Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Abstract

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10−11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10−10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10−10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Association results for the regions reaching genome-wide significance after stage 2.
Figure 2: Meta-analysis results.
Figure 3: ATXN2 and TXNRD2 are expressed in mouse retina and optic nerve head.

Similar content being viewed by others

Accession codes

Accessions

NCBI Reference Sequence

References

  1. Quigley, H.A. & Broman, A.T. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol. 90, 262–267 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tham, Y.C. et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 121, 2081–2090 (2014).

    Article  PubMed  Google Scholar 

  3. Wang, Y.X., Xu, L., Yang, H. & Jonas, J.B. Prevalence of glaucoma in North China: the Beijing Eye Study. Am. J. Ophthalmol. 150, 917–924 (2010).

    Article  PubMed  Google Scholar 

  4. Weinreb, R.N., Aung, T. & Medeiros, F.A. The pathophysiology and treatment of glaucoma: a review. J. Am. Med. Assoc. 311, 1901–1911 (2014).

    Article  CAS  Google Scholar 

  5. Thorleifsson, G. et al. Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat. Genet. 42, 906–909 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Burdon, K.P. et al. Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat. Genet. 43, 574–578 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Wiggs, J.L. et al. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet. 8, e1002654 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gharahkhani, P. et al. Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma. Nat. Genet. 46, 1120–1125 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Feuer, W.J. et al. The Ocular Hypertension Treatment Study: reproducibility of cup/disk ratio measurements over time at an optic disc reading center. Am. J. Ophthalmol. 133, 19–28 (2002).

    Article  PubMed  Google Scholar 

  11. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Howie, B., Fuchsberger, C., Stephens, M., Marchini, J. & Abecasis, G.R. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955–959 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fuchsberger, C., Abecasis, G.R. & Hinds, D.A. minimac2: faster genotype imputation. Bioinformatics 31, 782–784 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Aulchenko, Y.S., Struchalin, M.V. & van Duijn, C.M. ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11, 134 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Willer, C.J., Li, Y. & Abecasis, G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. van Koolwijk, L.M. et al. Common genetic determinants of intraocular pressure and primary open-angle glaucoma. PLoS Genet. 8, e1002611 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ozel, A.B. et al. Genome-wide association study and meta-analysis of intraocular pressure. Hum. Genet. 133, 41–57 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Hysi, P.G. et al. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma. Nat. Genet. 46, 1126–1130 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gorlova, O. et al. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genet. 7, e1002178 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Woo, D. et al. Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage. Am. J. Hum. Genet. 94, 511–521 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Anderson, D.R., Drance, S.M. & Schulzer, M. Natural history of normal-tension glaucoma. Ophthalmology 108, 247–253 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Carnes, M.U. et al. Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma. PLoS Genet. 10, e1004372 (2014).

    Article  PubMed  CAS  Google Scholar 

  24. ENCODE Project Consortium. A user's guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol. 9, e1001046 (2011).

  25. Gamazon, E.R. et al. SCAN: SNP and copy number annotation. Bioinformatics 26, 259–262 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Yang, T.P. et al. Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies. Bioinformatics 26, 2474–2476 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).

