Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Pirro G Hysi^#¹, Ching-Yu Cheng^#^{2

3

4

5}, Henriët Springelkamp^#^{6

7}, Stuart Macgregor^#⁸, Jessica N Cooke Bailey^#⁹, Robert Wojciechowski^#^{10

11}, Veronique Vitart¹², Abhishek Nag¹, Alex W Hewitt¹³, René Höhn¹⁴, Cristina Venturini^{1

15}, Alireza Mirshahi¹⁴, Wishal D Ramdas^{6

7}, Gudmar Thorleifsson¹⁶, Eranga Vithana^{2

3

5}, Chiea-Chuen Khor^{3

17}, Arni B Stefansson¹⁸, Jiemin Liao^{2

3}, Jonathan L Haines⁹, Najaf Amin⁷, Ya Xing Wang¹⁹, Philipp S Wild²⁰, Ayse B Ozel²¹, Jun Z Li²¹, Brian W Fleck²², Tanja Zeller²³, Sandra E Staffieri¹³, Yik-Ying Teo^{4

24}, Gabriel Cuellar-Partida⁸, Xiaoyan Luo²⁵, R Rand Allingham²⁶, Julia E Richards⁶, Andrea Senft²⁷, Lennart C Karssen⁷, Yingfeng Zheng^{2

4}, Céline Bellenguez^{28

29

30}, Liang Xu¹⁹, Adriana I Iglesias⁷, James F Wilson³¹, Jae H Kang³², Elisabeth M van Leeuwen⁷, Vesteinn Jonsson³³, Unnur Thorsteinsdottir¹⁶, Dominiek D G Despriet⁶, Sarah Ennis³⁴, Sayoko E Moroi³⁵, Nicholas G Martin³⁶, Nomdo M Jansonius³⁷, Seyhan Yazar³⁸, E-Shyong Tai^{4

5

39}, Philippe Amouyel^{27

28

29

40}, James Kirwan⁴¹, Leonieke M E van Koolwijk⁷, Michael A Hauser^{26

42}, Fridbert Jonasson⁴³, Paul Leo⁴⁴, Stephanie J Loomis⁴⁵, Rhys Fogarty⁴⁶, Fernando Rivadeneira^{7

47

48}, Lisa Kearns¹³, Karl J Lackner⁴⁹, Paulus T V M de Jong^{50

51

52}, Claire L Simpson¹¹, Craig E Pennell⁵³, Ben A Oostra⁵⁴, André G Uitterlinden^{7

47

48}, Seang-Mei Saw^{2

3

4

5}, Andrew J Lotery⁵⁵, Joan E Bailey-Wilson¹¹, Albert Hofman^{7

48}, Johannes R Vingerling^{6

7}, Cécilia Maubaret^{56

57}, Norbert Pfeiffer¹⁴, Roger C W Wolfs⁶, Hans G Lemij⁵⁸, Terri L Young²⁵, Louis R Pasquale^{32

45}, Cécile Delcourt^{56

57}, Timothy D Spector¹, Caroline C W Klaver^{6

7}, Kerrin S Small¹, Kathryn P Burdon⁴⁶, Kari Stefansson¹⁶, Tien-Yin Wong^{2

3

4}; BMES GWAS Group; NEIGHBORHOOD Consortium; Wellcome Trust Case Control Consortium 2; Ananth Viswanathan⁵⁹, David A Mackey^{13

38}, Jamie E Craig⁴⁶, Janey L Wiggs⁴⁵, Cornelia M van Duijn⁷, Christopher J Hammond¹, Tin Aung^{2

