Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 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 Llado; 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; Paivi Hartikainen; Danielle Seilhean; Douglas Galasko; Eliezer Masliah; Carl W. Cotman; M. Teresa Tunon; M. Cristina Caballero Martinez; 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 TDP43 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 Llado, 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, Paivi Hartikainen, Danielle Seilhean, Douglas Galasko, Eliezer Masliah, Carl W. Cotman, M. Teresa Tunon, M. Cristina Caballero Martinez, 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

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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) 1. 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 x 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 x 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 - U34
Number of pages	6
Journal	Nature Genetics
Volume	42
Issue number	3
DOIs	https://doi.org/10.1038/ng.536
Publication status	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 TDP43 inclusions. Nature Genetics, 42(3), 234 - U34. https://doi.org/10.1038/ng.536

@article{3bec3b9423df48ae82f5c8c614ae3971,

title = "Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 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) 1. 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 x 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 x 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 Li-San Wang 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 Llado and Manuela Neumann and Kretzschmar, {Hans A.} and Hulette, {Christine Marie} and Welsh-Bohmer, {Kathleen A.} and Miller, {Bruce L.} and Ainhoa Alzualde and {Lopez de Munain}, Adolfo 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 Paivi Hartikainen and Danielle Seilhean and Douglas Galasko and Eliezer Masliah and Cotman, {Carl W.} and Tunon, {M. Teresa} and Martinez, {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}",

year = "2010",

month = mar,

doi = "10.1038/ng.536",

language = "English",

volume = "42",

pages = "234 -- U34",

journal = "Nature Genetics",

issn = "1546-1718",

publisher = "Nature Research",

number = "3",

}

Van Deerlin, VM, Sleiman, PMA, Martinez-Lage, M, Chen-Plotkin, A, Wang, L-S, 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, Llado, A, Neumann, M, Kretzschmar, HA, Hulette, CM, Welsh-Bohmer, KA, Miller, BL, Alzualde, A, Lopez de Munain, A, 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, Tunon, MT, Martinez, MCC, Munoz, DG, Carroll, SL, Marson, D, Riederer, PF, Bogdanovic, N, Schellenberg, GD, Hakonarson, H, Trojanowski, JQ & Lee, VM-Y 2010, 'Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions', Nature Genetics, vol. 42, no. 3, pp. 234 - U34. https://doi.org/10.1038/ng.536

TY - JOUR

T1 - Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 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 - Llado, 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 - Lopez de Munain, Adolfo

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, Paivi

AU - Seilhean, Danielle

AU - Galasko, Douglas

AU - Masliah, Eliezer

AU - Cotman, Carl W.

AU - Tunon, M. Teresa

AU - Martinez, 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

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) 1. 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 x 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 x 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) 1. 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 x 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 x 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.

U2 - 10.1038/ng.536

DO - 10.1038/ng.536

M3 - Article

SN - 1546-1718

VL - 42

SP - 234 - U34

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions

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