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

Vivianna Van Deerlin; Patrick Sleiman; Maria Marinez-Lage; Alice Chen-Plotkin; Li-San Wang; Neill Graff-Radford; Dennis Dickson; Rosa Rademakers; Bradley Boeve; Murray Grossman; Steve Arnold; David Mann; Stuart Pickering-Brown; Harro Seelaar; Peter Heutink; John C van Swieten; Jill Murrell; Bernardino Ghetti; Salvatore Spina; Jordan Grafman; John Hodges; Maria Spillantini; Sid Gilman; Andrew Lieberman; Jeffrey Kaye; Randall Woltjer; Eileen Bigio; Marsel Mesulam; Safa al-Sarraj; Claire Troakes; Roger Rosenberg; Charles L White III; Isidro Ferrer; Albert Llado; Manuela Neumann; Hans Kretzschmar; Christine Hulette; Kathleen Welsh-Bohmer; Bruce Miller; Ainhoa Alzualde; Adolfo de Munain; Ann McKee; Marla Gearing; Allan Levey; James Lah; John Hardy; Jonathan Rohrer; Tammaryn Lashley; Ian Mackenzie; Howard Feldman; Ronald Hamilton; Steven Dekosky; Julie van der Zee; Samir Kumar-Singh; Christine Van Broeckhoven; Richard Mayeux; Jean Vonsattel; Juan Troncoso; Jillian Kril; John Kwok; Glenda Halliday; Thomas Bird; Paul Ince; Pamela Shaw; Nigel Cairns; John Morris; Catriona Ann McLean; Charles DeCarli; William Ellis; Stephanie Freeman; Matthew Frosch; John Growdon; Daniel Perl; Mary Sano; David Bennett; Julie Schneider; Thomas Beach; Eric Reiman; Brian Woodruff; Jeffrey Cummings; Harry Vinters; Carol Miller; Helena Chui; Irina Alafuzoff; Paivi Harkinkainen; Danielle Seilhean; Douglas Galasko; Eliezer Masliah; Carl Cotman; Maria Tunon; M 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 TDP-43 inclusions

Vivianna Van Deerlin, Patrick Sleiman, Maria Marinez-Lage, Alice Chen-Plotkin, Li-San Wang, Neill Graff-Radford, Dennis Dickson, Rosa Rademakers, Bradley Boeve, Murray Grossman, Steve Arnold, David Mann, Stuart Pickering-Brown, Harro Seelaar, Peter Heutink, John C van Swieten, Jill Murrell, Bernardino Ghetti, Salvatore Spina, Jordan GrafmanJohn Hodges, Maria Spillantini, Sid Gilman, Andrew Lieberman, Jeffrey Kaye, Randall Woltjer, Eileen Bigio, Marsel Mesulam, Safa al-Sarraj, Claire Troakes, Roger Rosenberg, Charles L White III, Isidro Ferrer, Albert Llado, Manuela Neumann, Hans Kretzschmar, Christine Hulette, Kathleen Welsh-Bohmer, Bruce Miller, Ainhoa Alzualde, Adolfo de Munain, Ann McKee, Marla Gearing, Allan Levey, James Lah, John Hardy, Jonathan Rohrer, Tammaryn Lashley, Ian Mackenzie, Howard Feldman, Ronald Hamilton, Steven Dekosky, Julie van der Zee, Samir Kumar-Singh, Christine Van Broeckhoven, Richard Mayeux, Jean Vonsattel, Juan Troncoso, Jillian Kril, John Kwok, Glenda Halliday, Thomas Bird, Paul Ince, Pamela Shaw, Nigel Cairns, John Morris, Catriona Ann McLean, Charles DeCarli, William Ellis, Stephanie Freeman, Matthew Frosch, John Growdon, Daniel Perl, Mary Sano, David Bennett, Julie Schneider, Thomas Beach, Eric Reiman, Brian Woodruff, Jeffrey Cummings, Harry Vinters, Carol Miller, Helena Chui, Irina Alafuzoff, Paivi Harkinkainen, Danielle Seilhean, Douglas Galasko, Eliezer Masliah, Carl Cotman, Maria Tunon, M 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

Medicine Alfred Hospital

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

500 Citations (Scopus)

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 i?? 10-11; odds ratio, minor allele (C) 0.61, 95 CI 0.53i??0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 i?? 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
Publication status	Published - 2010

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Van Deerlin, V., Sleiman, P., Marinez-Lage, M., Chen-Plotkin, A., Wang, L.-S., Graff-Radford, N., Dickson, D., Rademakers, R., Boeve, B., Grossman, M., Arnold, S., Mann, D., Pickering-Brown, S., Seelaar, H., Heutink, P., van Swieten, J. C., Murrell, J., 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{1b7afc815e534735be1deeddb0be865c,

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)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 i?? 10-11; odds ratio, minor allele (C) 0.61, 95 CI 0.53i??0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 i?? 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 and Patrick Sleiman and Maria Marinez-Lage and Alice Chen-Plotkin and Li-San Wang and Neill Graff-Radford and Dennis Dickson and Rosa Rademakers and Bradley Boeve and Murray Grossman and Steve Arnold and David Mann and Stuart Pickering-Brown and Harro Seelaar and Peter Heutink and \{van Swieten\}, \{John C\} and Jill Murrell and Bernardino Ghetti and Salvatore Spina and Jordan Grafman and John Hodges and Maria Spillantini and Sid Gilman and Andrew Lieberman and Jeffrey Kaye and Randall Woltjer and Eileen Bigio and Marsel Mesulam and Safa al-Sarraj and Claire Troakes and Roger Rosenberg and \{White III\}, \{Charles L\} and Isidro Ferrer and Albert Llado and Manuela Neumann and Hans Kretzschmar and Christine Hulette and Kathleen Welsh-Bohmer and Bruce Miller and Ainhoa Alzualde and \{de Munain\}, Adolfo and Ann McKee and Marla Gearing and Allan Levey and James Lah and John Hardy and Jonathan Rohrer and Tammaryn Lashley and Ian Mackenzie and Howard Feldman and Ronald Hamilton and Steven Dekosky and \{van der Zee\}, Julie and Samir Kumar-Singh and \{Van Broeckhoven\}, Christine and Richard Mayeux and Jean Vonsattel and Juan Troncoso and Jillian Kril and John Kwok and Glenda Halliday and Thomas Bird and Paul Ince and Pamela Shaw and Nigel Cairns and John Morris and McLean, \{Catriona Ann\} and Charles DeCarli and William Ellis and Stephanie Freeman and Matthew Frosch and John Growdon and Daniel Perl and Mary Sano and David Bennett and Julie Schneider and Thomas Beach and Eric Reiman and Brian Woodruff and Jeffrey Cummings and Harry Vinters and Carol Miller and Helena Chui and Irina Alafuzoff and Paivi Harkinkainen and Danielle Seilhean and Douglas Galasko and Eliezer Masliah and Carl Cotman and Maria Tunon and \{Caballero Martinez\}, M 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",

doi = "10.1038/ng.536",

language = "English",

volume = "42",

pages = "234 -- 239",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "3",

}

Van Deerlin, V, Sleiman, P, Marinez-Lage, M, Chen-Plotkin, A, Wang, L-S, Graff-Radford, N, Dickson, D, Rademakers, R, Boeve, B, Grossman, M, Arnold, S, Mann, D, Pickering-Brown, S, Seelaar, H, Heutink, P, van Swieten, JC, Murrell, J, Ghetti, B, Spina, S, Grafman, J, Hodges, J, Spillantini, M, Gilman, S, Lieberman, A, Kaye, J, Woltjer, R, Bigio, E, Mesulam, M, al-Sarraj, S, Troakes, C, Rosenberg, R, White III, CL, Ferrer, I, Llado, A, Neumann, M, Kretzschmar, H, Hulette, C, Welsh-Bohmer, K, Miller, B, Alzualde, A, de Munain, A, McKee, A, Gearing, M, Levey, A, Lah, J, Hardy, J, Rohrer, J, Lashley, T, Mackenzie, I, Feldman, H, Hamilton, R, Dekosky, S, van der Zee, J, Kumar-Singh, S, Van Broeckhoven, C, Mayeux, R, Vonsattel, J, Troncoso, J, Kril, J, Kwok, J, Halliday, G, Bird, T, Ince, P, Shaw, P, Cairns, N, Morris, J, McLean, CA, DeCarli, C, Ellis, W, Freeman, S, Frosch, M, Growdon, J, Perl, D, Sano, M, Bennett, D, Schneider, J, Beach, T, Reiman, E, Woodruff, B, Cummings, J, Vinters, H, Miller, C, Chui, H, Alafuzoff, I, Harkinkainen, P, Seilhean, D, Galasko, D, Masliah, E, Cotman, C, Tunon, M, Caballero Martinez, M, 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 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

AU - Sleiman, Patrick

AU - Marinez-Lage, Maria

AU - Chen-Plotkin, Alice

AU - Wang, Li-San

AU - Graff-Radford, Neill

AU - Dickson, Dennis

AU - Rademakers, Rosa

AU - Boeve, Bradley

AU - Grossman, Murray

AU - Arnold, Steve

AU - Mann, David

AU - Pickering-Brown, Stuart

AU - Seelaar, Harro

AU - Heutink, Peter

AU - van Swieten, John C

AU - Murrell, Jill

AU - Ghetti, Bernardino

AU - Spina, Salvatore

AU - Grafman, Jordan

AU - Hodges, John

AU - Spillantini, Maria

AU - Gilman, Sid

AU - Lieberman, Andrew

AU - Kaye, Jeffrey

AU - Woltjer, Randall

AU - Bigio, Eileen

AU - Mesulam, Marsel

AU - al-Sarraj, Safa

AU - Troakes, Claire

AU - Rosenberg, Roger

AU - White III, Charles L

AU - Ferrer, Isidro

AU - Llado, Albert

AU - Neumann, Manuela

AU - Kretzschmar, Hans

AU - Hulette, Christine

AU - Welsh-Bohmer, Kathleen

AU - Miller, Bruce

AU - Alzualde, Ainhoa

AU - de Munain, Adolfo

AU - McKee, Ann

AU - Gearing, Marla

AU - Levey, Allan

AU - Lah, James

AU - Hardy, John

AU - Rohrer, Jonathan

AU - Lashley, Tammaryn

AU - Mackenzie, Ian

AU - Feldman, Howard

AU - Hamilton, Ronald

AU - Dekosky, Steven

AU - van der Zee, Julie

AU - Kumar-Singh, Samir

AU - Van Broeckhoven, Christine

AU - Mayeux, Richard

AU - Vonsattel, Jean

AU - Troncoso, Juan

AU - Kril, Jillian

AU - Kwok, John

AU - Halliday, Glenda

AU - Bird, Thomas

AU - Ince, Paul

AU - Shaw, Pamela

AU - Cairns, Nigel

AU - Morris, John

AU - McLean, Catriona Ann

AU - DeCarli, Charles

AU - Ellis, William

AU - Freeman, Stephanie

AU - Frosch, Matthew

AU - Growdon, John

AU - Perl, Daniel

AU - Sano, Mary

AU - Bennett, David

AU - Schneider, Julie

AU - Beach, Thomas

AU - Reiman, Eric

AU - Woodruff, Brian

AU - Cummings, Jeffrey

AU - Vinters, Harry

AU - Miller, Carol

AU - Chui, Helena

AU - Alafuzoff, Irina

AU - Harkinkainen, Paivi

AU - Seilhean, Danielle

AU - Galasko, Douglas

AU - Masliah, Eliezer

AU - Cotman, Carl

AU - Tunon, Maria

AU - Caballero Martinez, M

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

Y1 - 2010

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 i?? 10-11; odds ratio, minor allele (C) 0.61, 95 CI 0.53i??0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 i?? 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 i?? 10-11; odds ratio, minor allele (C) 0.61, 95 CI 0.53i??0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 i?? 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.nature.com/ng/journal/v42/n3/abs/ng.536.html#supplementary-information

UR - https://www.scopus.com/pages/publications/77649136250

U2 - 10.1038/ng.536

DO - 10.1038/ng.536

M3 - Article

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

Abstract

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