  28. Ward, L.D. & Kellis, M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40, D930–D934 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Boyle, A.P. et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22, 1790–1797 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schuhmacher, L.N., Albadri, S., Ramialison, M. & Poggi, L. Evolutionary relationships and diversification of barhl genes within retinal cell lineages. BMC Evol. Biol. 11, 340 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Macgregor, S. et al. Genome-wide association identifies ATOH7 as a major gene determining human optic disc size. Hum. Mol. Genet. 19, 2716–2724 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen, J.H. et al. Interactive effects of ATOH7 and RFTN1 in association with adult-onset primary open-angle glaucoma. Invest. Ophthalmol. Vis. Sci. 53, 779–785 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Donovan, K., Alekseev, O., Qi, X., Cho, W. & Azizkhan-Clifford, J. O-GlcNAc modification of transcription factor Sp1 mediates hyperglycemia-induced VEGF-A upregulation in retinal cells. Invest. Ophthalmol. Vis. Sci. 55, 7862–7873 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mabuchi, F. et al. Estrogen receptor β gene polymorphism and intraocular pressure elevation in female patients with primary open-angle glaucoma. Am. J. Ophthalmol. 149, 826 −30.e1, 2 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Sun, Z. et al. Conserved recurrent gene mutations correlate with pathway deregulation and clinical outcomes of lung adenocarcinoma in never-smokers. BMC Med. Genomics 7, 32–43 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Grundberg, E. et al. Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat. Genet. 44, 1084–1089 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Buil, A.B. et al. Transcriptome sequencing reveals widespread gene-gene and gene-environment interactions. Nat. Genet. 47, 88–91 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Lu, T. et al. REST and stress resistance in ageing and Alzheimer's disease. Nature 507, 448–454 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ito, Y.A., Goping, I.S., Berry, F. & Walter, M.A. Dysfunction of the stress-responsive FOXC1 transcription factor contributes to the earlier-onset glaucoma observed in Axenfeld-Rieger syndrome patients. Cell Death Dis. 5, e1069 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. D'haene, B. et al. Expanding the spectrum of FOXC1 and PITX2 mutations and copy number changes in patients with anterior segment malformations. Invest. Ophthalmol. Vis. Sci. 52, 324–333 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Lattante, S. et al. Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders. Neurology 83, 990–995 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cirulli, E.T. et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347, 1436–1441 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Ikram, M.K. et al. Four novel loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. PLoS Genet. 6, e1001184 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Chen, Y., Cai, J. & Jones, D.P. Mitochondrial thioredoxin in regulation of oxidant-induced cell death. FEBS Lett. 580, 6596–6602 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chrysostomou, V., Rezania, F., Trounce, I.A. & Crowston, J.G. Oxidative stress and mitochondrial dysfunction in glaucoma. Curr. Opin. Pharmacol. 13, 12–15 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Caprioli, J., Munemasa, Y., Kwong, J.M. & Piri, N. Overexpression of thioredoxins 1 and 2 increases retinal ganglion cell survival after pharmacologically induced oxidative stress, optic nerve transection, and in experimental glaucoma. Trans. Am. Ophthalmol. Soc. 107, 161–165 (2009).

    PubMed  PubMed Central  Google Scholar 

  48. Purcell, S., Cherny, S.S. & Sham, P.C. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19, 149–150 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Flicek, P. et al. Ensembl 2014. Nucleic Acids Res. 42, D749–D755 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Kent, W.J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Safran, M. et al. GeneCards Version 3: the human gene integrator. Database (Oxford) 2010, baq020 (2010).

    Article  Google Scholar 

  52. Yang, J., Lee, S.H., Goddard, M.E. & Visscher, P.M. Genome-wide complex trait analysis (GCTA): methods, data analyses, and interpretations. Methods Mol. Biol. 1019, 215–236 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Liu, Y. et al. Serial analysis of gene expression (SAGE) in normal human trabecular meshwork. Mol. Vis. 17, 885–893 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Liu, Y. et al. Gene expression profile in human trabecular meshwork from patients with primary open-angle glaucoma. Invest. Ophthalmol. Vis. Sci. 54, 6382–6389 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

