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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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.)).
The authors declare no competing financial interests.
Integrated supplementary information
PCA was performed on the 1,971 GWAS samples (966 cases and 1,005 controls).
The genomic inflation factor (λ) in the GWAS was 1.016.
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.
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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). https://doi.org/10.1038/ng.3078
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