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

Eranga N Vithana^#^{1

2}, Chiea-Chuen Khor^#^{1

2

3

4

5

6}, Chunyan Qiao^#⁷, Monisha E Nongpiur^{1

2}, Ronnie George⁸, Li-Jia Chen⁹, Tan Do¹⁰, Khaled Abu-Amero^{11

12}, Chor Kai Huang¹³, Sancy Low¹⁴, Liza-Sharmini A Tajudin¹⁵, Shamira A Perera¹, Ching-Yu Cheng^{1

2

6}, Liang Xu¹⁶, Hongyan Jia⁷, Ching-Lin Ho¹, Kar Seng Sim⁴, Ren-Yi Wu^{1

17}, Clement C Y Tham⁹, Paul T K Chew², Daniel H Su¹, Francis T Oen¹, Sripriya Sarangapani⁸, Nagaswamy Soumittra⁸, Essam A Osman¹¹, Hon-Tym Wong¹⁸, Guangxian Tang¹⁹, Sujie Fan²⁰, Hailin Meng²¹, Dao T L Huong¹⁰, Hua Wang⁷, Bo Feng⁷, Mani Baskaran¹, Balekudaru Shantha⁸, Vedam L Ramprasad⁸, Govindasamy Kumaramanickavel⁸, Sudha K Iyengar²², Alicia C How¹, Kelvin Y Lee¹, Theru A Sivakumaran²², Victor H K Yong¹, Serena M L Ting¹, Yang Li¹⁵, Ya-Xing Wang¹⁶, Wan-Ting Tay¹, Xueling Sim²³, Raghavan Lavanya¹, Belinda K Cornes¹, Ying-Feng Zheng^{1

2}, Tina T Wong¹, Seng-Chee Loon², Vernon K Y Yong¹⁸, Naushin Waseem¹⁴, Azhany Yaakub¹⁵, Kee-Seng Chia⁶, R Rand Allingham²⁴, Michael A Hauser²⁴, Dennis S C Lam⁹, Martin L Hibberd^{3

6}, Shomi S Bhattacharya¹⁴, Mingzhi Zhang¹³, Yik Ying Teo^{4

6

23}, Donald T Tan^{1

2}, Jost B Jonas²⁵, E-Shyong Tai^{6

26

27}, Seang-Mei Saw^{1

6}, Do Nhu Hon¹⁰, Saleh A Al-Obeidan¹¹, Jianjun Liu^{4

6}, Tran Nguyen Bich Chau²⁸, Cameron P Simmons^{28

29}, Jin-Xin Bei^{30

31}, Yi-Xin Zeng^{30

31

32}, Paul J Foster¹⁴, Lingam Vijaya⁸, Tien-Yin Wong^{1

2

6}, Chi-Pui Pang⁹, Ningli Wang^#⁷, Tin Aung^#^{1

2}

Affiliations

¹ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
² Department of Ophthalmology, National University Health System & National University of Singapore, Singapore.
³ Infectious Diseases, Genome Institute of Singapore, Singapore.
⁴ Human Genetics, Genome Institute of Singapore, Singapore.
⁵ Department of Paediatrics, National University Health System & National University of Singapore, Singapore.
⁶ Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
⁷ Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
⁸ Vision Research Foundation, Sankara Nethralaya, Chennai, India.
⁹ Department of Ophthalmology & Visual Sciences, Chinese University of Hong Kong, Hong Kong, China.
¹⁰ Vietnam National Institute of Ophthalmology, Hanoi, Vietnam.
¹¹ Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹² Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, Florida, USA.
¹³ Shantou University-Chinese University of Hong Kong Joint Shantou International Eye Center, Shantou, China.
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.
¹⁵ Department of Ophthalmology, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia.
¹⁶ Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
¹⁷ Xiamen Eye Centre, Xiamen University, Xiamen, China.
¹⁸ Department of Ophthalmology, Tan Tock Seng Hospital, Singapore.
¹⁹ Xingtai Eye Hospital, Xingtai, China.
²⁰ Handan Eye Hospital, Handan, China.
²¹ Anyang Eye Hospital, Anyang, China.
²² Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
²³ Centre for Molecular Epidemiology, National University of Singapore, Singapore.
²⁴ Department of Opthamology, Duke University Medical Center, Durham, North Carolina, USA.
²⁵ Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
²⁶ Department of Medicine, National University Health System & National University of Singapore, Singapore.
²⁷ Duke-National University of Singapore Graduate Medical School, Singapore.
²⁸ Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
²⁹ Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.
³⁰ State Key Laboratory of Oncology in Southern China, Guangzhou, China.
³¹ Department of Experimental Research, Sun Yat-Sen University Cancer Centre, Guangzhou, China.
³² Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.

^# Contributed equally.

PMID: 22922875
PMCID: PMC4333205
DOI: 10.1038/ng.2390

Meta-Analysis

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

Eranga N Vithana et al. Nat Genet. 2012 Oct.

. 2012 Oct;44(10):1142-1146.

doi: 10.1038/ng.2390. Epub 2012 Aug 26.

Authors

Affiliations

¹ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
² Department of Ophthalmology, National University Health System & National University of Singapore, Singapore.
³ Infectious Diseases, Genome Institute of Singapore, Singapore.
⁴ Human Genetics, Genome Institute of Singapore, Singapore.
⁵ Department of Paediatrics, National University Health System & National University of Singapore, Singapore.
⁶ Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
⁷ Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
⁸ Vision Research Foundation, Sankara Nethralaya, Chennai, India.
⁹ Department of Ophthalmology & Visual Sciences, Chinese University of Hong Kong, Hong Kong, China.
¹⁰ Vietnam National Institute of Ophthalmology, Hanoi, Vietnam.
¹¹ Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹² Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, Florida, USA.
¹³ Shantou University-Chinese University of Hong Kong Joint Shantou International Eye Center, Shantou, China.
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.
¹⁵ Department of Ophthalmology, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia.
¹⁶ Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
¹⁷ Xiamen Eye Centre, Xiamen University, Xiamen, China.
¹⁸ Department of Ophthalmology, Tan Tock Seng Hospital, Singapore.
¹⁹ Xingtai Eye Hospital, Xingtai, China.
²⁰ Handan Eye Hospital, Handan, China.
²¹ Anyang Eye Hospital, Anyang, China.
²² Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
²³ Centre for Molecular Epidemiology, National University of Singapore, Singapore.
²⁴ Department of Opthamology, Duke University Medical Center, Durham, North Carolina, USA.
²⁵ Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
²⁶ Department of Medicine, National University Health System & National University of Singapore, Singapore.
²⁷ Duke-National University of Singapore Graduate Medical School, Singapore.
²⁸ Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
²⁹ Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.
³⁰ State Key Laboratory of Oncology in Southern China, Guangzhou, China.
³¹ Department of Experimental Research, Sun Yat-Sen University Cancer Centre, Guangzhou, China.
³² Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.

^# Contributed equally.

PMID: 22922875
PMCID: PMC4333205
DOI: 10.1038/ng.2390

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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Figures

**Figure 1**
Manhattan plot of all stage 1 data for 1,854 PACG cases and 9,609 controls. SNP markers are plotted according to chromosomal location on the x axis, with the −log₁₀ P values on the y axis derived from the 1-degree-of-freedom score test. The blue horizontal dashed line (P < 1 × 10⁻⁵) denotes the threshold for bringing genetic loci forward for further testing in stage 2. The red horizontal dashed line (P < 5 × 10⁻⁸) shows the formal threshold for genome-wide significance.

**Figure 2**
Regional association and recombination rate plots for stage 1 data. (**a–c**) Data are shown for the *PLEKHA7* locus around rs11024102 (a), the *COL11A1* locus around rs3753841 (b) and the chromosome 8q locus around rs1015213 (c). Data shown are for both imputed (gray circles) and directly genotyped (black diamonds) SNPs. The genotyped SNP with the most significant association is denoted with a blue diamond. The left y axis represents −log₁₀ P values for association with PACG in stage 1, the right y axis represents the recombination rate, and the x axis represents base-pair positions along the chromosome (human genome Build 37). The blue and red horizontal lines denote P = 1 × 10⁻⁵ and P = 5 × 10⁻⁸, respectively.

See this image and copyright information in PMC

References

1. Thylefors B, Negrel AD, Pararajasegaram R, Dadzie KY. Global data on blindness. Bull. World Health Organ. 1995;73:115–121. - PMC - PubMed
1. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol. 2006;90:262–267. - PMC - PubMed
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Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous