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Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma


Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10−15), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10−16), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10−14), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10−11), and DPM2FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10−12). We also confirmed significant association at three previously described loci (P < 5 × 10−8 for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1ST18)1, providing new insights into the biology of PACG.

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Figure 1: Distribution of PACG cases and controls from the GWAS discovery stage, which encompassed collections from 15 countries.
Figure 2: Results of the discovery GWAS meta-analysis.
Figure 3: Forest plots for the five new genome-wide significant loci.


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This research is supported by the Singapore Ministry of Health's National Medical Research Council under its Translational and Clinical Research (TCR) Flagship Programme Grant Stratified Medicine for Primary Angle Closure Glaucoma (NMRC/TCR/008-SERI/2013) and the Singapore Translational Research (STaR) Investigator Award Singapore Angle Closure Glaucoma Program Characterization, Prevention, and Management (NMRC/STAR/0023/2014), as well as the Biomedical Research Council, Agency for Science, Technology and Research (A-STAR), Singapore. A.T.L.-S. gratefully acknowledges support from grants RUI 1001/PPSP/812101 and RUI 1001/PPSP/812152 from the Universiti Sains Malaysia. H.J., C.Q., and N. Wang acknowledge support from the Program of Beijing Scholars (2013), Leading Talents–High-Level Talents of the Health System of Beijing (2009-1-05), and the National Major Scientific and Technological Special Project for 'Significant New Drugs Development' (2011ZX09302-007-05), as well as Project of the National Natural Science Foundation of China (81570837) grants.

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Authors and Affiliations



T.A. and C.C. Khor conceived the project. T. Do., H.J., M.N., R.G., K.A.-A., R. Duvesh., L.J.C., Z.L., M.E.N., S.A.P., C.Q., H.-T.W., H. Sakai., M.B.d.M., Y.A., T.L.H.D., Y.I., R.A.P.-G., T.Z., A.C.D., J.B.J., P.O.S.T., T.A.T., H.A., F.A., S.M., P.T.K.C., L.A.A., T. Dada., T.T.L., M.S.A., N.K., B.W., Y.Y.A., J.M.-N., S.V., S.S., R.H., A.J., M.B., D.G., D.H.S., H.W., V.K.Y., L.W.Y., T.B.T., M.M., T.T.N., E.U.L., K.-H.P., W.A.W., R.S.K., C.T., Y.K., S.S.T., K.P., J.F.S., Y.H.S., A.F., M.O., J.S.M.L., V.T., C.C. Khaing., T.M., S.N., C.-Y.K., G.T., S.F., R.W., H.M., T.T.G.N., T.D.T., M.U., J.M.M., N.R., Y.M.A., R.D.R., S.A.V., S.K.F., Z.X., X.Y.C., J.N.F., K.S.S., T.T.W., D.T.Q., R.V., S. Kavitha., S.R.K., N. Soumittra., B.S., B.-A.L., J.O., J.P.C.d.V., V.P.C., R.Y.A., B.B.d.S., C.C.S., M.C.A., E.K.-J., G.B.F., V.C.T., R.F., Y.J., N. Waseem., S.L., H.N.P., S.A.-S., E.R.C., M.I.K., R. Dada., K. Mohanty., M.A.F., A.W.H., K.P.B., E.H.G., A.P., T.P., M.A.T.C., I.R.F., C.S.L., E.R., V.W.I., G.C., G.P., C.L., P.R., L.M., S.C., J.C.H.C., B.N.K.C., J.W.H.S., H.M.T., K.T.O., A.T.H., V.H.Y., X.-Y.N., F.P., D.P., P.F., J.J.W., P.M., J.H.F., R.R.A., M.A.H., R. Stead., R. Quino., S.N.Z., U.L., R. Shetty., M.Z., H.W.B., N.L.O., T.K., A.M., W.L.H., L.D., Y.H.H., C.A.K., M.K., Z.E.D., J.I.M.P., A.G., J.W.J., T.S.H., N. Srisamran, T.S., S.H.S., V.H.D., S.S.B., C.-L.H., D.T.T., R. Sihota., S.-C.L., K. Mori., S. Kinoshita., A.I.d.H., R. Qamar., Y.-X.W., Y.Y.T., E.-S.T., C.H.-M., D.L.-G., S.M.S., C.-Y.C., J.C.Z., C.P.P., H.T.T.B., O.H., J.E.C., D.P.E., M.Y., J.M.N., M.L.G.-F., L.X., R.R., A.T.L.-S., T.Y.W., S.A.-O., N.H.D., P.S., C.C.T., P.J.F., L.V., K.T., E.N.V., and N. Wang were responsible for sample collection, data analysis, and sample administration. M.L.H., M.S., E.P., S.J.D., N.V.V.C., J.B., Y.X.Z., A.K., S.T.L., S.H.C., R.P.E., A.S., K.H.P., J.A., G.B., H. Snippe., and B.B. contributed control data sets with genome-wide genotyping data. M.-C.L., A.S.C., S.R.G., Y.F.C., and E.N.V. were responsible for molecular biology work and pathological tissue staining and interpretation. The manuscript was written by C.C. Khor, with approval from all authors. All authors read and approved the final version of the manuscript for publication. T.A. was responsible for obtaining financial support for the study.

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Correspondence to Chiea Chuen Khor, Ningli Wang or Tin Aung.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Regional association analysis for the five newly identified loci surpassing genome-wide significance.

The horizontal axis represents physical distance in megabases on hg37 coordinates. The vertical axis of the left represents –log10 (P values) for association with PACG. The vertical axis on the right represents the recombination rate in centiMorgans and is taken from the HapMap panels.

Supplementary Figure 2 Ocular expression of genes at PACG-associated loci.

(a) Expression analysis of EPDR1, GLIS3, DPM2, FAM102A, FERMT2, and PIP5KL1 in human ocular tissues by RT-PCR using gene-specific primers (Supplementary Table 9). RT-PCR products were observed differentially in sclera (S), cornea (Co), lens with lens capsule (L), iris (I), trabecular meshwork (TM), ciliary body (CB), retina (R), choroid (Ch), optic nerve head (ONH), and optic nerve (ON). The ubiquitously expressed gene ACTB was used as the normalizing control. A no-template sample acted as the negative control (NC) to ensure no contamination of the RT-PCR reaction mix. M denotes the molecular weight marker. (bh) Immunoblots of whole-cell lysates from retinal pigment epithelial (ARPE19), non-pigmented ciliary epithelial (NPCE), human trabecular meshwork (HTM), human cervical adenocarcinoma (Hela S), human breast adenocarcinoma (MCF7), and human embryonic kidney epithelial (HEK 293) cells, probed for CHAT, EPDR1, GLIS3, DPM2, FAM102A, FERMT2, and PIP5KL1 proteins and GAPDH, as a loading control. The protein isoforms detected by the respective antibodies were CHAT (83 kDa), EPDR1 (~25 kDa and ~18 kDa corresponding to two alternatively spliced forms of EPDR1), GLIS3 (~118 kDa and 90 kDa corresponding to two alternatively spliced forms of GLIS3), DPM2 (~17 kDa), FAM102A (37 kDa), FERMT2 (~78 kDa), and PIP5KL1 (22 kDa). The arrowheads indicate specific protein bands.

Supplementary Figure 3 Analysis of CHAT distribution in human ocular tissues.

(a) Strong diffuse immunoreactivity of CHAT was detected in the posterior iris epithelium (PIE) and anterior iris border (AIB). In the iris stroma (IS), the iris stromal cells also show moderate to strong positive staining for CHAT, whereas the iris dilator muscle shows only weak and variable immunoreactivity. (b) In the ciliary body, pronounced yet diffuse staining of CHAT was detected in the pigmented ciliary epithelium (PCE). (c) The ciliary muscles (CM) showed strong and diffuse staining of the CHAT protein, whereas more moderate immunoreactivity was detected in the trabecular meshwork (TM) along the trabecular beams. (d,e) The corneal epithelium (C. Epi) and Descemet’s membrane (Descemet’s) demonstrated positive immunoreactivity for CHAT in contrast to the negative staining in stromal keratocytes, corneal stroma (C. Stroma), and endothelial cells (C. Endo). (f) In the retina, CHAT expression was diffusely and strongly positive in photoreceptors (PR). Negative immunoreactivity was seen in the nerve fiber layer, ganglion cell layer (GCL) inner plexiform layer, inner nuclear layer (INL), outer plexiform layer, and outer nuclear layer (ONL).

Supplementary Figure 4 Analysis of EPDR1 distribution in human ocular tissues.

(a) In the iris, diffuse and strong immunoreactivity for EPDR1 was seen throughout the iris tissue. These areas included the posterior iris epithelium (PIE), iris dilator muscle (IDM), cells within the iris stroma (IS) as well as the iris capillaries (IC), and anterior iris border (AIB). (b) In the ciliary body, EPDR1 protein expression was detected as diffuse and strongly positive immunoreactivity in ciliary body vessels (CBV) and non-pigmented ciliary epithelium (NPCE). Although positive staining was detected in pigmented ciliary epithelium (PCE), the intensity was weaker than those for NPCE and CBV. (c) EPDR1 protein was also expressed throughout the trabecular meshwork (TM) and Schlemm’s canal (SC). (d,e) In the cornea, EPDR1 was detected in the cornea epithelium (C. Epi.) and cornea endothelial (C. Endo) layers. (f) In the retina, EPDR1 staining was detected in the nerve fiber layer (NFL), ganglion cell layer (GCL), inner plexiform layer (IPL), outer plexiform layer (OPL), and photoreceptors (PR).

Supplementary Figure 5 Analysis of FERMT2 distribution in human ocular tissues.

(a) In the iris, strong and diffuse FERMT2 immunoreactivity was detected in the iris dilator muscle (IDM). Moderate to strong immunoreactivity was also seen in cells within the iris stroma (IS) and iris capillaries (IC), whereas the anterior iris border showed only moderate immunoreactivity. (b) In the ciliary body, strong FERMT2 expression was detected in both non-pigmented ciliary epithelium (NPCE) and pigmented ciliary epithelium (PCE). (c) Strong FERMT2 immunoreactivity was detected in the ciliary muscles (CM), trabecular meshwork (TM), and Schlemm’s canal (SC). (d,e) In the cornea, FERMT2 expression was observed in cornea epithelium (C. Epi.) and cornea endothelium (C. Endo.). (f) In the retina, FERMT2 was variably expressed in the retinal layers, with strong and diffuse immunoreactivity detected in the photoreceptors (PR) and moderate immunoreactivity seen in the outer plexiform layer (OPL).

Supplementary Figure 6 Analysis of GLIS3 distribution in human ocular tissues.

(a) In the iris, GLIS3 showed strong and diffuse immunoreactivity in iris dilator muscle (IDM) and the anterior iris border (AIB). A positive punctate membranous staining pattern in addition to weaker cytoplasmic staining was observed in posterior pigment epithelium of the posterior iris epithelium (PIE). The cells in the iris stroma (IS) also demonstrated strong positive GLIS3 immunoreactivity. (b) GLIS3 protein expression was prominently seen in the ciliary muscle (CM). Strong and diffuse immunoreactivity was detected in the non-pigmented ciliary epithelium (NPCE), pigmented ciliary epithelium (PCE), and ciliary muscle (CM). (c) In the trabecular meshwork (TM) and Schlemm’s canal (SC), strong and diffuse immunoreactivity was detected. (d,e) In the cornea, GLIS3 expression was detected in the cornea epithelium (C. Epi.) and cornea endothelium (C. Endo.). (f) In the retina, distinct strong and diffuse GLIS3 immunoreactivity was detected in the photoreceptors (PR) and outer plexiform layer (OPL), with much weaker variable immunoreactivity detected in the ganglion cell layer (GCL).

Supplementary Figure 7 Analysis of DPM2 distribution in human ocular tissues.

(a) In the iris, strong DPM2 expression was detected in the anterior iris border (AIB), cells within the iris stroma (IS), and iris capillaries (IC), with only moderate intensity of DPM2 immunostaining detected in iris dilator muscle (IDM). (b) DPM2 protein was found to be diffusely expressed in the ciliary body. Strong immunoreactivity was detected in both non-pigmented ciliary epithelium (NPCE) and pigmented ciliary epithelium (PCE), ciliary body blood vessels (CBV), and also ciliary muscle (CM). (c) DPM2 immunoreactivity was seen in trabecular meshwork (TM) and Schlemm’s canal (SC). (d,e) In the cornea, DPM2 expression was observed in cornea stromal (C. stroma) collagen fibers but not keratocytes. Immunoreactivity to DPM2 was also seen in the cornea epithelium (C. Epi) and cornea endothelium (C. Endo.) IDM. (f) In the retina, strong and diffuse immunoreactivity of DPM2 was detected in the photoreceptors (PR) in contrast to the much weaker immunoreactivity seen in the outer plexiform layer (OPL) and the ganglion cell layer (GCL).

Supplementary Figure 8 Analysis of PIP5KL1 distribution in human ocular tissues.

(a) In the iris, pronounced and diffuse staining of PIP5KL1 was detected in the iris dilator muscle (IDM). Strong immunoreactivity was also seen in iris stromal cells (IS) and iris capillaries (IC). (b) PIP5KL1 expression was diffuse with strong positive staining observed in the non-pigmented ciliary epithelium (NPCE). A weaker staining profile was observed in pigmented ciliary epithelium (PCE), which is constrained to PCE cell–cell borders. (c) In the trabecular meshwork (TM) and Schlemm’s canal (SC), strong immunoreactivity of PIP5KL1 was detected in TM beams and endothelial cells of the Schlemm’s canal. (d,e) In the cornea, PIP5KL1 was strongly expressed in the nuclei and cytoplasm of the corneal epithelium (C. Epi.). Positive staining of stromal keratocytes was also seen. The corneal endothelium (C. Endo) showed intense immunoreactivity to PIP5KL1. (f) In the retina, PIP5KL1 immunoreactivity in the outer limiting membrane (OLM) was distinctly prominent in comparison to the rest of the retinal layers. Similarly, the ganglion cell layer (GCL) also showed strong nuclear positive staining for PIP5KL1. In contrast, mild to moderate variable expression of PIP5KL1 protein was seen in photoreceptors (PR). Weak and variable immunoreactivity could be seen in the inner plexiform layer (IPL) and the inner nuclear layer (INL). The rest of the retina showed no significant immunoreactivity to PIP5KL1.

Supplementary Figure 9 Analysis of FAM102A distribution in human ocular tissues.

(a) In the iris, strong immunoreactivity of FAM102A protein was seen in the anterior iris border (AIB), iris stromal cells (IS), and the iris dilator muscle (IDM). Moderate and punctate staining of the posterior border of the posterior pigment epithelium portion of the posterior iris epithelium (PIE) was also seen. (b) In the ciliary body, strong immunoreactivity for FAM102A protein was limited to pigmented ciliary epithelium (PCE) and non-pigmented ciliary epithelium (NPCE), with PCE having stronger immunoreactivity. (c) Moderate immunoreactivity of FAM102A was observed in the trabecular meshwork (TM), Schlemm’s canal (SC), and ciliary muscle (CM). (d,e) In cornea, only the basal epithelial layer of the cornea epithelium (C. Epi.) and corneal endothelial cells (C. Endo.) showed moderate FAM102A protein immunoreactivity. (f) In the retina, strong FAM102A immunoreactivity was distinctly localized to the outer limiting membrane (OLM), photoreceptors (PR), and nuclei of the ganglion cell layer (GCL). Patchy moderate immunoreactivity of FAM102A was also noted in the outer plexiform layer (OPL). The rest of the retinal layers showed no significant immunoreactivity to FAM102A.

Supplementary Figure 10 Distribution of PACG cases and controls of East Asian descent from the GWAS discovery stage.

PACG cases and controls are projected onto the top two principal components of genetic stratification, with cases on the left panel and controls on the right panel.

Supplementary Figure 11 Detailed ancestry analysis of PACG cases and controls from the GWAS discovery stage, which encompassed collections from 15 countries.

(a-f) The genetic principal components (PCs) for cases and controls are projected onto PC1 vs. PC3 (a), PC1 vs. PC4 (b), PC1 vs. PC5 (c), PC2 vs. PC3 (d), PC3 vs. PC4 (e), and PC4 vs PC5 (f). For each panel, PACG cases are projected on the left and controls on the right.

Supplementary Figure 12 Quantile-quantile plot showing the association results for the GWAS discovery stage encompassing 6,525 PACG cases and 19,929 controls.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12, Supplementary Note and Supplementary Tables 1–8, 10 and 11. (PDF 5580 kb)

Supplementary Table 9

Variants located within predicted regulatory regions and in LD (r2 >0.8) with the top SNPs in the five newly identified loci. (XLSX 29 kb)

Supplementary Data Set

Summary association statistics of the PACG GWAS SNPs with direct microarray genotyping together with imputation fine-mapping of the genome-wide significant loci. (TXT 29091 kb)

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Khor, C., Do, T., Jia, H. et al. Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma. Nat Genet 48, 556–562 (2016).

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