3}

Affiliations

¹ Department of Twin Research and Genetic Epidemiology, King's College London, UK.
² Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
³ Department of Ophthalmology, National University of Singapore and National University Health System, Singapore.
⁴ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
⁵ Duke-National University of Singapore, Graduate Medical School, Singapore.
⁶ Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
⁷ Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
⁸ Statistical Genetics, QIMR Berghofer Medical Research Institute Royal Brisbane Hospital, Brisbane, Australia 4029.
⁹ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
¹⁰ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and, Baltimore, MD, USA.
¹¹ National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, USA.
¹² MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh.
¹³ Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Australia.
¹⁴ Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.
¹⁵ Institute of Ophthalmology, University College London, UK.
¹⁶ deCODE/Amgen, 101 Reykjavik, Iceland.
¹⁷ Division of Human Genetics, Genome Institute of Singapore, Singapore.
¹⁸ Eye Clinic, 105 Reykjavik, Iceland.
¹⁹ Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China 100730.
²⁰ Department of Internal Medicine II, University Medical Center Mainz, Mainz, Germany.
²¹ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
²² NHS Princess Alexandra Eye Pavilion, Edinburgh, UK.
²³ Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Germany.
²⁴ Department of Statistics and Applied Probability, National University of Singapore, Singapore.
²⁵ Duke University, Duke Eye Center, Durham, NC, USA.
²⁶ Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA.
²⁷ Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Lübeck, Germany.
²⁸ Inserm, UMR774, Lille, France.
²⁹ Université Lille 2, Lille, France.
³⁰ Institut Pasteur de Lille, France.
³¹ Centre for Population Health Sciences, University of Edinburgh Medical School, Edinburgh, UK.
³² Channing Division of Network Medicine, Harvard Medical School, Boston, MA, USA.
³³ Department of Ophthalmology, Landspitali National University Hospital, Reykjavik, Iceland.
³⁴ Human Genetics & Genomic Medicine, Faulty of Medicine, University of Southampton, UK.
³⁵ Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA.
³⁶ Genetic Epidemiology, QIMR Berghofer Medical Research Institute Royal Brisbane Hospital, Brisbane, Australia.
³⁷ Department of Ophthalmology, University Medical Center Groningen, the Netherlands.
³⁸ Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.
³⁹ Department of Medicine, National University of Singapore and National University Health System, Singapore.
⁴⁰ Centre Hospitalier Régional Universitaire de Lille, France.
⁴¹ Department of Ophthalmology, Portsmouth Hospitals NHS Trust, Portsmouth, UK.
⁴² Department of Medicine, Duke University Medical Center, Durham, NC, USA.
⁴³ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁴⁴ The University of Queensland, Diamantina Institute, Woollongabba, Australia.
⁴⁵ Dept. Ophthalmology Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
⁴⁶ Department of Ophthalmology, Flinders University, Adelaide, Australia.
⁴⁷ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
⁴⁸ Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, The Hague, the Netherlands.
⁴⁹ Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany.
⁵⁰ Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
⁵¹ Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
⁵² Department of Ophthalmology, Academic Medical Center, Amsterdam, the Netherlands.
⁵³ School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.
⁵⁴ Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
⁵⁵ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, UK.
⁵⁶ Univ. Bordeaux, ISPED, Bordeaux, France.
⁵⁷ Inserm, Centre INSERM U897-Epidemiologie-Biostatistique Bordeaux, France.
⁵⁸ Glaucoma Service, the Rotterdam Eye Hospital, Rotterdam, the Netherlands.
⁵⁹ NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.

^# Contributed equally.

PMID: 25173106
PMCID: PMC4177225
DOI: 10.1038/ng.3087

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Pirro G Hysi et al. Nat Genet. 2014 Oct.

. 2014 Oct;46(10):1126-1130.

doi: 10.1038/ng.3087. Epub 2014 Aug 31.

Authors

Affiliations

¹ Department of Twin Research and Genetic Epidemiology, King's College London, UK.
² Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
³ Department of Ophthalmology, National University of Singapore and National University Health System, Singapore.
⁴ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
⁵ Duke-National University of Singapore, Graduate Medical School, Singapore.
⁶ Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
⁷ Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
⁸ Statistical Genetics, QIMR Berghofer Medical Research Institute Royal Brisbane Hospital, Brisbane, Australia 4029.
⁹ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
¹⁰ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and, Baltimore, MD, USA.
¹¹ National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, USA.
¹² MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh.
¹³ Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Australia.
¹⁴ Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.
¹⁵ Institute of Ophthalmology, University College London, UK.
¹⁶ deCODE/Amgen, 101 Reykjavik, Iceland.
¹⁷ Division of Human Genetics, Genome Institute of Singapore, Singapore.
¹⁸ Eye Clinic, 105 Reykjavik, Iceland.
¹⁹ Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China 100730.
²⁰ Department of Internal Medicine II, University Medical Center Mainz, Mainz, Germany.
²¹ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
²² NHS Princess Alexandra Eye Pavilion, Edinburgh, UK.
²³ Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Germany.
²⁴ Department of Statistics and Applied Probability, National University of Singapore, Singapore.
²⁵ Duke University, Duke Eye Center, Durham, NC, USA.
²⁶ Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA.
²⁷ Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Lübeck, Germany.
²⁸ Inserm, UMR774, Lille, France.
²⁹ Université Lille 2, Lille, France.
³⁰ Institut Pasteur de Lille, France.
³¹ Centre for Population Health Sciences, University of Edinburgh Medical School, Edinburgh, UK.
³² Channing Division of Network Medicine, Harvard Medical School, Boston, MA, USA.
³³ Department of Ophthalmology, Landspitali National University Hospital, Reykjavik, Iceland.
³⁴ Human Genetics & Genomic Medicine, Faulty of Medicine, University of Southampton, UK.
³⁵ Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA.
³⁶ Genetic Epidemiology, QIMR Berghofer Medical Research Institute Royal Brisbane Hospital, Brisbane, Australia.
³⁷ Department of Ophthalmology, University Medical Center Groningen, the Netherlands.
³⁸ Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.
³⁹ Department of Medicine, National University of Singapore and National University Health System, Singapore.
⁴⁰ Centre Hospitalier Régional Universitaire de Lille, France.
⁴¹ Department of Ophthalmology, Portsmouth Hospitals NHS Trust, Portsmouth, UK.
⁴² Department of Medicine, Duke University Medical Center, Durham, NC, USA.
⁴³ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁴⁴ The University of Queensland, Diamantina Institute, Woollongabba, Australia.
⁴⁵ Dept. Ophthalmology Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
⁴⁶ Department of Ophthalmology, Flinders University, Adelaide, Australia.
⁴⁷ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
⁴⁸ Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, The Hague, the Netherlands.
⁴⁹ Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany.
⁵⁰ Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
⁵¹ Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
⁵² Department of Ophthalmology, Academic Medical Center, Amsterdam, the Netherlands.
⁵³ School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.
⁵⁴ Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
⁵⁵ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, UK.
⁵⁶ Univ. Bordeaux, ISPED, Bordeaux, France.
⁵⁷ Inserm, Centre INSERM U897-Epidemiologie-Biostatistique Bordeaux, France.
⁵⁸ Glaucoma Service, the Rotterdam Eye Hospital, Rotterdam, the Netherlands.
⁵⁹ NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.

^# Contributed equally.

PMID: 25173106
PMCID: PMC4177225
DOI: 10.1038/ng.3087

Abstract

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

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Figures

**Figure 1. Flowchart of the analyses**
Results from a meta-analysis of IOP in participants from 18 general population cohorts were validated in four clinical case control cohorts and checked for transcription regulation activity in three tissues from 856 British subjects.

**Figure 2. Manhattan plots of the results from the meta-analyses of results from 18 multi-ethnic cohorts from the IGGC**
The 22 autosomes are plotted along the x-axis, whereas the values in the y-axis denote the −log10 -transformed p-values from the meta-analysis of association with IOP observed for any of the SNPs. Loci previously associated with IOP or glaucoma have been grayed out.

See this image and copyright information in PMC

References

1. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262–7. - PMC - PubMed
1. Heijl A, Leske MC, Bengtsson B, Hyman L, Hussein M. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268–79. - PubMed
1. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol. 1998;126:498–505. - PubMed
1. Kass MA, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701–13. Discussion 829-30. - PubMed
1. Wolfs RC, et al. Genetic risk of primary open-angle glaucoma. Population-based familial aggregation study. Arch Ophthalmol. 1998;116:1640–5. - PubMed

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Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Affiliations

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Authors

Affiliations

Abstract

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical