, {William G.} and Freeman, {Stefanie H.} and Frosch, {Matthew P.} and Growdon, {John H.} and Perl, {Daniel P.} and Mary Sano and Bennett, {David A.} and Schneider, {Julie A.} and Beach, {Thomas G.} and Reiman, {Eric M.} and Woodruff, {Bryan K.} and Jeffrey Cummings and Vinters, {Harry V.} and Miller, {Carol A.} and Chui, {Helena C.} and Irina Alafuzoff and P{\"a}ivi Hartikainen and Danielle Seilhean and Douglas Galasko and Eliezer Masliah and Cotman, {Carl W.} and Tũ{\'o}n, {M. Teresa} and Mart{\'i}nez, {M. Cristina Caballero} and Munoz, {David G.} and Carroll, {Steven L.} and Daniel Marson and Riederer, {Peter F.} and Nenad Bogdanovic and Schellenberg, {Gerard D.} and Hakon Hakonarson and Trojanowski, {John Q.} and Lee, {Virginia M.Y.}",

note = "Funding Information: This project was enabled by the contributions and efforts of many individuals in several supportive capacities. Most importantly, we extend our appreciation to the study subjects and families who made this research possible. Extensive technical assistance was provided by R. Greene, T. Unger and C. Kim and study coordination was provided by E. McCarty Wood. The following individuals contributed through sample ascertainment, epidemiology, coordination, and/or clinical evaluation of cases: S.Weintraub, N. Johnson, C. Shaw, V. Haroutunian, R.C. Petersen, D.S. Knopman, K.A. Josephs, D. Neary, J. Snowden, J. Heidebrink, N. Barbas, R. Re{\~n}e, J.R. Burke, K. Hayden, J. Browndyke, P. Gaskell, M. Szymanski, J.D. Glass, M. Rossor, F. Moreno, B. Indakoetxea, M. Barandiaran, S. Engelborghs, P.P. De Deyn, W.S. Brooks, T. Chow, V. Meininger, L. Lacomblez and E. Gruenblatt. The following individuals contributed through pathological characterization and evaluation of cases: D. Clark, A. King, I. Bodi, D. Purohit, L. Kwong, J.E. Parisi, W. Kamphorst, I. Ruiz, T. Revesz, J.J. Martin, R. Highley and C. Duyckaerts. The following individuals contributed through general technical assistance and/or genetic studies: J. Kirby, E. Moore, M. Baker, R. Crook, S. Rollinson, N. Halliwell, S. Usher, R.M. Richardson, M. Mishra, C. Foong, J. Ervin, K. Price Bryan, J. Ervin, C. Kubilus, A. Gorostidi, M. Cruts, I. Gijselinck, H. McCann, P.R. Schofield, G. Forster, K. Firch, J. Pomaician, I. Leber, V. Sazdovitch and I. Volkmann. We also thank the Brain Bank of University of Barcelona, Hospital Clinic, Clinic for Alzheimer{\textquoteright}s Disease and Related Disorders University of British Columbia, Australian Brain Donor Programs supported by the National Health and Medical Research Council of Australia, Biobank at the Institute BornBunge, University of Antwerp, Antwerpen, Belgium and the French clinical and genetic research network on FTD/FTDmotor neuron disease (MND). Many grant funding agencies provided financial support for this study, including the US National Institutes of Health (NIH) (grant numbers AG10124, AG17586, AG16574, AG03949, AG17586, NS44266, AG15116, NS53488, AG10124, AG010133, AG08671, NS044233, NS15655, AG008017, AG13854, AG12300, AG028377, AG 019724, AG13846, AG025688, AG05133, AG08702, AG05146, AG005136, AG005681, AG03991, AG010129, AG05134, NS038372, AG02219, AG05138, AG10161, AG19610, AG19610, AG16570, AG16570, AG05142, AG005131, AG5131, AG18440, AG16582, AG16573, AG033101 and NIH Intramural Program). Additional funds were provided by Robert and Clarice Smith and Abigail Van Buren Alzheimer{\textquoteright}s Disease Research Program, the Pacific Alzheimer{\textquoteright}s disease Research Foundation (PARF) grant #C0601, the Alzheimer{\textquoteright}s Research Trust, Alzheimer{\textquoteright}s Society, Medical Research Council (Programme Grant and Returning Scientist Award), Stichting Dioraphte (07010500), Hersenstichting (15F07.2.34), Prinses Beatrix Fonds (0060204), Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, the McCune Foundation, Instituto Carlos III, Federal Ministry of Education and Research (01GI0505), SAIOTEK Program (Basque Government), Department of Innovation, Diputaci{\'o}n Foral de Gip{\'u}zkoa (DFG 0876/08), ILUNDAIN Fundazioa, Centro de Investigaciones Biomedicas en Red en Enfermededades Neurodegenerativas (CIBERNED), Wellcome Trust, Canadian Institutes of Health Research (75480), Fund for Scientific Research Flanders (FWOV), Alzheimer Research (SAO/FRMA), Interuniversity Attraction Poles (IAP) P6/43 network of the Belgian Science Policy Office (BELSPO), J.v.d.Z receives a postdoctoral fellowship from the FWOV, the Joseph Iseman Fund, the Louis and Rachel Rudin Foundation, National Health and Medical Research Council of Australia, Veteran{\textquoteright}s Affairs Research Funds, Arizona Department of Health Services (contract 211002, Arizona Alzheimer{\textquoteright}s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011 and 05901 to the Arizona Parkinson{\textquoteright}s Disease Consortium), the Prescott Family Initiative of the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research, the Daljits and Elaine Sarkara Chair in Diagnostic Medicine, BrainNet Europe II, Ministerio de Ciencia y Tecnolog{\'i}a, Ref Saud y Farmacia 2001–4888, Burroghs Wellcome Fund Career Award for Medical Scientists and Fundacion 'La Caxia'.",

