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

Beben Benyamin^{1

2}, Ji He³, Qiongyi Zhao¹, Jacob Gratten^{1

2}, Fleur Garton^{1

2}, Paul J Leo^{4

5}, Zhijun Liu^{1

2}, Marie Mangelsdorf¹, Ammar Al-Chalabi⁶, Lisa Anderson^{4

5}, Timothy J Butler¹, Lu Chen³, Xiang-Ding Chen⁷, Katie Cremin^{4

5}, Hong-Weng Deng⁸, Matthew Devine⁹, Janette Edson¹, Jennifer A Fifita¹⁰, Sarah Furlong¹, Ying-Ying Han¹¹, Jessica Harris^{4

5}, Anjali K Henders^{1

2}, Rosalind L Jeffree¹², Zi-Bing Jin¹³, Zhongshan Li¹⁴, Ting Li¹⁵, Mengmeng Li¹⁵, Yong Lin¹¹, Xiaolu Liu³, Mhairi Marshall^{4

5}, Emily P McCann¹⁰, Bryan J Mowry¹, Shyuan T Ngo^{1

16}, Roger Pamphlett¹⁷, Shu Ran¹¹, David C Reutens¹⁸, Dominic B Rowe¹⁹, Perminder Sachdev^{20

21}, Sonia Shah¹, Sharon Song^{4

5}, Li-Jun Tan⁷, Lu Tang³, Leonard H van den Berg²², Wouter van Rheenen²², Jan H Veldink²², Robyn H Wallace¹, Lawrie Wheeler^{4

5}, Kelly L Williams¹⁰, Jinyu Wu¹⁴, Xin Wu¹⁵, Jian Yang^{1

2}, Weihua Yue^{23

24}, Zong-Hong Zhang¹, Dai Zhang^{23

24}, Peter G Noakes⁹, Ian P Blair¹⁰, Robert D Henderson^{1

9}, Pamela A McCombe^{9

25}, Peter M Visscher^{1

2}, Huji Xu¹⁵, Perry F Bartlett¹, Matthew A Brown^{4

5}, Naomi R Wray^{26

27}, Dongsheng Fan³

Affiliations

¹ Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, 4072, Australia.
² Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
³ Department of Neurology, Peking University, Third Hospital, No. 49, North Garden Road, Haidian District, 100191, Beijing, China.
⁴ University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, 4102, Australia.
⁵ Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Queensland, 4102, Australia.
⁶ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, WC2 R2LS, UK.
⁷ Laboratory of Molecular and Statistical Genetics and State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China.
⁸ Department of Global Biostatistics and Data Science, School of Public Health and Tropical Medicine, Center for Bioinformatics and Genomics, Tulane University, 1440 Canal St, Suite 2001, New Orleans, LA, 70112, USA.
⁹ Department of Neurology, Royal Brisbane & Women's Hospital, Brisbane, Queensland, 4029, Australia.
¹⁰ Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, 2109, Australia.
¹¹ Center of System Biomedical Sciences, University of Shanghai for Science and Technology, 334, Jungong Road, Yangpu District, 200093, Shanghai, China.
¹² Kenneth G. Jamieson Department of Neurosurgery, Royal Brisbane & Women's Hospital, Herston, Queensland, 4029, Australia.
¹³ Division of Ophthalmic Genetics, Laboratory for Stem Cell and Retinal Regeneration, The Eye Hospital of Wenzhou Medical University, 325027, Wenzhou, China.
¹⁴ Institute of Genomic Medicine, Wenzhou Medical University, 325027, Wenzhou, China.
¹⁵ Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, 200003, Shanghai, China.
¹⁶ School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, 4072, Australia.
¹⁷ Stacey MND Laboratory, Discipline of Pathology, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, 2006, Australia.
¹⁸ The Centre for Advanced Imaging, The University of Queensland, Brisbane, Queensland, 4072, Australia.
¹⁹ Department of Medicine, Faculty of Medicine and Health Sciences, Multidisciplinary Motor Neurone Disease Clinic, Macquarie University, Sydney, New South Wales, 2109, Australia.
²⁰ Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, The University of New South Wales, Sydney, New South Wales, 2052, Australia.
²¹ Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, New South Wales, 2031, Australia.
²² Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
²³ Institute of Mental Health, The Sixth Hospital, Peking University, 100191, Beijing, China.
²⁴ Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders, Peking University, 100191, Beijing, China.
²⁵ UQ Centre for Clinical Research, The University of Queensland, Royal Brisbane & Women's Hospital, Brisbane, Queensland, 4029, Australia.
²⁶ Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, 4072, Australia. naomi.wray@uq.edu.au.
²⁷ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia. naomi.wray@uq.edu.au.