NEIGHBORHOOD data collection and analysis are supported by US National Institutes of Health/National Eye Institute (NIH/NEI) grant R01EY022305 (J.L.W.). Support for recruitment in ANZRAG (Australian and New Zealand Registry of Advanced Glaucoma) was provided by the Royal Australian and New Zealand College of Ophthalmology (RANZCO) Eye Foundation and by the National Health and Medical Research Council (NHMRC) of Australia (535074, 1031362, 1023911 and 1021105). EPIC-Norfolk infrastructure and core functions are supported by grants from the UK Medical Research Council (G1000143) and Cancer Research UK (C864/A14136). BMES (Blue Mountains Eye Study) was supported by the NHMRC, the Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases, NHMRC Senior Research Fellowships and the Wellcome Trust, UK. Collection and genotyping for the South London Case-Control cohort (UK) were supported by a National Institute for Health Research (NIHR) Senior Research Fellowship (C.J.H.), and analysis was supported by a Fight for Sight Early Career Investigator Award (P.J.H.). The Singapore study (E.N.V., T.A. and C.C.K.) was supported by a Biomedical Research Council (BMRC) grant in Singapore, reference BMRC 10/1/35/19/675. This research was also partly supported by a grant (NMRC/TCR/008-SERI/2013) from the Singapore National Research Foundation under its Translational and Clinical Research Flagship Programme and administered by the Singapore Ministry of Health's National Medical Research Council. Additional acknowledgment and funding details are in the Supplementary Note.

Author information

Authors and Affiliations

Authors

Consortia

Contributions

J.N.C.B., L.R.P., J.H.K., J.L.H. and J.L.W. were involved in designing the study. R.R.A., C.C.K., M.B., D.L.B., H.C., W.G.C., G.C., I.D.V., J.H.F., P.J.F., C.F., D.G., T.G., A.W.H., F.H., D.J.H., R.K.L., Z.L., P.R.L., D.A.M., P. McGuffin, P. Mitchell, S.E.M., S.A.P., Q.Q., T.R., J.E.R., P.M.R., E.R., R.R., J.S.S., W.K.S., K. Singh, A.J.S., R.M.T., F.T., A.C.V., D.V., G.W., T.Y.W., B.L.Y., D.J.Z., K.Z., N.W., B.W., R.N.W., M.A.P.-V., T.A., E.N.V., S.M., J.E.C., M.A.H., L.R.P., J.L.H. and J.L.W. were involved in participant recruitment, sample collection or genotyping. Analysis was performed by J.N.C.B., S.J.L., J.H.K., P.G., C.C.K., K.P.B., A.A.B., A.B., H.A., D.I.C., R.P.I., P.G.H., C.A.G., A.A.-K., C.-Y.C., A.P.K., M.R., K. Small, Y.E.S., S.S.V., J.J.W., C.J.H., P.K., L.R.P., S.M., J.L.H. and J.L.W. The laboratory experiments were designed and conducted by K.W.P., Y.L., G.H. and J.L.W. Clinician assessments were performed by R.R.A., D.L.B., W.G.C., J.H.F., D.G., A.W.H., R.K.L., P.R.L., D.A.M., S.E.M., T.R., R.R., J.S.S., K. Singh, A.J.S., F.T., A.C.V., G.W., T.Y.W., D.J.Z., K.Z., J.E.C., L.R.P. and J.L.W. The initial draft of the manuscript was written by J.N.C.B., L.R.P., J.H.K., J.L.H. and J.L.W.

Corresponding author

Correspondence to Janey L Wiggs.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

A list of members and affiliations is provided in the Supplementary Note.

Integrated supplementary information

Supplementary Figure 1 QQ plots for individual data sets meta-analyzed in NEIGHBORHOOD and the NEIGHBORHOOD meta-analysis.

The top eight panels are QQ plots for individual data sets; the bottom panel is for the NEIGHBORHOOD meta-analysis. NEIGHBORHOOD, National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database; NHS/HPFS, Nurses Health Study/Health Professionals Follow-up Study; MEEI, Massachusetts Eye and Ear Infirmary; NEIGHBOR, National Eye Institute Glaucoma Human Genetics Collaboration; OHTS, Ocular Hypertension Treatment Study; WGHS, Women’s Genome Health Study. Individual λ values are: NHS/HPFS Affymetrix, 1.008; NHS/HPFS Illumina, 1.024; Iowa, 1.031; Marshfield, 1.003; MEEI, 1.007; NEIGHBOR, 1.051; OHTS, 1.015; WGHS, 1.011. The overall NEIGHBORHOOD λ value is 1.064.

Supplementary Figure 2 Sensitivity analysis using the leave-one-out method.

