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. 2016 Feb;48(2):189-94.
doi: 10.1038/ng.3482. Epub 2016 Jan 11.

Genome-wide Association Analysis Identifies TXNRD2, ATXN2 and FOXC1 as Susceptibility Loci for Primary Open-Angle Glaucoma

Jessica N Cooke Bailey  1 Stephanie J Loomis  2 Jae H Kang  3 R Rand Allingham  4 Puya Gharahkhani  5 Chiea Chuen Khor  6   7 Kathryn P Burdon  8   9 Hugues Aschard  10 Daniel I Chasman  11 Robert P Igo Jr  1 Pirro G Hysi  12 Craig A Glastonbury  12 Allison Ashley-Koch  13 Murray Brilliant  14 Andrew A Brown  15 Donald L Budenz  16 Alfonso Buil  15 Ching-Yu Cheng  7   17   18 Hyon Choi  19 William G Christen  11 Gary Curhan  3   20 Immaculata De Vivo  3 John H Fingert  21   22 Paul J Foster  23   24 Charles Fuchs  3   25 Douglas Gaasterland  26 Terry Gaasterland  27 Alex W Hewitt  28   29 Frank Hu  10   30 David J Hunter  10   31 Anthony P Khawaja  32 Richard K Lee  33 Zheng Li  6 Paul R Lichter  34 David A Mackey  8   35 Peter McGuffin  36 Paul Mitchell  37 Sayoko E Moroi  34 Shamira A Perera  17   38 Keating W Pepper  39 Qibin Qi  40 Tony Realini  41 Julia E Richards  34   42 Paul M Ridker  11 Eric Rimm  3   10   30 Robert Ritch  43 Marylyn Ritchie  44 Joel S Schuman  45 William K Scott  46 Kuldev Singh  47 Arthur J Sit  48 Yeunjoo E Song  1 Rulla M Tamimi  3 Fotis Topouzis  49 Ananth C Viswanathan  23 Shefali Setia Verma  44 Douglas Vollrath  50 Jie Jin Wang  37 Nicole Weisschuh  51 Bernd Wissinger  51 Gadi Wollstein  45 Tien Y Wong  7   17 Brian L Yaspan  52 Donald J Zack  53 Kang Zhang  54 Epic-Norfolk Eye Study  55 ANZRAG ConsortiumRobert N Weinreb  54 Margaret A Pericak-Vance  46 Kerrin Small  12 Christopher J Hammond  12 Tin Aung  17   18 Yutao Liu  55   56 Eranga N Vithana  17   18 Stuart MacGregor  5 Jamie E Craig  9 Peter Kraft  10   31 Gareth Howell  39 Michael A Hauser  4   13 Louis R Pasquale  2   3 Jonathan L Haines  1 Janey L Wiggs  2
Free PMC article

Genome-wide Association Analysis Identifies TXNRD2, ATXN2 and FOXC1 as Susceptibility Loci for Primary Open-Angle Glaucoma

Jessica N Cooke Bailey et al. Nat Genet. .
Free PMC article


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.


Figure 1
Figure 1. Association results for the regions reaching genome-wide significance after stage 2
These plots show the regional association and recombination rates for the top SNPs in the discovery cohort (NEIGHBORHOOD, 3,853 cases and 33,480 controls) after meta-analysis with data for these SNPs from ANZRAG (1,155 cases and 1,992 controls). In each plot, the solid diamond indicates the top-ranked SNP in the region based on two-sided P values. The colored box at the right or left corner of each plot indicates the pairwise correlation (r2) between the top SNP and the other SNPs in the region. The blue spikes show the estimated recombination rates. The box underneath each plot shows the gene annotations in the region. Each plot was created using LocusZoom for the top-ranked SNP in each region with a 400 kb region surrounding it. (a) The top SNP for this plot is rs2745572 on chromosome 6 upstream of FOXC1 with P = 6.50×10−11. (b) The top SNP for this plot is rs7137828 on chromosome 12 within ATXN2 with P = 9.20×10−9. (c) The top SNP for this plot is rs35934224 on chromosome 22 within TXNRD2 with P = 1.08×10−9.
Figure 2
Figure 2. Meta-analysis Results
Forest plots showing effect estimates for participating studies, as well as for the replication effort. Pooled estimates for odds ratios and 95% confidence intervals were calculated by fixed effects, inverse variance weighting meta-analysis. Individual dataset results are indicated by blue squares and summary values are indicated by black diamonds. (Top) Association results for rs2745572 (FOXC1 region top SNP). (Middle) Association results for rs7137828 (ATXN2 region top SNP). (Bottom) Association results for rs35934224 (TXNRD2 region top SNP). For the overall NEIGHBORHOOD (NBH), the summary value for the population cohorts (POP; NHS/HPFS/WGHS) are presented separately from the case/control cohorts (CC; Iowa, OHTS (Ocular Hypertension Treatment Study), Marshfield, MEEI, NEIGHBOR). Results for the individual NBH datasets are shown in Supplementary Figure 4. Individual and summary results for Stage 2 (ANZ and ANZ+NBH) and Stage 3 cohorts (EPIC, GER, UK, BMES, SC) and summary points for all European ancestry (EU) datasets and all datasets (EU + SC) are shown. For rs7137828 replication could not be completed in SC due to rare minor allele frequency. Total sample size for rs2745572 and rs35934224 is 7,027 cases and 42,772 controls, and for rs7137828, 5,990 cases and 40,179 controls. Abbreviations: ANZ, ANZRAG;EPIC, European Prospective Investigation into Cancer-Norfolk Eye Study; GER, Germany; UK, United Kingdom; SC, Singapore Chinese; EU, European ancestry.
Figure 3
Figure 3. ATXN2 and TXNRD2 are expressed in the retina and optic nerve head
(A) Representative images of immunofluorescence using an anti-ATXN2 antibody shows ATXN2 (green) present in cells in the ganglion cell layer (arrows, upper panels) as well as punctate staining in the inner plexiform layer (arrowhead, right most upper panel). Only a low level of punctate staining was observed in the optic nerve head (arrowhead, lower panels). (B) Representative images of immunofluorescence using an anti-TXNRD2 antibody shows TXNRD2 (green) present in cells in the ganglion cell layer (arrows, upper panels) as well as significant punctate staining in the inner plexiform layer (arrowheads, right most panel). Significant staining was also observed in cells in the optic nerve head (lower panels) indicative of astrocytes that form pial columns (arrows, right most panel). Punctate staining was also observed in the optic nerve head (arrowheads, lower panels). For each antibody, at least 3 sections from 6 eyes were assessed. No staining (not even punctate staining) was observed in the no primary control tissue (data not shown). Blue=DAPI. In all rows, right most panels are boxed regions in center panels. Scale bars: Upper left and center panels in A and B = 20 μm; Lower left and center panels in A = 15 μm; Lower left center and panels in B = 25 μm; Right most panels in A and B = 5 μm.

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