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

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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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Figure 1: Manhattan plot of all stage 1 data for 1,854 PACG cases and 9,609 controls.
Figure 2: Regional association and recombination rate plots for stage 1 data.

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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

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.

Correspondence to Ningli Wang or Tin Aung.

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