For this analysis, each NEIGHBORHOOD data set was excluded from a meta-analysis of the other data sets. The odds ratios from the meta-analyses were compared by calculating the Pearson’s product-moment correlation coefficient between each leave-one-out analysis and the overall meta-analysis of all eight NEIGHBORHOOD data sets (stage 1). Correlations were calculated in R using the corrplot package and ellipse option. Color intensity and ellipse sharpness increase with increasing Pearson’s correlation coefficient.

Supplementary Figure 3 Association results for POAG in the NEIGHBORHOOD (stage 1) meta-analysis.

SNPs located in novel regions are colored pink, and those in previously known associated regions are colored green. The P values used to create this figure were corrected for the genomic inflation factor (λ = 1.06). Regions reaching genome-wide significance include one novel region (FOXC1) and three regions previously identified (TMCO1, CDKN2BAS and SIX6). The GAS7 region was previously associated with the quantitative risk factor for POAG, IOP. AFAP1 and ABCA1 previously associated with POAG did not reach genome-wide significance. ATXN2 and TXNRD2 surpassed the significance level of P < 1 × 10−5 at stage 1, along with other interesting regions, including 1p, 2p, 2q, 5p, 6p, 6q, 10q and 20p (3,853 cases and 33,480 controls).

Supplementary Figure 4 Forest plots for NEIGHBORHOOD data sets showing association results for the top SNPs in the three novel regions identified in this study.

Square symbols are positioned along the x axis according to OR, with lines representing the confidence interval. The size of the square is inversely proportional to the width of the 95% confidence interval. A summary for all eight NEIGHBORHOOD data sets is shown as the black diamond. OHTS, Ocular Hypertension Treatment Study; MEEI, Massachusetts Eye and Ear Infirmary; MFC, Marshfield Clinic; NHS/HPFS, Nurses Health Study/Health Professionals Follow-up Study; Affy, Affymetrix; Illu, Illumina; WGHS, Women’s Genome Health Study.

Supplementary Figure 5 Association results for NTG in NEIGHBORHOOD (stage 1).

Association results for NTG in NEIGHBORHOOD (stage 1). Regions reaching genome-wide significance include one novel region (C12orf23) and two regions previously identified (8q22 and CDKN2BAS) (725 NTG cases and 11,145 controls).

Supplementary Figure 6 Association results for HTG in NEIGHBORHOOD (stage 1).

Regions reaching genome-wide significance include one novel region (FOXC1) and two regions previously associated with POAG (TMCO1 and SIX6) (1,868 cases and 31,497 controls).

Supplementary Figure 7 FOXC1 5′ regulatory region as annotated by ENCODE.

Seven SNPs in this region reach genome-wide significance (P < 5 × 10−8) in the POAG meta-analysis (stage 2), indicated in black type at the top of the figure. Cell types: GM12878 (B lymphocytes, lymphoblastoid), H1-hESC (embryonic stem cells), K562 (leukemia), HepG2 (hepatocellular carcinoma), HUVEC (umbilical vein endothelial cells), HMEC (mammary epithelial cells), HSMM (skeletal muscle myoblasts), NHEK (epidermal keratinocytes), NHLF (lung fibroblasts). ENCODE annotation: bright red, active promoter; light red, weak promoter; purple, inactive/poised promoter; orange, strong enhancer; yellow, weak/poised enhancer; blue, insulator; dark green, transcriptional transition and transcriptional elongation; light green, weakly transcribed; gray, Polycomb repressed; light gray, heterochromatin, low signal.

Supplementary Figure 8 TXNRD2 eQTL results.

Six of the 22 SNPs significantly associated with POAG in the TXNRD2 region (rs6518585, rs9754418, rs7285948, rs7288170, rs8141610 and rs12158214) on chromosome 22 are eQTLs in lymphoblasts and skin in MuTHER Twins (Grundberg et al., 2012) (GENEVAR http://www.sanger.ac.uk/science/tools/genevar-gene-expression-variation-archive). These data were obtained using microarrays for expression and HapMap 2 imputation. Shown here are the results for rs7288170, which is representative of similar results for all six SNPs. The –log(P value) for the association of the tested SNP (in this example, rs7288170) with RNA level is plotted on the y axis, and the location of the RNA is plotted on the x axis. The TXNRD2 region under the expression peak (chr22:18,229,251–18,251,941; NCBI36/hg18) includes all six eQTL SNPs (expanded region). This region includes a number of regulatory elements annotated by ENCODE. Cell types: GM12878 (B lymphocytes, lymphoblastoid), H1-hESC (embryonic stem cells), K562 (leukemia), HepG2 (hepatocellular carcinoma), HUVEC (umbilical vein endothelial cells), HMEC (mammary epithelial cells), HSMM (skeletal muscle myoblasts), NHEK (epidermal keratinocytes), NHLF (lung fibroblasts). ENCODE annotation: bright red, active promoter; light red, weak promoter; purple, inactive/poised promoter; orange, strong enhancer; yellow, weak/poised enhancer; blue, insulator; dark green, transcriptional transition and transcriptional elongation; light green, weak transcribed; gray, Polycomb repressed; light gray, heterochromatin, low signal.

Supplementary Figure 9 TXNRD2 eQTL results from GTEx.

All 22 SNPs located in the TXNRD2 region significantly associated with POAG after stage 2 are significant cis eQTLs for TXNRD2 in thyroid tissue (shown in the figure), and 19 are also significant cis eQTLs in tibial nerve (P values for expression correlation < 1 × 10−4) in the GTEx database (GTEx Consortium, 2015). The –log10 (P value) is shown on the y axis. rs6518585, rs12158214 and rs3424993 are only significant in thyroid tissue. The location of the significant SNPs is shown in this figure as red dots. Gray dots in the figure are cis-eQTL SNPs in thyroid tissue that did not reach genome-wide significance for association with POAG. The most significant cis-eQTL SNPs are also those that are significantly associated with POAG. The location of the TXNRD2 exons and introns is shown in blue as depicted in the UCSC Genome Browser (http://genome.ucsc.edu/).

Supplementary Figure 10 Conditional analysis for the FOXC1 locus.

Locus zoom plots for the FOXC1 associated region before (top panel) and after (middle panel) analysis conditional on the top GMDS SNP (rs11969985) (Gharahkhani et al., 2014). The bottom panel shows the effect of conditioning on the top FOXC1 SNP from this study (rs2745572). The OR and P value for the top SNP rs2745572 is OR = 1.254, 95% CI = (1.164, 1.351), P = 2.36 x 10−9 before conditioning and OR = 1.252, 95% CI = (1.159, 1.352), P = 1.03 x 10−8 after conditioning on rs11969985.

Supplementary Figure 11 The expression of TXNRD2 and ATXN2 in human ocular tissues by RT-PCR.

Lanes (from left to right): 1, Low mass DNA ladder (100 bp, 200 bp, 400 bp, 800 bp, 1200 bp and 2000 bp); 2, cornea #1; 3, cornea #2; 4, cornea #3; 5, cornea #4; 6, trabecular meshwork #1; 7, trabecular meshwork #2; 8, trabecular meshwork #3; 9, ciliary body #1; 10, ciliary body #2; 11, retina #1; 12, retina #2; 13, optic nerve head #1; 14, optic nerve head #2; 15, optic nerve head #3; 16, low mass DNA ladder. Multiple bands indicate the presence of alternative transcripts for the amplified cDNA. The expected PCR products were 400-500 bp in size. Abbreviations: L, is for low mass DNA ladder, C is for cornea, TM is for trabecular meshwork, CB is for ciliary body, R is for retina, and ON is for optic nerve head.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11, Supplementary Tables 1–10 and Supplementary Note. (PDF 6131 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bailey, J., Loomis, S., Kang, J. et al. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet 48, 189–194 (2016). https://doi.org/10.1038/ng.3482

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.3482

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing