Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis

Beben Benyamin; Ji He; Qiongyi Zhao; Jacob Gratten; Fleur Garton; Paul J. Leo; Zhijun Liu; Marie Mangelsdorf; Ammar Al-Chalabi; Lisa Anderson; Timothy J. Butler; Lu Chen; Xiang Ding Chen; Katie Cremin; Hong Weng Deng; Matthew Devine; Janette Edson; Jennifer A. Fifita; Sarah Furlong; Ying Ying Han; Jessica Harris; Anjali K. Henders; Rosalind L. Jeffree; Zi Bing Jin; Zhongshan Li; Ting Li; Mengmeng Li; Yong Lin; Xiaolu Liu; Mhairi Marshall; Emily P. McCann; Bryan J. Mowry; Shyuan T. Ngo; Roger Pamphlett; Shu Ran; David C. Reutens; Dominic B. Rowe; Perminder Sachdev; Sonia Shah; Sharon Song; Li Jun Tan; Lu Tang; Leonard H. Van Den Berg; Wouter Van Rheenen; Jan H. Veldink; Robyn H. Wallace; Lawrie Wheeler; Kelly L. Williams; Jinyu Wu; Xin Wu; Jian Yang; Weihua Yue; Zong Hong Zhang; Dai Zhang; Peter G. Noakes; Ian P. Blair; Robert D. Henderson; Pamela A. McCombe; Peter M. Visscher; Huji Xu; Perry F. Bartlett; Matthew A. Brown; Naomi R. Wray; Dongsheng Fan

doi:10.1038/s41467-017-00471-1

Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis

Beben Benyamin, Ji He, Qiongyi Zhao, Jacob Gratten, Fleur Garton, Paul J. Leo, Zhijun Liu, Marie Mangelsdorf, Ammar Al-Chalabi, Lisa Anderson, Timothy J. Butler, Lu Chen, Xiang Ding Chen, Katie Cremin, Hong Weng Deng, Matthew Devine, Janette Edson, Jennifer A. Fifita, Sarah Furlong, Ying Ying HanJessica Harris, Anjali K. Henders, Rosalind L. Jeffree, Zi Bing Jin, Zhongshan Li, Ting Li, Mengmeng Li, Yong Lin, Xiaolu Liu, Mhairi Marshall, Emily P. McCann, Bryan J. Mowry, Shyuan T. Ngo, Roger Pamphlett, Shu Ran, David C. Reutens, Dominic B. Rowe, Perminder Sachdev, Sonia Shah, Sharon Song, Li Jun Tan, Lu Tang, Leonard H. Van Den Berg, Wouter Van Rheenen, Jan H. Veldink, Robyn H. Wallace, Lawrie Wheeler, Kelly L. Williams, Jinyu Wu, Xin Wu, Jian Yang, Weihua Yue, Zong Hong Zhang, Dai Zhang, Peter G. Noakes, Ian P. Blair, Robert D. Henderson, Pamela A. McCombe, Peter M. Visscher, Huji Xu, Perry F. Bartlett, Matthew A. Brown, Naomi R. Wray, Dongsheng Fan

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Abstract

Cross-ethnic genetic studies can leverage power from differences in disease epidemiology and population-specific genetic architecture. In particular, the differences in linkage disequilibrium and allele frequency patterns across ethnic groups may increase gene-mapping resolution. Here we use cross-ethnic genetic data in sporadic amyotrophic lateral sclerosis (ALS), an adult-onset, rapidly progressing neurodegenerative disease. We report analyses of novel genome-wide association study data of 1,234 ALS cases and 2,850 controls. We find a significant association of rs10463311 spanning GPX3-TNIP1 with ALS (p = 1.3 × 10^-8), with replication support from two independent Australian samples (combined 576 cases and 683 controls, p = 1.7 × 10^-3). Both GPX3 and TNIP1 interact with other known ALS genes (SOD1 and OPTN, respectively). In addition, GGNBP2 was identified using gene-based analysis and summary statistics-based Mendelian randomization analysis, although further replication is needed to confirm this result. Our results increase our understanding of genetic aetiology of ALS.

Original language	English
Article number	611
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00471-1
Publication status	Published - 1 Dec 2017
Externally published	Yes

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Benyamin, B., He, J., Zhao, Q., Gratten, J., Garton, F., Leo, P. J., Liu, Z., Mangelsdorf, M., Al-Chalabi, A., Anderson, L., Butler, T. J., Chen, L., Chen, X. D., Cremin, K., Deng, H. W., Devine, M., Edson, J., Fifita, J. A., Furlong, S., ... Fan, D. (2017). Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis. Nature Communications, 8(1), Article 611. https://doi.org/10.1038/s41467-017-00471-1

@article{fdaa6b3be58745f79a48932d09105672,

title = "Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis",

abstract = "Cross-ethnic genetic studies can leverage power from differences in disease epidemiology and population-specific genetic architecture. In particular, the differences in linkage disequilibrium and allele frequency patterns across ethnic groups may increase gene-mapping resolution. Here we use cross-ethnic genetic data in sporadic amyotrophic lateral sclerosis (ALS), an adult-onset, rapidly progressing neurodegenerative disease. We report analyses of novel genome-wide association study data of 1,234 ALS cases and 2,850 controls. We find a significant association of rs10463311 spanning GPX3-TNIP1 with ALS (p = 1.3 × 10-8), with replication support from two independent Australian samples (combined 576 cases and 683 controls, p = 1.7 × 10-3). Both GPX3 and TNIP1 interact with other known ALS genes (SOD1 and OPTN, respectively). In addition, GGNBP2 was identified using gene-based analysis and summary statistics-based Mendelian randomization analysis, although further replication is needed to confirm this result. Our results increase our understanding of genetic aetiology of ALS.",

author = "Beben Benyamin and Ji He and Qiongyi Zhao and Jacob Gratten and Fleur Garton and Leo, {Paul J.} and Zhijun Liu and Marie Mangelsdorf and Ammar Al-Chalabi and Lisa Anderson and Butler, {Timothy J.} and Lu Chen and Chen, {Xiang Ding} and Katie Cremin and Deng, {Hong Weng} and Matthew Devine and Janette Edson and Fifita, {Jennifer A.} and Sarah Furlong and Han, {Ying Ying} and Jessica Harris and Henders, {Anjali K.} and Jeffree, {Rosalind L.} and Jin, {Zi Bing} and Zhongshan Li and Ting Li and Mengmeng Li and Yong Lin and Xiaolu Liu and Mhairi Marshall and McCann, {Emily P.} and Mowry, {Bryan J.} and Ngo, {Shyuan T.} and Roger Pamphlett and Shu Ran and Reutens, {David C.} and Rowe, {Dominic B.} and Perminder Sachdev and Sonia Shah and Sharon Song and Tan, {Li Jun} and Lu Tang and {Van Den Berg}, {Leonard H.} and {Van Rheenen}, Wouter and Veldink, {Jan H.} and Wallace, {Robyn H.} and Lawrie Wheeler and Williams, {Kelly L.} and Jinyu Wu and Xin Wu and Jian Yang and Weihua Yue and Zhang, {Zong Hong} and Dai Zhang and Noakes, {Peter G.} and Blair, {Ian P.} and Henderson, {Robert D.} and McCombe, {Pamela A.} and Visscher, {Peter M.} and Huji Xu and Bartlett, {Perry F.} and Brown, {Matthew A.} and Wray, {Naomi R.} and Dongsheng Fan",

note = "Funding Information: We thank all the participants for their generous contribution to this study. We also thank staff and researchers at the Peking University Third Hospital (Beijing, China), the Royal Brisbane and Women Hospital (Brisbane, Australia) and Multidisciplinary Motor Neurone Disease Clinic (Sydney, Australia). This work was funded by the Australian Research Council (ARC) Linkage Grant (M.A.B., P.F.B., P.M.V., H.X., R.J.W., B.J.M., D.C.R. and M.M), the Peter Goodenough Foundation, the National Natural Science Foundation of China (grants to D.S.F.: 81030019, and J.H.: 81601105 and Z.B.J.: 81522014), the National Health and Medical Research Council (NHMRC) (N.R.W.: 1078901, 1083187, B.B.: 1084417, 1079583, P.M.V.: 1078037, I.P.B.: 1095215, K.L.W.: 1092023), MNDRIA (P.G.N.: Grant-in-Aid 2013, B.B.: Mick Roger Benalla Grant, F.G.: Bill Gole Fellowship, I.P.B.: MND Australia Leadership Grant, E.P.M. and J.A.F.: scholarship top ups), Ross Maclean Senior Research Fellowships (M.M, R.J.W.), the Sylvia & Charles Viertel Charitable Foundation (J.Y.). O.A.T.S. was supported by an NHMRC/ARC Strategic Award (Grant 401162) and the Project Grant (104532) and was facilitated through access to the Australian Twin Registry, which is funded by an NHMRC Enabling Grant (310667). Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-00471-1",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Benyamin, B, He, J, Zhao, Q, Gratten, J, Garton, F, Leo, PJ, Liu, Z, Mangelsdorf, M, Al-Chalabi, A, Anderson, L, Butler, TJ, Chen, L, Chen, XD, Cremin, K, Deng, HW, Devine, M, Edson, J, Fifita, JA, Furlong, S, Han, YY, Harris, J, Henders, AK, Jeffree, RL, Jin, ZB, Li, Z, Li, T, Li, M, Lin, Y, Liu, X, Marshall, M, McCann, EP, Mowry, BJ, Ngo, ST, Pamphlett, R, Ran, S, Reutens, DC, Rowe, DB, Sachdev, P, Shah, S, Song, S, Tan, LJ, Tang, L, Van Den Berg, LH, Van Rheenen, W, Veldink, JH, Wallace, RH, Wheeler, L, Williams, KL, Wu, J, Wu, X, Yang, J, Yue, W, Zhang, ZH, Zhang, D, Noakes, PG, Blair, IP, Henderson, RD, McCombe, PA, Visscher, PM, Xu, H, Bartlett, PF, Brown, MA, Wray, NR & Fan, D 2017, 'Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis', Nature Communications, vol. 8, no. 1, 611. https://doi.org/10.1038/s41467-017-00471-1

TY - JOUR

T1 - Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis

AU - Benyamin, Beben

AU - He, Ji

AU - Zhao, Qiongyi

AU - Gratten, Jacob

AU - Garton, Fleur

AU - Leo, Paul J.

AU - Liu, Zhijun

AU - Mangelsdorf, Marie

AU - Al-Chalabi, Ammar

AU - Anderson, Lisa

AU - Butler, Timothy J.

AU - Chen, Lu

AU - Chen, Xiang Ding

AU - Cremin, Katie

AU - Deng, Hong Weng

AU - Devine, Matthew

AU - Edson, Janette

AU - Fifita, Jennifer A.

AU - Furlong, Sarah

AU - Han, Ying Ying

AU - Harris, Jessica

AU - Henders, Anjali K.

AU - Jeffree, Rosalind L.

AU - Jin, Zi Bing

AU - Li, Zhongshan

AU - Li, Ting

AU - Li, Mengmeng

AU - Lin, Yong

AU - Liu, Xiaolu

AU - Marshall, Mhairi

AU - McCann, Emily P.

AU - Mowry, Bryan J.

AU - Ngo, Shyuan T.

AU - Pamphlett, Roger

AU - Ran, Shu

AU - Reutens, David C.

AU - Rowe, Dominic B.

AU - Sachdev, Perminder

AU - Shah, Sonia

AU - Song, Sharon

AU - Tan, Li Jun

AU - Tang, Lu

AU - Van Den Berg, Leonard H.

AU - Van Rheenen, Wouter

AU - Veldink, Jan H.

AU - Wallace, Robyn H.

AU - Wheeler, Lawrie

AU - Williams, Kelly L.

AU - Wu, Jinyu

AU - Wu, Xin

AU - Yang, Jian

AU - Yue, Weihua

AU - Zhang, Zong Hong

AU - Zhang, Dai

AU - Noakes, Peter G.

AU - Blair, Ian P.

AU - Henderson, Robert D.

AU - McCombe, Pamela A.

AU - Visscher, Peter M.

AU - Xu, Huji

AU - Bartlett, Perry F.

AU - Brown, Matthew A.

AU - Wray, Naomi R.

AU - Fan, Dongsheng

N1 - Funding Information: We thank all the participants for their generous contribution to this study. We also thank staff and researchers at the Peking University Third Hospital (Beijing, China), the Royal Brisbane and Women Hospital (Brisbane, Australia) and Multidisciplinary Motor Neurone Disease Clinic (Sydney, Australia). This work was funded by the Australian Research Council (ARC) Linkage Grant (M.A.B., P.F.B., P.M.V., H.X., R.J.W., B.J.M., D.C.R. and M.M), the Peter Goodenough Foundation, the National Natural Science Foundation of China (grants to D.S.F.: 81030019, and J.H.: 81601105 and Z.B.J.: 81522014), the National Health and Medical Research Council (NHMRC) (N.R.W.: 1078901, 1083187, B.B.: 1084417, 1079583, P.M.V.: 1078037, I.P.B.: 1095215, K.L.W.: 1092023), MNDRIA (P.G.N.: Grant-in-Aid 2013, B.B.: Mick Roger Benalla Grant, F.G.: Bill Gole Fellowship, I.P.B.: MND Australia Leadership Grant, E.P.M. and J.A.F.: scholarship top ups), Ross Maclean Senior Research Fellowships (M.M, R.J.W.), the Sylvia & Charles Viertel Charitable Foundation (J.Y.). O.A.T.S. was supported by an NHMRC/ARC Strategic Award (Grant 401162) and the Project Grant (104532) and was facilitated through access to the Australian Twin Registry, which is funded by an NHMRC Enabling Grant (310667). Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Cross-ethnic genetic studies can leverage power from differences in disease epidemiology and population-specific genetic architecture. In particular, the differences in linkage disequilibrium and allele frequency patterns across ethnic groups may increase gene-mapping resolution. Here we use cross-ethnic genetic data in sporadic amyotrophic lateral sclerosis (ALS), an adult-onset, rapidly progressing neurodegenerative disease. We report analyses of novel genome-wide association study data of 1,234 ALS cases and 2,850 controls. We find a significant association of rs10463311 spanning GPX3-TNIP1 with ALS (p = 1.3 × 10-8), with replication support from two independent Australian samples (combined 576 cases and 683 controls, p = 1.7 × 10-3). Both GPX3 and TNIP1 interact with other known ALS genes (SOD1 and OPTN, respectively). In addition, GGNBP2 was identified using gene-based analysis and summary statistics-based Mendelian randomization analysis, although further replication is needed to confirm this result. Our results increase our understanding of genetic aetiology of ALS.

AB - Cross-ethnic genetic studies can leverage power from differences in disease epidemiology and population-specific genetic architecture. In particular, the differences in linkage disequilibrium and allele frequency patterns across ethnic groups may increase gene-mapping resolution. Here we use cross-ethnic genetic data in sporadic amyotrophic lateral sclerosis (ALS), an adult-onset, rapidly progressing neurodegenerative disease. We report analyses of novel genome-wide association study data of 1,234 ALS cases and 2,850 controls. We find a significant association of rs10463311 spanning GPX3-TNIP1 with ALS (p = 1.3 × 10-8), with replication support from two independent Australian samples (combined 576 cases and 683 controls, p = 1.7 × 10-3). Both GPX3 and TNIP1 interact with other known ALS genes (SOD1 and OPTN, respectively). In addition, GGNBP2 was identified using gene-based analysis and summary statistics-based Mendelian randomization analysis, although further replication is needed to confirm this result. Our results increase our understanding of genetic aetiology of ALS.

UR - http://www.scopus.com/inward/record.url?scp=85029654904&partnerID=8YFLogxK

U2 - 10.1038/s41467-017-00471-1

DO - 10.1038/s41467-017-00471-1

M3 - Article

C2 - 28931804

AN - SCOPUS:85029654904

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 611

ER -

Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis

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