Letter | Published:

Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma

Nature Genetics volume 44, pages 11421146 (2012) | Download Citation

Abstract

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10−12), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10−10) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10−9). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

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Acknowledgements

The authors thank all individuals with PACG and controls who have participated in this genetic study. We thank the following for contribution of cases and controls: J. Chua, D. Goh, R. Husain, N. Amerasinghe and A. Narayanaswamy of the Singapore National Eye Centre/Singapore Eye Research Institute; L.H. Thean, C. Aquino, C. Sng and A. Tan of the National University Hospital, Singapore; B.-A. Lim and L. Yip of Tan Tock Seng Hospital, Singapore; and Y. Liang, S. Li, X. Duan, F. Wang, X. Yang, Q. Zhou and X. Yang of the Handan Eye Study, China. The authors would also like to thank C. Chakarova, P. Ostergaard, S. Jeffery, H.J. Cordell, P.T. Khaw, D.F. Garway-Heath, A.C. Viswanathan, W.-Y. Meah, S. Chen, D. Venkataraman, L.-W. Koh, X.Y. Ng, H.-B. Toh, K.-K. Heng and X.Y. Chen for administrative, technical and genotyping support. This work was supported by grants from the National Medical Research Council, Singapore (NMRC/TCR/002-SERI/2008 (R626/47/2008TCR), CSA R613/34/2008, NMRC 0796/2003 and STaR/0003/2008), the National Research Foundation of Singapore, the Biomedical Research Council, Singapore (BMRC 09/1/35/19/616 and 08/1/35/19/550), Genome Institute of Singapore Intramural funding, the Beijing Municipal Natural Science Foundation (7102036), the Key Project of the Beijing Municipal Natural Science Foundation (7081001) and the Key Project of the National Natural Science Foundation of China (81030016).

Author information

Author notes

    • Eranga N Vithana
    • , Chiea-Chuen Khor
    • , Chunyan Qiao
    • , Ningli Wang
    •  & Tin Aung

    These authors contributed equally to this work.

    • Eranga N Vithana
    • , Chiea-Chuen Khor
    • , Ningli Wang
    •  & Tin Aung

    These authors jointly directed this work.

Affiliations

  1. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

    • Eranga N Vithana
    • , Chiea-Chuen Khor
    • , Monisha E Nongpiur
    • , Shamira A Perera
    • , Ching-Yu Cheng
    • , Ching-Lin Ho
    • , Ren-Yi Wu
    • , Daniel H Su
    • , Francis T Oen
    • , Mani Baskaran
    • , Alicia C How
    • , Kelvin Y Lee
    • , Victor H K Yong
    • , Serena M L Ting
    • , Wan-Ting Tay
    • , Raghavan Lavanya
    • , Belinda K Cornes
    • , Ying-Feng Zheng
    • , Tina T Wong
    • , Donald T Tan
    • , Seang-Mei Saw
    • , Tien-Yin Wong
    •  & Tin Aung
  2. Department of Ophthalmology, National University Health System & National University of Singapore, Singapore.

    • Eranga N Vithana
    • , Chiea-Chuen Khor
    • , Monisha E Nongpiur
    • , Ching-Yu Cheng
    • , Paul T K Chew
    • , Ying-Feng Zheng
    • , Seng-Chee Loon
    • , Donald T Tan
    • , Tien-Yin Wong
    •  & Tin Aung
  3. Infectious Diseases, Genome Institute of Singapore, Singapore.

    • Chiea-Chuen Khor
    •  & Martin L Hibberd
  4. Human Genetics, Genome Institute of Singapore, Singapore.

    • Chiea-Chuen Khor
    • , Kar Seng Sim
    • , Yik Ying Teo
    •  & Jianjun Liu
  5. Department of Paediatrics, National University Health System & National University of Singapore, Singapore.

    • Chiea-Chuen Khor
  6. Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

    • Chiea-Chuen Khor
    • , Ching-Yu Cheng
    • , Kee-Seng Chia
    • , Martin L Hibberd
    • , Yik Ying Teo
    • , E-Shyong Tai
    • , Seang-Mei Saw
    • , Jianjun Liu
    •  & Tien-Yin Wong
  7. Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

    • Chunyan Qiao
    • , Hongyan Jia
    • , Hua Wang
    • , Bo Feng
    •  & Ningli Wang
  8. Vision Research Foundation, Sankara Nethralaya, Chennai, India.

    • Ronnie George
    • , Sripriya Sarangapani
    • , Nagaswamy Soumittra
    • , Balekudaru Shantha
    • , Vedam L Ramprasad
    • , Govindasamy Kumaramanickavel
    •  & Lingam Vijaya
  9. Department of Ophthalmology & Visual Sciences, Chinese University of Hong Kong, Hong Kong, China.

    • Li-Jia Chen
    • , Clement C Y Tham
    • , Dennis S C Lam
    •  & Chi-Pui Pang
  10. Vietnam National Institute of Ophthalmology, Hanoi, Vietnam.

