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

VM Van Deerlin; PMA Sleiman; M Martinez-Lage; A Chen-Plotkin; LS (Li-San) Wang; NR Graff-Radford; DW Dickson; R Rademakers; BF Boeve; M Grossman; SE Arnold; DMA Mann; SM Pickering-Brown; Harro Seelaar; P Heutink; J.C. van Swieten; JR Murrell; B Ghetti; S Spina; J Grafman; J Hodges; MG Spillantini; S Gilman; AP Lieberman; JA Kaye; RL Woltjer; EH Bigio; M Mesulam; S Al-Sarraj; C Troakes; RN Rosenberg; CL White; I Ferrer; A Llado; M (Manuela) Neumann; HA Kretzschmar; CM Hulette; KA Welsh-Bohmer; BL Miller; A Alzualde; AL de Munain; AC McKee; M Gearing; AI Levey; JJ Lah; J Hardy; JD Rohrer; T Lashley; IRA Mackenzie; HH Feldman; RL Hamilton; ST DeKosky; JA Zee; S Kumar-Singh; C van Broeckhoven; R Mayeux; JPG Vonsattel; JC Troncoso; JJ Kril; JBJ Kwok; GM Halliday; TD Bird; PG Ince; PJ Shaw; NJ Cairns; JC Morris; CA McLean; C DeCarli; WG Ellis; SH Freeman; MP Frosch; JH Growdon; DP Perl; M Sano; DA Bennett; JA Schneider; TG Beach; EM Reiman; BK Woodruff; J Cummings; HV Vinters; CA Miller; HC Chui; I Alafuzoff; P Hartikainen; D Seilhean; D Galasko; E Masliah; CW Cotman; MT Tunon; MCC Martinez; DG Munoz; SL Carroll; D Marson; PF Riederer; N Bogdanovic; GD Schellenberg; H Hakonarson; JQ Trojanowski; VMY Lee

doi:10.1038/ng.536

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

VM Van Deerlin, PMA Sleiman, M Martinez-Lage, A Chen-Plotkin, LS (Li-San) Wang, NR Graff-Radford, DW Dickson, R Rademakers, BF Boeve, M Grossman, SE Arnold, DMA Mann, SM Pickering-Brown, Harro Seelaar, P Heutink, J.C. van Swieten, JR Murrell, B Ghetti, S Spina, J GrafmanJ Hodges, MG Spillantini, S Gilman, AP Lieberman, JA Kaye, RL Woltjer, EH Bigio, M Mesulam, S Al-Sarraj, C Troakes, RN Rosenberg, CL White, I Ferrer, A Llado, M (Manuela) Neumann, HA Kretzschmar, CM Hulette, KA Welsh-Bohmer, BL Miller, A Alzualde, AL de Munain, AC McKee, M Gearing, AI Levey, JJ Lah, J Hardy, JD Rohrer, T Lashley, IRA Mackenzie, HH Feldman, RL Hamilton, ST DeKosky, JA Zee, S Kumar-Singh, C van Broeckhoven, R Mayeux, JPG Vonsattel, JC Troncoso, JJ Kril, JBJ Kwok, GM Halliday, TD Bird, PG Ince, PJ Shaw, NJ Cairns, JC Morris, CA McLean, C DeCarli, WG Ellis, SH Freeman, MP Frosch, JH Growdon, DP Perl, M Sano, DA Bennett, JA Schneider, TG Beach, EM Reiman, BK Woodruff, J Cummings, HV Vinters, CA Miller, HC Chui, I Alafuzoff, P Hartikainen, D Seilhean, D Galasko, E Masliah, CW Cotman, MT Tunon, MCC Martinez, DG Munoz, SL Carroll, D Marson, PF Riederer, N Bogdanovic, GD Schellenberg, H Hakonarson, JQ Trojanowski, VMY Lee

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

353 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 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	Undefined/Unknown
Pages (from-to)	234-U34
Number of pages	8
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, 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, J. C., Murrell, JR., Ghetti, B., Spina, S., ... Lee, VMY. (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

Van Deerlin, VM ; Sleiman, PMA ; Martinez-Lage, M ; Chen-Plotkin, A ; Wang, LS (Li-San) ; Graff-Radford, NR ; Dickson, DW ; Rademakers, R ; Boeve, BF ; Grossman, M ; Arnold, SE ; Mann, DMA ; Pickering-Brown, SM ; Seelaar, Harro ; Heutink, P ; van Swieten, J.C. ; 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 (Manuela) ; 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 ; Zee, JA ; 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, VMY. / Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions. In: Nature Genetics. 2010 ; Vol. 42, No. 3. pp. 234-U34.

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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}, VM and PMA Sleiman and M Martinez-Lage and A Chen-Plotkin and Wang, {LS (Li-San)} and NR Graff-Radford and DW Dickson and R Rademakers and BF Boeve and M Grossman and SE Arnold and DMA Mann and SM Pickering-Brown and Harro Seelaar and P Heutink and {van Swieten}, J.C. and JR Murrell and B Ghetti and S Spina and J Grafman and J Hodges and MG Spillantini and S Gilman and AP Lieberman and JA Kaye and RL Woltjer and EH Bigio and M Mesulam and S Al-Sarraj and C Troakes and RN Rosenberg and CL White and I Ferrer and A Llado and Neumann, {M (Manuela)} and HA Kretzschmar and CM Hulette and KA Welsh-Bohmer and BL Miller and A Alzualde and {de Munain}, AL and AC McKee and M Gearing and AI Levey and JJ Lah and J Hardy and JD Rohrer and T Lashley and IRA Mackenzie and HH Feldman and RL Hamilton and ST DeKosky and JA Zee and S Kumar-Singh and {van Broeckhoven}, C and R Mayeux and JPG Vonsattel and JC Troncoso and JJ Kril and JBJ Kwok and GM Halliday and TD Bird and PG Ince and PJ Shaw and NJ Cairns and JC Morris and CA McLean and C DeCarli and WG Ellis and SH Freeman and MP Frosch and JH Growdon and DP Perl and M Sano and DA Bennett and JA Schneider and TG Beach and EM Reiman and BK Woodruff and J Cummings and HV Vinters and CA Miller and HC Chui and I Alafuzoff and P Hartikainen and D Seilhean and D Galasko and E Masliah and CW Cotman and MT Tunon and MCC Martinez and DG Munoz and SL Carroll and D Marson and PF Riederer and N Bogdanovic and GD Schellenberg and H Hakonarson and JQ Trojanowski and VMY Lee",

year = "2010",

doi = "10.1038/ng.536",

language = "Undefined/Unknown",

volume = "42",

pages = "234--U34",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "3",

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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, Llado, 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, Zee, JA, 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, VMY 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

Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions. / Van Deerlin, VM; Sleiman, PMA; Martinez-Lage, M; Chen-Plotkin, A; Wang, LS (Li-San); Graff-Radford, NR; Dickson, DW; Rademakers, R; Boeve, BF; Grossman, M; Arnold, SE; Mann, DMA; Pickering-Brown, SM; Seelaar, Harro; Heutink, P; van Swieten, J.C.; 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 (Manuela); 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; Zee, JA; 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, VMY.

In: Nature Genetics, Vol. 42, No. 3, 2010, p. 234-U34.

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

TY - JOUR

T1 - Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions

AU - Van Deerlin, VM

AU - Sleiman, PMA

AU - Martinez-Lage, M

AU - Chen-Plotkin, A

AU - Wang, LS (Li-San)

AU - Graff-Radford, NR

AU - Dickson, DW

AU - Rademakers, R

AU - Boeve, BF

AU - Grossman, M

AU - Arnold, SE

AU - Mann, DMA

AU - Pickering-Brown, SM

AU - Seelaar, Harro

AU - Heutink, P

AU - van Swieten, J.C.

AU - Murrell, JR

AU - Ghetti, B

AU - Spina, S

AU - Grafman, J

AU - Hodges, J

AU - Spillantini, MG

AU - Gilman, S

AU - Lieberman, AP

AU - Kaye, JA

AU - Woltjer, RL

AU - Bigio, EH

AU - Mesulam, M

AU - Al-Sarraj, S

AU - Troakes, C

AU - Rosenberg, RN

AU - White, CL

AU - Ferrer, I

AU - Llado, A

AU - Neumann, M (Manuela)

AU - Kretzschmar, HA

AU - Hulette, CM

AU - Welsh-Bohmer, KA

AU - Miller, BL

AU - Alzualde, A

AU - de Munain, AL

AU - McKee, AC

AU - Gearing, M

AU - Levey, AI

AU - Lah, JJ

AU - Hardy, J

AU - Rohrer, JD

AU - Lashley, T

AU - Mackenzie, IRA

AU - Feldman, HH

AU - Hamilton, RL

AU - DeKosky, ST

AU - Zee, JA

AU - Kumar-Singh, S

AU - van Broeckhoven, C

AU - Mayeux, R

AU - Vonsattel, JPG

AU - Troncoso, JC

AU - Kril, JJ

AU - Kwok, JBJ

AU - Halliday, GM

AU - Bird, TD

AU - Ince, PG

AU - Shaw, PJ

AU - Cairns, NJ

AU - Morris, JC

AU - McLean, CA

AU - DeCarli, C

AU - Ellis, WG

AU - Freeman, SH

AU - Frosch, MP

AU - Growdon, JH

AU - Perl, DP

AU - Sano, M

AU - Bennett, DA

AU - Schneider, JA

AU - Beach, TG

AU - Reiman, EM

AU - Woodruff, BK

AU - Cummings, J

AU - Vinters, HV

AU - Miller, CA

AU - Chui, HC

AU - Alafuzoff, I

AU - Hartikainen, P

AU - Seilhean, D

AU - Galasko, D

AU - Masliah, E

AU - Cotman, CW

AU - Tunon, MT

AU - Martinez, MCC

AU - Munoz, DG

AU - Carroll, SL

AU - Marson, D

AU - Riederer, PF

AU - Bogdanovic, N

AU - Schellenberg, GD

AU - Hakonarson, H

AU - Trojanowski, JQ

AU - Lee, VMY

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 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

VL - 42

SP - 234-U34

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 3

ER -