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

Neurology

Research output: Contribution to journal › Article

294 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 (US)
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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Genetics

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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

Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. / Van Deerlin, Vivianna M.; Sleiman, Patrick M A; Martinez-Lage, Maria; Chen-Plotkin, Alice; Wang, Li San; Graff-Radford, Neill R.; Dickson, Dennis W.; Rademakers, Rosa; Boeve, Bradley F.; Grossman, Murray; Arnold, Steven E.; Mann, David M A; Pickering-Brown, Stuart M.; Seelaar, Harro; Heutink, Peter; Van Swieten, John C.; Murrell, Jill R.; Ghetti, Bernardino; Spina, Salvatore; Grafman, Jordan; Hodges, John; Spillantini, Maria Grazia; Gilman, Sid; Lieberman, Andrew P.; Kaye, Jeffrey A.; Woltjer, Randall L.; Bigio, Eileen H.; Mesulam, Marsel; Al-Sarraj, Safa; Troakes, Claire; Rosenberg, Roger N.; White, Charles L.; Ferrer, Isidro; Lladó, Albert; Neumann, Manuela; Kretzschmar, Hans A.; Hulette, Christine Marie; Welsh-Bohmer, Kathleen A.; Miller, Bruce L.; Alzualde, Ainhoa; De Munain, Adolfo Lopez; McKee, Ann C.; Gearing, Marla; Levey, Allan I.; Lah, James J.; Hardy, John; Rohrer, Jonathan D.; Lashley, Tammaryn; MacKenzie, Ian R A; Feldman, Howard H.; Hamilton, Ronald L.; Dekosky, Steven T.; Van Der Zee, Julie; Kumar-Singh, Samir; Van Broeckhoven, Christine; Mayeux, Richard; Vonsattel, Jean Paul G; Troncoso, Juan C.; Kril, Jillian J.; Kwok, John B J; Halliday, Glenda M.; Bird, Thomas D.; Ince, Paul G.; Shaw, Pamela J.; Cairns, Nigel J.; Morris, John C.; McLean, Catriona Ann; DeCarli, Charles; Ellis, William G.; Freeman, Stefanie H.; Frosch, Matthew P.; Growdon, John H.; Perl, Daniel P.; Sano, Mary; Bennett, David A.; Schneider, Julie A.; Beach, Thomas G.; Reiman, Eric M.; Woodruff, Bryan K.; Cummings, Jeffrey; Vinters, Harry V.; Miller, Carol A.; Chui, Helena C.; Alafuzoff, Irina; Hartikainen, Päivi; Seilhean, Danielle; Galasko, Douglas; Masliah, Eliezer; Cotman, Carl W.; Tũón, M. Teresa; Martínez, M. Cristina Caballero; Munoz, David G.; Carroll, Steven L.; Marson, Daniel; Riederer, Peter F.; Bogdanovic, Nenad; Schellenberg, Gerard D.; Hakonarson, Hakon; Trojanowski, John Q.; Lee, Virginia M Y.

In: Nature Genetics, Vol. 42, No. 3, 03.2010, p. 234-239.

Research output: Contribution to journal › Article

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

Van Deerlin, Vivianna M. ; Sleiman, Patrick M A ; Martinez-Lage, Maria ; Chen-Plotkin, Alice ; Wang, Li San ; Graff-Radford, Neill R. ; Dickson, Dennis W. ; Rademakers, Rosa ; Boeve, Bradley F. ; Grossman, Murray ; Arnold, Steven E. ; Mann, David M A ; Pickering-Brown, Stuart M. ; Seelaar, Harro ; Heutink, Peter ; Van Swieten, John C. ; Murrell, Jill R. ; Ghetti, Bernardino ; Spina, Salvatore ; Grafman, Jordan ; Hodges, John ; Spillantini, Maria Grazia ; Gilman, Sid ; Lieberman, Andrew P. ; Kaye, Jeffrey A. ; Woltjer, Randall L. ; Bigio, Eileen H. ; Mesulam, Marsel ; Al-Sarraj, Safa ; Troakes, Claire ; Rosenberg, Roger N. ; White, Charles L. ; Ferrer, Isidro ; Lladó, Albert ; Neumann, Manuela ; Kretzschmar, Hans A. ; Hulette, Christine Marie ; Welsh-Bohmer, Kathleen A. ; Miller, Bruce L. ; Alzualde, Ainhoa ; De Munain, Adolfo Lopez ; McKee, Ann C. ; Gearing, Marla ; Levey, Allan I. ; Lah, James J. ; Hardy, John ; Rohrer, Jonathan D. ; Lashley, Tammaryn ; MacKenzie, Ian R A ; Feldman, Howard H. ; Hamilton, Ronald L. ; Dekosky, Steven T. ; Van Der Zee, Julie ; Kumar-Singh, Samir ; Van Broeckhoven, Christine ; Mayeux, Richard ; Vonsattel, Jean Paul G ; Troncoso, Juan C. ; Kril, Jillian J. ; Kwok, John B J ; Halliday, Glenda M. ; Bird, Thomas D. ; Ince, Paul G. ; Shaw, Pamela J. ; Cairns, Nigel J. ; Morris, John C. ; McLean, Catriona Ann ; DeCarli, Charles ; Ellis, William G. ; Freeman, Stefanie H. ; Frosch, Matthew P. ; Growdon, John H. ; Perl, Daniel P. ; Sano, Mary ; Bennett, David A. ; Schneider, Julie A. ; Beach, Thomas G. ; Reiman, Eric M. ; Woodruff, Bryan K. ; Cummings, Jeffrey ; Vinters, Harry V. ; Miller, Carol A. ; Chui, Helena C. ; Alafuzoff, Irina ; Hartikainen, Päivi ; Seilhean, Danielle ; Galasko, Douglas ; Masliah, Eliezer ; Cotman, Carl W. ; Tũón, M. Teresa ; Martínez, M. Cristina Caballero ; Munoz, David G. ; Carroll, Steven L. ; Marson, Daniel ; Riederer, Peter F. ; Bogdanovic, Nenad ; Schellenberg, Gerard D. ; Hakonarson, Hakon ; Trojanowski, John Q. ; Lee, Virginia M Y. / Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. In: Nature Genetics. 2010 ; Vol. 42, No. 3. pp. 234-239.

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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.",

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doi = "10.1038/ng.536",

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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.

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AU - Perl, Daniel P.

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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

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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.

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