year = "2010",

month = mar,

doi = "10.1038/ng.536",

language = "English",

volume = "42",

pages = "234--239",

journal = "Nature Genetics",

issn = "1061-4036",

number = "3",

}

Van Deerlin, VM, Sleiman, PMA, Martinez-Lage, M, Chen-Plotkin, A, Wang, LS, Graff-Radford, NR, Dickson, DW, Rademakers, R, Boeve, BF, Grossman, M, Arnold, SE, Mann, DMA, Pickering-Brown, SM, Seelaar, H, Heutink, P, Van Swieten, JC, Murrell, JR, Ghetti, B, Spina, S, Grafman, J, Hodges, J, Spillantini, MG, Gilman, S, Lieberman, AP, Kaye, JA, Woltjer, RL, Bigio, EH, Mesulam, M, Al-Sarraj, S, Troakes, C, Rosenberg, RN, White, CL, Ferrer, I, Lladó, A, Neumann, M, Kretzschmar, HA, Hulette, CM, Welsh-Bohmer, KA, Miller, BL, Alzualde, A, De Munain, AL, McKee, AC, Gearing, M, Levey, AI, Lah, JJ, Hardy, J, Rohrer, JD, Lashley, T, MacKenzie, IRA, Feldman, HH, Hamilton, RL, Dekosky, ST, Van Der Zee, J, Kumar-Singh, S, Van Broeckhoven, C, Mayeux, R, Vonsattel, JPG, Troncoso, JC, Kril, JJ, Kwok, JBJ, Halliday, GM, Bird, TD, Ince, PG, Shaw, PJ, Cairns, NJ, Morris, JC, McLean, CA, Decarli, C, Ellis, WG, Freeman, SH, Frosch, MP, Growdon, JH, Perl, DP, Sano, M, Bennett, DA, Schneider, JA, Beach, TG, Reiman, EM, Woodruff, BK, Cummings, J, Vinters, HV, Miller, CA, Chui, HC, Alafuzoff, I, Hartikainen, P, Seilhean, D, Galasko, D, Masliah, E, Cotman, CW, Tũón, MT, Martínez, MCC, Munoz, DG, Carroll, SL, Marson, D, Riederer, PF, Bogdanovic, N, Schellenberg, GD, Hakonarson, H, Trojanowski, JQ & Lee, VMY 2010, 'Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions', Nature Genetics, vol. 42, no. 3, pp. 234-239. https://doi.org/10.1038/ng.536

TY - JOUR

T1 - Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

AU - Van Deerlin, Vivianna M.

AU - Sleiman, Patrick M.A.

AU - Martinez-Lage, Maria

AU - Chen-Plotkin, Alice

AU - Wang, Li San

AU - Graff-Radford, Neill R.

AU - Dickson, Dennis W.

AU - Rademakers, Rosa

AU - Boeve, Bradley F.

AU - Grossman, Murray

AU - Arnold, Steven E.

AU - Mann, David M.A.

AU - Pickering-Brown, Stuart M.

AU - Seelaar, Harro

AU - Heutink, Peter

AU - Van Swieten, John C.

AU - Murrell, Jill R.

AU - Ghetti, Bernardino

AU - Spina, Salvatore

AU - Grafman, Jordan

AU - Hodges, John

AU - Spillantini, Maria Grazia

AU - Gilman, Sid

AU - Lieberman, Andrew P.

AU - Kaye, Jeffrey A.

AU - Woltjer, Randall L.

AU - Bigio, Eileen H.

AU - Mesulam, Marsel

AU - Al-Sarraj, Safa

AU - Troakes, Claire

AU - Rosenberg, Roger N.

AU - White, Charles L.

AU - Ferrer, Isidro

AU - Lladó, Albert

AU - Neumann, Manuela

AU - Kretzschmar, Hans A.

AU - Hulette, Christine Marie

AU - Welsh-Bohmer, Kathleen A.

AU - Miller, Bruce L.

AU - Alzualde, Ainhoa

AU - De Munain, Adolfo Lopez

AU - McKee, Ann C.

AU - Gearing, Marla

AU - Levey, Allan I.

AU - Lah, James J.

AU - Hardy, John

AU - Rohrer, Jonathan D.

AU - Lashley, Tammaryn

AU - MacKenzie, Ian R.A.

AU - Feldman, Howard H.

AU - Hamilton, Ronald L.

AU - Dekosky, Steven T.

AU - Van Der Zee, Julie

AU - Kumar-Singh, Samir

AU - Van Broeckhoven, Christine

AU - Mayeux, Richard

AU - Vonsattel, Jean Paul G.

AU - Troncoso, Juan C.

AU - Kril, Jillian J.

AU - Kwok, John B.J.

AU - Halliday, Glenda M.

AU - Bird, Thomas D.

AU - Ince, Paul G.

AU - Shaw, Pamela J.

AU - Cairns, Nigel J.

AU - Morris, John C.

AU - McLean, Catriona Ann

AU - Decarli, Charles

AU - Ellis, William G.

AU - Freeman, Stefanie H.

AU - Frosch, Matthew P.

AU - Growdon, John H.

AU - Perl, Daniel P.

AU - Sano, Mary

AU - Bennett, David A.

AU - Schneider, Julie A.

AU - Beach, Thomas G.

AU - Reiman, Eric M.

AU - Woodruff, Bryan K.

AU - Cummings, Jeffrey

AU - Vinters, Harry V.

AU - Miller, Carol A.

AU - Chui, Helena C.

AU - Alafuzoff, Irina

AU - Hartikainen, Päivi

AU - Seilhean, Danielle

AU - Galasko, Douglas

AU - Masliah, Eliezer

AU - Cotman, Carl W.

AU - Tũón, M. Teresa

AU - Martínez, M. Cristina Caballero

AU - Munoz, David G.

AU - Carroll, Steven L.

AU - Marson, Daniel

AU - Riederer, Peter F.

AU - Bogdanovic, Nenad

AU - Schellenberg, Gerard D.

AU - Hakonarson, Hakon

AU - Trojanowski, John Q.

AU - Lee, Virginia M.Y.

N1 - Funding Information: This project was enabled by the contributions and efforts of many individuals in several supportive capacities. Most importantly, we extend our appreciation to the study subjects and families who made this research possible. Extensive technical assistance was provided by R. Greene, T. Unger and C. Kim and study coordination was provided by E. McCarty Wood. The following individuals contributed through sample ascertainment, epidemiology, coordination, and/or clinical evaluation of cases: S.Weintraub, N. Johnson, C. Shaw, V. Haroutunian, R.C. Petersen, D.S. Knopman, K.A. Josephs, D. Neary, J. Snowden, J. Heidebrink, N. Barbas, R. Reñe, J.R. Burke, K. Hayden, J. Browndyke, P. Gaskell, M. Szymanski, J.D. Glass, M. Rossor, F. Moreno, B. Indakoetxea, M. Barandiaran, S. Engelborghs, P.P. De Deyn, W.S. Brooks, T. Chow, V. Meininger, L. Lacomblez and E. Gruenblatt. The following individuals contributed through pathological characterization and evaluation of cases: D. Clark, A. King, I. Bodi, D. Purohit, L. Kwong, J.E. Parisi, W. Kamphorst, I. Ruiz, T. Revesz, J.J. Martin, R. Highley and C. Duyckaerts. The following individuals contributed through general technical assistance and/or genetic studies: J. Kirby, E. Moore, M. Baker, R. Crook, S. Rollinson, N. Halliwell, S. Usher, R.M. Richardson, M. Mishra, C. Foong, J. Ervin, K. Price Bryan, J. Ervin, C. Kubilus, A. Gorostidi, M. Cruts, I. Gijselinck, H. McCann, P.R. Schofield, G. Forster, K. Firch, J. Pomaician, I. Leber, V. Sazdovitch and I. Volkmann. We also thank the Brain Bank of University of Barcelona, Hospital Clinic, Clinic for Alzheimer’s Disease and Related Disorders University of British Columbia, Australian Brain Donor Programs supported by the National Health and Medical Research Council of Australia, Biobank at the Institute BornBunge, University of Antwerp, Antwerpen, Belgium and the French clinical and genetic research network on FTD/FTDmotor neuron disease (MND). Many grant funding agencies provided financial support for this study, including the US National Institutes of Health (NIH) (grant numbers AG10124, AG17586, AG16574, AG03949, AG17586, NS44266, AG15116, NS53488, AG10124, AG010133, AG08671, NS044233, NS15655, AG008017, AG13854, AG12300, AG028377, AG 019724, AG13846, AG025688, AG05133, AG08702, AG05146, AG005136, AG005681, AG03991, AG010129, AG05134, NS038372, AG02219, AG05138, AG10161, AG19610, AG19610, AG16570, AG16570, AG05142, AG005131, AG5131, AG18440, AG16582, AG16573, AG033101 and NIH Intramural Program). Additional funds were provided by Robert and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program, the Pacific Alzheimer’s disease Research Foundation (PARF) grant #C0601, the Alzheimer’s Research Trust, Alzheimer’s Society, Medical Research Council (Programme Grant and Returning Scientist Award), Stichting Dioraphte (07010500), Hersenstichting (15F07.2.34), Prinses Beatrix Fonds (0060204), Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, the McCune Foundation, Instituto Carlos III, Federal Ministry of Education and Research (01GI0505), SAIOTEK Program (Basque Government), Department of Innovation, Diputación Foral de Gipúzkoa (DFG 0876/08), ILUNDAIN Fundazioa, Centro de Investigaciones Biomedicas en Red en Enfermededades Neurodegenerativas (CIBERNED), Wellcome Trust, Canadian Institutes of Health Research (75480), Fund for Scientific Research Flanders (FWOV), Alzheimer Research (SAO/FRMA), Interuniversity Attraction Poles (IAP) P6/43 network of the Belgian Science Policy Office (BELSPO), J.v.d.Z receives a postdoctoral fellowship from the FWOV, the Joseph Iseman Fund, the Louis and Rachel Rudin Foundation, National Health and Medical Research Council of Australia, Veteran’s Affairs Research Funds, Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011 and 05901 to the Arizona Parkinson’s Disease Consortium), the Prescott Family Initiative of the Michael J. Fox Foundation for Parkinson’s Research, the Daljits and Elaine Sarkara Chair in Diagnostic Medicine, BrainNet Europe II, Ministerio de Ciencia y Tecnología, Ref Saud y Farmacia 2001–4888, Burroghs Wellcome Fund Career Award for Medical Scientists and Fundacion 'La Caxia'.

PY - 2010/3

Y1 - 2010/3

N2 - Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 × 10 11; odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 × 10 4). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

AB - Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 × 10 11; odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 × 10 4). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

UR - http://www.scopus.com/inward/record.url?scp=77649136250&partnerID=8YFLogxK

U2 - 10.1038/ng.536

DO - 10.1038/ng.536

M3 - Article

C2 - 20154673

AN - SCOPUS:77649136250

SN - 1061-4036

VL - 42

SP - 234

EP - 239

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

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