PMID: 28931804
PMCID: PMC5606989
DOI: 10.1038/s41467-017-00471-1

Meta-Analysis

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

Beben Benyamin et al. Nat Commun. 2017.

. 2017 Sep 20;8(1):611.

doi: 10.1038/s41467-017-00471-1.

Authors

Affiliations

¹ Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, 4072, Australia.
² Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
³ Department of Neurology, Peking University, Third Hospital, No. 49, North Garden Road, Haidian District, 100191, Beijing, China.
⁴ University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, 4102, Australia.
⁵ Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Queensland, 4102, Australia.
⁶ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, WC2 R2LS, UK.
⁷ Laboratory of Molecular and Statistical Genetics and State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China.
⁸ Department of Global Biostatistics and Data Science, School of Public Health and Tropical Medicine, Center for Bioinformatics and Genomics, Tulane University, 1440 Canal St, Suite 2001, New Orleans, LA, 70112, USA.
⁹ Department of Neurology, Royal Brisbane & Women's Hospital, Brisbane, Queensland, 4029, Australia.
¹⁰ Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, 2109, Australia.
¹¹ Center of System Biomedical Sciences, University of Shanghai for Science and Technology, 334, Jungong Road, Yangpu District, 200093, Shanghai, China.
¹² Kenneth G. Jamieson Department of Neurosurgery, Royal Brisbane & Women's Hospital, Herston, Queensland, 4029, Australia.
¹³ Division of Ophthalmic Genetics, Laboratory for Stem Cell and Retinal Regeneration, The Eye Hospital of Wenzhou Medical University, 325027, Wenzhou, China.
¹⁴ Institute of Genomic Medicine, Wenzhou Medical University, 325027, Wenzhou, China.
¹⁵ Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, 200003, Shanghai, China.
¹⁶ School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, 4072, Australia.
¹⁷ Stacey MND Laboratory, Discipline of Pathology, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, 2006, Australia.
¹⁸ The Centre for Advanced Imaging, The University of Queensland, Brisbane, Queensland, 4072, Australia.
¹⁹ Department of Medicine, Faculty of Medicine and Health Sciences, Multidisciplinary Motor Neurone Disease Clinic, Macquarie University, Sydney, New South Wales, 2109, Australia.
²⁰ Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, The University of New South Wales, Sydney, New South Wales, 2052, Australia.
²¹ Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, New South Wales, 2031, Australia.
²² Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
²³ Institute of Mental Health, The Sixth Hospital, Peking University, 100191, Beijing, China.
²⁴ Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders, Peking University, 100191, Beijing, China.
²⁵ UQ Centre for Clinical Research, The University of Queensland, Royal Brisbane & Women's Hospital, Brisbane, Queensland, 4029, Australia.
²⁶ Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, 4072, Australia. naomi.wray@uq.edu.au.
²⁷ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia. naomi.wray@uq.edu.au.

PMID: 28931804
PMCID: PMC5606989
DOI: 10.1038/s41467-017-00471-1

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.Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Here, Wray and colleagues identify association of the GPX3-TNIP1 locus with ALS using cross-ethnic meta-analyses.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interests.

Figures

**Fig. 1**
Manhattan plot of the meta-analysis between European and Chinese GWAS revealed a novel locus, *GPX3-TNIP1* (*red*). Loci previously identified in the largest European GWAS are presented in *blue*. The p values are from the linear mixed model

**Fig. 2**
Regional ALS association plot of the *GPX3-TNIP1* locus from the meta-analysis results created using LocusZoom. From the meta-analysis, rs10463311 is the SNP with the strongest association with ALS (p = 1.3 × 10⁻⁸). This SNP is replicated in two independent Australian cohorts with combined p = 1.7 × 10⁻³

See this image and copyright information in PMC

References

1. Chiò A, et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology. 2013;41:118–30. doi: 10.1159/000351153. - DOI - PMC - PubMed
1. Johnston CA, et al. Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. J. Neurol. 2006;253:1642–3. doi: 10.1007/s00415-006-0195-y. - DOI - PubMed
1. Kiernan MC, et al. Amyotrophic lateral sclerosis. in. Lancet. 2011;377:942–955. doi: 10.1016/S0140-6736(10)61156-7. - DOI - PubMed
1. Chio A, et al. Prognostic factors in ALS: A critical review. Amyotroph. Lateral Scler. 2009;10:310–323. doi: 10.3109/17482960802566824. - DOI - PMC - PubMed
1. Renton AE, et al. State of play in amyotrophic lateral sclerosis genetics. Nat. Neurosci. 2014;17:17–23. doi: 10.1038/nn.3584. - DOI - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical