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Common variants near ABCA1 and in PMM2 are associated with primary open-angle glaucoma

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We performed a genome-wide association study for primary open-angle glaucoma (POAG) in 1,007 cases with high-pressure glaucoma (HPG) and 1,009 controls from southern China. We observed genome-wide significant association at multiple SNPs near ABCA1 at 9q31.1 (rs2487032; P = 1.66 × 10−8) and suggestive evidence of association in PMM2 at 16p13.2 (rs3785176; P = 3.18 × 10−6). We replicated these findings in a set of 525 HPG cases and 912 controls from Singapore and a further set of 1,374 POAG cases and 4,053 controls from China. We observed genome-wide significant association with more than one SNP at the two loci (P = 2.79 × 10−19 for rs2487032 representing ABCA1 and P = 5.77 × 10−10 for rs3785176 representing PMM2). Both ABCA1 and PMM2 are expressed in the trabecular meshwork, optic nerve and other ocular tissues. In addition, ABCA1 is highly expressed in the ganglion cell layer of the retina, a finding consistent with it having a role in the development of glaucoma.

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Figure 1: Regional association and recombination rate plots.
Figure 2: ABCA1 and PMM2 expression and localization in ocular tissues.

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  • 09 September 2014

    In the version of this article initially published online, there were separate errors in the affiliations and in the Acknowledgments. In the affiliations, Chiea Chuen Khor and Chi Pui Pang are not affiliated with Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China, and the last four authors (Chiea Chuen Khor, Chi Pui Pang, Xinghuai Sun and Zhenglin Yang) jointly directed the work. In the Acknowledgments, two grants from the Biomedical Research Council, Singapore, were incorrectly assigned. Tien Yin Wong is the recipient of BMRC 09/1/35/19/616, and Eranga N. Vithana and Chiea Chuen Khor are the joint recipients of BMRC 10/1/35/19/675. These errors have been corrected for the print, PDF and HTML versions of this article.


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We thank all the individuals with POAG and their families for participating in this study. The samples from Fudan University used for the analyses described in this manuscript were obtained from the EENT Hospital Biobank. We also thank B. Zhao and J. Sang of Beijing Tongren Hospital for sample collection. This research project was supported by the National Natural Science Foundation of China (81025006 (Z.Y.), 81170883 (Z.Y.), 81430008 (Z.Y.), 81200723 (Y. Chen), 81271007 (X. Zhu) and 81271005 (N.W.)); the National Basic Research Program of China (973 Program, 2011CB504604 to Z.Y.); the Department of Science and Technology of Sichuan Province, China (2014SZ0169 (Z.Y.), 2012SZ0219 (Z.Y.) and 2011jtd0020 (Z.Y.)); the Special Scientific Research Project of Health Professions (201302015 (X.S.)); research grants 467708 (C.P.P. and C.C.Y.T.) and 468810 (C.P.P. and C.K.S.L.) from the General Research Fund, Hong Kong; the National Medical Research Council, Singapore (NMRC/TCR/002-SERI/2008 (R626/47/2008TCR (T.A.)), CSA R613/34/2008 (T.A.), NMRC 0796/2003 (T.Y.W.) and STaR/0003/2008 (T.Y.W.)); the National Research Foundation of Singapore, Biomedical Research Council, Singapore (BMRC 09/1/35/19/616 (T.Y.W.), 08/1/35/19/550 (T.A.) and 10/1/35/19/675 (E.N.V. and C.C.K.)); and the Genome Institute of Singapore (GIS/12-AR2105 (C.C.K.)).

Author information

Authors and Affiliations



Z.Y., X.S., C.P.P. and Y. Chen designed the study. Y. Chen, Y.L., E.N.V., L.J., T.Y.W., L.J.C., P.O.S.T., S.Q., Z.L., B.M., Q.L., C.G., C.K.S.L., W.C., C.C.Y.T., Y. Cheng, N.W., T.A., C.C.K., C.P.P., X.S. and Z.Y. recruited the participants. C.C.K., Y.L., X. Li and Z.Y. performed the genotyping. X. Zuo, Y. Chen, Y.L., C.C.K., X. Liu, X. Zhang, Q.Y. and Z.Y. performed the statistical analysis. B.G., X. Zhu, X. Liu and Z.Y. performed the immunohistochemistry and gene expression studies. Z.Y. wrote the initial draft, with edits from C.C.K. Q.Y. and C.P.P. corrected the English spelling and grammar. All authors critically revised and gave final approval of this manuscript.

Corresponding authors

Correspondence to Xinghuai Sun or Zhenglin Yang.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Flow chart of experimental work.

Supplementary Figure 2 Principal-components analysis (PCA) for the GWAS samples.

PCA was performed on the 1,971 GWAS samples (966 cases and 1,005 controls).

Supplementary Figure 3 Quantile-quantile plots of observed P values (−log10 P) for association.

The genomic inflation factor (λ) in the GWAS was 1.016.

Supplementary Figure 4 Association results for genotyped SNPs at the discovery stage.

The genome-wide distribution of −log10 P values from the unadjusted Cochran-Armitage trend test is shown across the chromosomes. Values are shown for 870,261 SNPs that were of sufficient quality, after quality control filtering, in 966 unrelated Han Chinese cases with HPG and in 1,005 unrelated Han Chinese controls, after genetic matching and correction for the inflation factor of 1.016. Each chromosome is depicted in a different color. −log10 (UNADJ), the −log10 P value of the Cochran-Armitage trend test, was not adjusted for multiple testing.

Supplementary Figure 5 LD block analysis of the POAG-associated SNPs at the chromosome 9 ABCA1 locus (top) and the chromosome 16 PMM2 locus (bottom).

Numbers within the filled diamonds reflect the pairwise LD value between the markers using the r2 algorithm.

Supplementary Figure 6 LD block analysis of the disease-associated SNPs in the ABCA1 gene and their relationship with previously described markers also mapping to ABCA1 showing association with HDL and CAD.

LD block analysis was performed using CHB genotyping data from the dbSNP database. Previous studies indicated that rs4149274 in intron 5 of the ABCA1 gene was significantly associated with HDL and CAD, and rs4149274 and rs1883025 in intron 2 of the ABCA1 gene were shown to be significantly associated with AMD. rs2164560, rs2472459 and rs2472519 are associated with POAG in this study. Values for r2 (left) and D′ (right) are shown in the block.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1–7 and Supplementary Note. (PDF 3242 kb)

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Chen, Y., Lin, Y., Vithana, E. et al. Common variants near ABCA1 and in PMM2 are associated with primary open-angle glaucoma. Nat Genet 46, 1115–1119 (2014).

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