    • Tan Do
    • , Dao T L Huong
    •  & Do Nhu Hon
  11. Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

    • Khaled Abu-Amero
    • , Essam A Osman
    •  & Saleh A Al-Obeidan
  12. Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, Florida, USA.

    • Khaled Abu-Amero
  13. Shantou University–Chinese University of Hong Kong Joint Shantou International Eye Center, Shantou, China.

    • Chor Kai Huang
    •  & Mingzhi Zhang
  14. National Institute for Health Research (NIHR) Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and University College London (UCL) Institute of Ophthalmology, London, UK.

    • Sancy Low
    • , Naushin Waseem
    • , Shomi S Bhattacharya
    •  & Paul J Foster
  15. Department of Ophthalmology, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia.

    • Liza-Sharmini A Tajudin
    • , Yang Li
    •  & Azhany Yaakub
  16. Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

    • Liang Xu
    •  & Ya-Xing Wang
  17. Xiamen Eye Centre, Xiamen University, Xiamen, China.

    • Ren-Yi Wu
  18. Department of Ophthalmology, Tan Tock Seng Hospital, Singapore.

    • Hon-Tym Wong
    •  & Vernon K Y Yong
  19. Xingtai Eye Hospital, Xingtai, China.

    • Guangxian Tang
  20. Handan Eye Hospital, Handan, China.

    • Sujie Fan
  21. Anyang Eye Hospital, Anyang, China.

    • Hailin Meng
  22. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.

    • Sudha K Iyengar
    •  & Theru A Sivakumaran
  23. Centre for Molecular Epidemiology, National University of Singapore, Singapore.

    • Xueling Sim
    •  & Yik Ying Teo
  24. Department of Opthamology, Duke University Medical Center, Durham, North Carolina, USA.

    • R Rand Allingham
    •  & Michael A Hauser
  25. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.

    • Jost B Jonas
  26. Department of Medicine, National University Health System & National University of Singapore, Singapore.

    • E-Shyong Tai
  27. Duke–National University of Singapore Graduate Medical School, Singapore.

    • E-Shyong Tai
  28. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

    • Tran Nguyen Bich Chau
    •  & Cameron P Simmons
  29. Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.

    • Cameron P Simmons
  30. State Key Laboratory of Oncology in Southern China, Guangzhou, China.

    • Jin-Xin Bei
    •  & Yi-Xin Zeng
  31. Department of Experimental Research, Sun Yat-Sen University Cancer Centre, Guangzhou, China.

    • Jin-Xin Bei
    •  & Yi-Xin Zeng
  32. Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.

    • Yi-Xin Zeng

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Contributions

T.A., N. Wang, E.N.V. and C.-C.K. are the overall principal investigators who were jointly responsible for conception of the project, funding, study design and planning of the analysis strategy. C.Q., M.E.N., R.G., L.-J.C., T.D., K.A.-A., C.K.H., S.L., M.Z. and L.-S.A.T. are the lead coordinators for sample collection. S.A.P., L.X., H.J., C.-L.H., C.C.Y.T., R.-Y.W., P.T.K.C., D.H.S., F.T.O., N.S., E.A.O., H.-T.W., G.T., S.F., H.M., D.T.L.H., H.W., B.F., M.B., B.S., A.C.H., K.Y.L., Y.L., Y.-X.W., D.N.H., T.T.W., S.-C.L., V.K.Y.Y., A.Y., D.S.C.L. and S.A.A.-O. were the clinicians responsible for obtaining informed consent and enrolling study participants. K.S.S., W.-T.T. and X.S. performed statistical analysis. V.H.K.Y. performed gene expression analysis. C.Q., H.J., N. Wang, R.G., S.S., L.V., L.-J.C., C.K.H., M.Z. and C.-P.P. contributed to the genotyping and analysis of cases and controls for the Beijing, Chennai and Shantou samples. T.N.B.C. and C.P.S. contributed to the genotyping and analysis of the Vietnamese control group. J.-X.B. and Y.-X.Z. contributed to the genotyping and analysis of the Guangdong control group. P.J.F., L.V., T.-Y.W., C.-P.P., D.N.H., S.A.A.-O. and L.-S.A.T. are site principal investigators for their respective sample collections. S.S., C.-Y.C., V.L.R., G.K., S.K.I., T.A.S., S.M.L.T., R.L., B.K.C., Y.-F.Z., N. Waseem, K.-S.C., R.R.A., M.A.H., M.L.H., S.S.B., Y.Y.T., D.T.T., J.B.J., E.-S.T., S.-M.S. and J.L. provided intellectual input and/or contributed laboratory reagents or analysis for the project. All authors were responsible for critical revision of the manuscript. The manuscript was written by C.-C.K., E.N.V., M.E.N. and T.A.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ningli Wang or Tin Aung.

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https://doi.org/10.1038/ng.2390

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