Epistasis pp 217-255 | Cite as

Identification of Genome-Wide SNP–SNP and SNP–Clinical Boolean Interactions in Age-Related Macular Degeneration

  • Carlos RiverosEmail author
  • Renato Vimieiro
  • Elizabeth G. Holliday
  • Christopher Oldmeadow
  • Jie Jin Wang
  • Paul Mitchell
  • John Attia
  • Rodney J. Scott
  • Pablo A. Moscato
Part of the Methods in Molecular Biology book series (MIMB, volume 1253)


We propose here a methodology to uncover modularities in the network of SNP–SNP interactions most associated with disease. We start by computing all possible Boolean binary SNP interactions across the whole genome. By constructing a weighted graph of the most relevant interactions and via a combinatorial optimization approach, we find the most highly interconnected SNPs. We show that the method can be easily extended to find SNP/environment interactions. Using a modestly sized GWAS dataset of age-related macular degeneration (AMD), we identify a group of only 19 SNPs, which include those in previously reported regions associated to AMD. We also uncover a larger set of loci pointing to a matrix of key processes and functions that are affected. The proposed integrative methodology extends and overlaps traditional statistical analysis in a natural way. Combinatorial optimization techniques allow us to find the kernel of the most central interactions, complementing current methods of GWAS analysis and also enhancing the search for gene–environment interaction.

Key words

Epistasis Machine learning Association studies Combinatorial optimization GPU-based methods Gene–environment 



This work was supported by the National Health and Medical Research Council [Grant 512423 Genes and environment in the risk of early age-related macular degeneration: a population-based case-control study, to J.J.W., P.M., and J.A., and fellowship scheme to E.G.H.]. We are grateful to Katrina Bogan for her careful revision of the manuscript.


  1. 1.
    Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TFC, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461(7265):747–753PubMedCentralPubMedGoogle Scholar
  2. 2.
    Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007) PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575PubMedCentralPubMedGoogle Scholar
  3. 3.
    Ruczinski I, Kooperberg C, LeBlanc M (2003) Logic regression. J Comput Graph Stat 12(3):475–511Google Scholar
  4. 4.
    Ruczinski I (2004) Exploring interactions in high-dimensional genomic data: an overview of Logic Regression, with applications. J Multivar Anal 90(1):178–195Google Scholar
  5. 5.
    Kooperberg C, Ruczinski I (2005) Identifying interacting SNPs using Monte Carlo logic regression. Genet Epidemiol 28(2):157–170PubMedGoogle Scholar
  6. 6.
    Wan X, Yang C, Yang Q, Xue H, Fan X, Tang NLS, Yu W (2010) BOOST: A fast approach to detecting gene-gene interactions in genome-wide case-control studies. Am J Hum Genet 87(3):325–340PubMedCentralPubMedGoogle Scholar
  7. 7.
    Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, Moore JH (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 69(1):138–147PubMedCentralPubMedGoogle Scholar
  8. 8.
    Hahn LW, Ritchie MD, Moore JH (2003) Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics 19(3):376–382PubMedGoogle Scholar
  9. 9.
    Sinnott-Armstrong N, Greene C, Cancare F, Moore J (2009) Accelerating epistasis analysis in human genetics with consumer graphics hardware. BMC Res Notes 2(1):149PubMedCentralPubMedGoogle Scholar
  10. 10.
    Hu X, Liu Q, Zhang Z, Li Z, Wang S, He L, Shi Y (2010) SHEsisEpi, a GPU-enhanced genome-wide SNP-SNP interaction scanning algorithm, efficiently reveals the risk genetic epistasis in bipolar disorder. Cell Res 20(7):854–857PubMedGoogle Scholar
  11. 11.
    Yung LS, Yang C, Wan X, Yu W (2011) GBOOST: a GPU-based tool for detecting gene-gene interactions in genome-wide case control studies. Bioinformatics 27(9):1309–1310PubMedCentralPubMedGoogle Scholar
  12. 12.
    Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJH, Silvestri G, Russell SR, Klaver CCW, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean M, Allikmets R (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102(20):7227–7232PubMedCentralPubMedGoogle Scholar
  13. 13.
    Klein RJ, Zeiss C, Chew EY, Tsai J-Y, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308(5720):385–389PubMedCentralPubMedGoogle Scholar
  14. 14.
    Scholl HPN, Weber BHF, Nöthen MM, Wienker T, Holz FG (2005) Y402H polymorphism in complement factor H and age-related macula degeneration (AMD). Ophthalmologe 102(11):1029–1035PubMedGoogle Scholar
  15. 15.
    Rivera A, Fisher SA, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, Weber BHF (2005) Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 14(21):3227–3236PubMedGoogle Scholar
  16. 16.
    Edwards AO, Fridley BL, James KM, Sharma AK, Sharma AS, Cunningham JM, Tosakulwong N (2008) Evaluation of clustering and genotype distribution for replication in genome wide association studies: the age-related eye disease study. PLoS One 3(11):e3813PubMedCentralPubMedGoogle Scholar
  17. 17.
    Janik-Papis K, Mg Z, Skłodowska A, Ulińska M, Borucka AI, Błasiak J (2009) Genetic aspects of age-related macular degeneration. Klinika Oczna 111(4–6):178–182PubMedGoogle Scholar
  18. 18.
    Lin W-Y, Lee W-C (2010) Incorporating prior knowledge to facilitate discoveries in a genome-wide association study on age-related macular degeneration. BMC Res Notes 3:26PubMedCentralPubMedGoogle Scholar
  19. 19.
    Wegscheider BJ, Weger M, Renner W, Steinbrugger I, März W, Mossböck G, Temmel W, El-Shabrawi Y, Schmut O, Jahrbacher R, Haas A (2007) Association of complement factor H Y402H gene polymorphism with different subtypes of exudative age-related macular degeneration. Ophthalmology 114(4):738–742PubMedGoogle Scholar
  20. 20.
    Zhang H, Morrison MA, Dewan A, Adams S, Andreoli M, Huynh N, Regan M, Brown A, Miller JW, Kim IK, Hoh J, Deangelis MM (2008) The NEI/NCBI dbGAP database: genotypes and haplotypes that may specifically predispose to risk of neovascular age-related macular degeneration. BMC Med Genet 9:51PubMedCentralPubMedGoogle Scholar
  21. 21.
    Yu Y, Bhangale TR, Fagerness J, Ripke S, Thorleifsson G, Tan PL, Souied EH, Richardson AJ, Merriam JE, Buitendijk GHS, Reynolds R, Raychaudhuri S, Chin KA, Sobrin L, Evangelou E, Lee PH, Lee AY, Leveziel N, Zack DJ, Campochiaro B, Campochiaro P, Smith RT, Barile GR, Guymer RH, Hogg R, Chakravarthy U, Robman LD, Gustafsson O, Sigurdsson H, Ortmann W, Behrens TW, Stefansson K, Uitterlinden AG, van Duijn CM, Vingerling JR, Klaver CCW, Allikmets R, Brantley MA, Baird PN, Katsanis N, Thorsteinsdottir U, Ioannidis JPA, Daly MJ, Graham RR, Seddon JM (2011) Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Hum Mol Genet 20(18):3699–3709PubMedCentralPubMedGoogle Scholar
  22. 22.
    VanderWeele TJ (2010) Epistatic interactions. Stat Appl Genet Mol Biol 9(1):Article 1Google Scholar
  23. 23.
    Ozkiris A (2010) Anti-VEGF agents for age-related macular degeneration. Expert Opin Ther Pat 20(1):103–118PubMedGoogle Scholar
  24. 24.
    Gotoh N, Yamada R, Nakanishi H, Saito M, Iida T, Matsuda F, Yoshimura N (2008) Correlation between CFH Y402H and HTRA1 rs11200638 genotype to typical exudative age-related macular degeneration and polypoidal choroidal vasculopathy phenotype in the Japanese population. Clin Exp Ophthalmol 36(5):437–442Google Scholar
  25. 25.
    Kondo N, Honda S, S-i K, Negi A (2009) Coding variant I62V in the complement factor H gene is strongly associated with polypoidal choroidal vasculopathy. Ophthalmology 116(2):304–310PubMedGoogle Scholar
  26. 26.
    Lee KY, Vithana EN, Mathur R, Yong VH, Yeo IY, Thalamuthu A, Lee M-W, Koh AH, Lim MC, How AC, Wong DW, Aung T (2008) Association analysis of CFH, C2, BF, and HTRA1 gene polymorphisms in Chinese patients with polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 49(6):2613–2619PubMedGoogle Scholar
  27. 27.
    Neuner B, Komm A, Wellmann J, Dietzel M, Pauleikhoff D, Walter J, Busch M, Hense H-W (2009) Smoking history and the incidence of age-related macular degeneration–results from the Muenster Aging and Retina Study (MARS) cohort and systematic review and meta-analysis of observational longitudinal studies. Addict Behav 34(11):938–947PubMedGoogle Scholar
  28. 28.
    Yasuda M, Kiyohara Y, Hata Y, Arakawa S, Yonemoto K, Doi Y, Iida M, Ishibashi T (2009) Nine-year incidence and risk factors for age-related macular degeneration in a defined Japanese population the Hisayama study. Ophthalmology 116(11):2135–2140PubMedGoogle Scholar
  29. 29.
    Kalariya NM, Wills NK, Ramana KV, Srivastava SK, van Kuijk FJGM (2009) Cadmium-induced apoptotic death of human retinal pigment epithelial cells is mediated by MAPK pathway. Exp Eye Res 89(4):494–502PubMedGoogle Scholar
  30. 30.
    Wang JJ, Rochtchina E, Smith W, Klein R, Klein BEK, Joshi T, Sivakumaran TA, Iyengar S, Mitchell P (2009) Combined effects of complement factor H genotypes, fish consumption, and inflammatory markers on long-term risk for age-related macular degeneration in a cohort. Am J Epidemiol 169(5):633–641PubMedCentralPubMedGoogle Scholar
  31. 31.
    Conley YP, Thalamuthu A, Jakobsdottir J, Weeks DE, Mah T, Ferrell RE, Gorin MB (2005) Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy. Hum Mol Genet 14(14):1991–2002PubMedGoogle Scholar
  32. 32.
    Singerman LJ, Brucker AJ, Jampol LM, Lim JI, Rosenfeld P, Schachat AP, Spaide RF (2005) Neovascular age-related macular degeneration: roundtable. Retina 25(7 Suppl):S1–S22PubMedGoogle Scholar
  33. 33.
    Oldmeadow CJ, Riveros C, Holliday EG, Scott R, Moscato P, Wang JJ, Mitchell P, Buitendijk GHS, Vingerling JR, Klaver CCW, Klein R, Attia J (2011) Sifting the wheat from the chaff: prioritizing GWAS results by identifying consistency across analytical methods. Genet Epidemiol 35(8):745–754PubMedGoogle Scholar
  34. 34.
    Mitchell P, Smith W, Attebo K, Wang JJ (1995) Prevalence of age-related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology 102(10):1450–1460PubMedGoogle Scholar
  35. 35.
    Foran S, Wang JJ, Mitchell P (2003) Causes of visual impairment in two older population cross-sections: the Blue Mountains Eye Study. Ophthalmic Epidemiol 10(4):215–225PubMedGoogle Scholar
  36. 36.
    Wang JJ, Rochtchina E, Lee AJ, Chia E-M, Smith W, Cumming RG, Mitchell P (2007) Ten-year incidence and progression of age-related maculopathy: the Blue Mountains Eye Study. Ophthalmology 114(1):92–98PubMedGoogle Scholar
  37. 37.
    Tan JSL, Wang JJ, Flood V, Mitchell P (2009) Dietary fatty acids and the 10-year incidence of age-related macular degeneration: the Blue Mountains Eye Study. Arch Ophthalmol 127(5):656–665PubMedGoogle Scholar
  38. 38.
    Tan JSL, Mitchell P, Kifley A, Flood V, Smith W, Wang JJ (2007) Smoking and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Arch Ophthalmol 125(8):1089–1095PubMedGoogle Scholar
  39. 39.
    Fayyad UM, Irani KB (1993) Multi-interval discretization of continuous-valued attributes for classification learning. Int Joint Conf Artif Intel 13:1022–1027Google Scholar
  40. 40.
    Fisher RA (1932) Statistical methods for research workers. Genesis, New DelhiGoogle Scholar
  41. 41.
    Agresti A (1992) A survey of exact inference for contingency tables. Stat Sci 7(1):131–153Google Scholar
  42. 42.
    Baldi P, Sr B, Chauvin Y, Andersen CAF, Nielsen H (2000) Assessing the accuracy of prediction algorithms for classification: an overview. Bioinformatics 16(5):412–424PubMedGoogle Scholar
  43. 43.
    Matthews BW (1975) Comparison of the predicted and observed secondary structure of T4 phage lysozyme. Biochim Biophys Acta 405(2):442–451PubMedGoogle Scholar
  44. 44.
    Cotta C, Langston M, Moscato P (2007) Combinatorial and algorithmic issues for microarray data analysis. In: González TF (ed) Handbook of Approximation Algorithms and Metaheuristics. Champman & Hall/CRC, pp 74.1–74.14Google Scholar
  45. 45.
    NVIDIA Corporation (2010) CUDA Home Page. In: Nvidia Developer Zone. Accessed 27 Nov 2013
  46. 46.
    R Core Team (2011) R: A Language and Environment for Statistical Computing. In: R Foundation for Statistical Computing, Vienna, Austria. Accessed 11 May 2011Google Scholar
  47. 47.
    Csárdi G, Nepusz T (2006) The igraph software package for complex network research. InterJournal Complex Systems:1695Google Scholar
  48. 48.
    Oliveros JC (2007) VENNY: An interactive tool for comparing lists with Venn Diagrams.
  49. 49.
    Krzywinski M, Schein J, Birol I, Connors J, Gascoyne R, Horsman D, Jones SJ, Marra MA (2009) Circos: an information aesthetic for comparative genomics. Genome Res 19(9):1639–1645PubMedCentralPubMedGoogle Scholar
  50. 50.
    Chen J, Bardes EE, Aronow BJ, Jegga AG (2009) ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res 37:W305–W311, Web server issuePubMedCentralPubMedGoogle Scholar
  51. 51.
    Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, Jakobsdottir J, Tosakulwong N, Pericak-Vance MA, Campochiaro PA, Klein ML, Tan PL, Conley YP, Kanda A, Kopplin L, Li Y, Augustaitis KJ, Karoukis AJ, Scott WK, Agarwal A, Kovach JL, Schwartz SG, Postel EA, Brooks M, Baratz KH, Brown WL, Brucker AJ, Orlin A, Brown G, Ho A, Regillo C, Donoso L, Tian L, Kaderli B, Hadley D, Hagstrom SA, Peachey NS, Klein R, Klein BEK, Gotoh N, Yamashiro K, Ferris Iii F, Fagerness JA, Reynolds R, Farrer LA, Kim IK, Miller JW, Cortón M, Carracedo A, Sanchez-Salorio M, Pugh EW, Doheny KF, Brion M, Deangelis MM, Weeks DE, Zack DJ, Chew EY, Heckenlively JR, Yoshimura N, Iyengar SK, Francis PJ, Katsanis N, Seddon JM, Haines JL, Gorin MB, Abecasis GR, Swaroop A (2010) Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A 107(16):7401–7406PubMedCentralPubMedGoogle Scholar
  52. 52.
    Pai AS-I, Mitchell P, Rochtchina E, Iyengar S, Wang JJ (2009) Complement factor H and the bilaterality of age-related macular degeneration. Arch Ophthalmol 127(10):1339–1344PubMedGoogle Scholar
  53. 53.
    Tsuchihashi T, Mori K, Horie-Inoue K, Gehlbach PL, Kabasawa S, Takita H, Ueyama K, Okazaki Y, Inoue S, Awata T, Katayama S, Yoneya S (2011) Complement factor H and high-temperature requirement A-1 genotypes and treatment response of age-related macular degeneration. Ophthalmology 118(1):93–100PubMedGoogle Scholar
  54. 54.
    Kloeckener-Gruissem B, Barthelmes D, Labs S, Schindler C, Kurz-Levin M, Michels S, Fleischhauer J, Berger W, Sutter F, Menghini M (2011) Genetic association with response to intravitreal ranibizumab in patients with neovascular AMD. Invest Ophthalmol Vis Sci 52(7):4694–4702PubMedGoogle Scholar
  55. 55.
    Farwick A, Dasch B, Weber BHF, Pauleikhoff D, Stoll M, Hense HW (2009) Variations in five genes and the severity of age-related macular degeneration: results from the Muenster aging and retina study. Eye (Lond) 23(12):2238–2244Google Scholar
  56. 56.
    Ding X, Patel M, Chan C-C (2009) Molecular pathology of age-related macular degeneration. Prog Retin Eye Res 28(1):1–18PubMedCentralPubMedGoogle Scholar
  57. 57.
    Montezuma SR, Sobrin L, Seddon JM (2007) Review of genetics in age related macular degeneration. Semin Ophthalmol 22(4):229–240PubMedGoogle Scholar
  58. 58.
    Seitsonen S, Järvelä I, Meri S, Tommila P, Ranta P, Immonen I (2008) Complement factor H Y402H polymorphism and characteristics of exudative age-related macular degeneration lesions. Acta Ophthalmol (Copenh) 86(4):390–394Google Scholar
  59. 59.
    Swaroop A, Branham KE, Chen W, Abecasis G (2007) Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. Human Mol Genet 16 (Spec No. 2):R174–182Google Scholar
  60. 60.
    Chen Y, Zeng J, Zhao C, Wang K, Trood E, Buehler J, Weed M, Kasuga D, Bernstein PS, Hughes G, Fu V, Chin J, Lee C, Crocker M, Bedell M, Salasar F, Yang Z, Goldbaum M, Ferreyra H, Freeman WR, Kozak I, Zhang K (2011) Assessing susceptibility to age-related macular degeneration with genetic markers and environmental factors. Arch Ophthalmol 129(3):344–351PubMedCentralPubMedGoogle Scholar
  61. 61.
    Ryu E, Fridley BL, Tosakulwong N, Bailey KR, Edwards AO (2010) Genome-wide association analyses of genetic, phenotypic, and environmental risks in the age-related eye disease study. Mol Vis 16:2811–2821PubMedCentralPubMedGoogle Scholar
  62. 62.
    Dong L, Qu Y, Jiang H, Dai H, Zhou F, Xu X, Bi H, Pan X, Dang G (2011) Correlation of complement factor H gene polymorphisms with exudative age-related macular degeneration in a Chinese cohort. Neurosci Lett 488(3):283–287PubMedGoogle Scholar
  63. 63.
    Nakanishi H, Yamashiro K, Yamada R, Gotoh N, Hayashi H, Nakata I, Saito M, Iida T, Oishi A, Kurimoto Y, Matsuo K, Tajima K, Matsuda F, Yoshimura N (2010) Joint effect of cigarette smoking and CFH and LOC387715/HTRA1 polymorphisms on polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 51(12):6183–6187PubMedGoogle Scholar
  64. 64.
    Teixeira AG, Silva AS, Lin FLH, Velletri R, Bavia L, Belfort R Jr, Isaac L (2010) Association of complement factor H Y402H polymorphism and age-related macular degeneration in Brazilian patients. Acta Ophthalmol (Copenh) 88(5):e165–e169Google Scholar
  65. 65.
    Raychaudhuri S, Ripke S, Li M, Neale BM, Fagerness J, Reynolds R, Sobrin L, Swaroop A, Ga A, Seddon JM, Daly MJ (2010) Associations of CFHR1-CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent. Nat Genet 42(7):553–555, author reply 555–556–553PubMedCentralPubMedGoogle Scholar
  66. 66.
    Hayashi H, Yamashiro K, Gotoh N, Nakanishi H, Nakata I, Tsujikawa A, Otani A, Saito M, Iida T, Matsuo K, Tajima K, Yamada R, Yoshimura N (2010) CFH and ARMS2 variations in age-related macular degeneration, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation. Invest Ophthalmol Vis Sci 51(11):5914–5919PubMedGoogle Scholar
  67. 67.
    Yang X, Hu J, Zhang J, Guan H (2010) Polymorphisms in CFH, HTRA1 and CX3CR1 confer risk to exudative age-related macular degeneration in Han Chinese. Br J Ophthalmol 94(9):1211–1214PubMedGoogle Scholar
  68. 68.
    Liu X, Zhao P, Tang S, Lu F, Hu J, Lei C, Yang X, Lin Y, Ma S, Yang J, Zhang D, Shi Y, Li T, Chen Y, Fan Y, Yang Z (2010) Association study of complement factor H, C2, CFB, and C3 and age-related macular degeneration in a Han Chinese population. Retina 30(8):1177–1184PubMedGoogle Scholar
  69. 69.
    McKay GJ, Dasari S, Patterson CC, Chakravarthy U, Silvestri G (2010) Complement component 3: an assessment of association with AMD and analysis of gene-gene and gene-environment interactions in a Northern Irish cohort. Mol Vis 16:194–199PubMedCentralPubMedGoogle Scholar
  70. 70.
    Goto A, Akahori M, Okamoto H, Minami M, Terauchi N, Haruhata Y, Obazawa M, Noda T, Honda M, Mizota A, Tanaka M, Hayashi T, Tanito M, Ogata N, Iwata T (2009) Genetic analysis of typical wet-type age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese population. J Ocul Biol Dis Infor 2(4):164–175PubMedCentralPubMedGoogle Scholar
  71. 71.
    Mori K, Horie-Inoue K, Gehlbach PL, Takita H, Kabasawa S, Kawasaki I, Ohkubo T, Kurihara S, Iizuka H, Miyashita Y, Katayama S, Awata T, Yoneya S, Inoue S (2010) Phenotype and genotype characteristics of age-related macular degeneration in a Japanese population. Ophthalmology 117(5):928–938PubMedGoogle Scholar
  72. 72.
    Katta S, Kaur I, Chakrabarti S (2009) The molecular genetic basis of age-related macular degeneration: an overview. J Genet 88(4):425–449PubMedGoogle Scholar
  73. 73.
    Leveziel N, Puche N, Richard F, Somner JEA, Zerbib J, Bastuji-Garin S, Cohen SY, Korobelnik J-F, Sahel J, Soubrane G, Benlian P, Souied EH (2010) Genotypic influences on severity of exudative age-related macular degeneration. Invest Ophthalmol Vis Sci 51(5):2620–2625PubMedGoogle Scholar
  74. 74.
    Losonczy G, Fekete Á, Vokó Z, Takács L, Káldi I, Ajzner É, Kasza M, Vajas A, Berta A, Balogh I (2011) Analysis of complement factor H Y402H, LOC387715, HTRA1 polymorphisms and ApoE alleles with susceptibility to age-related macular degeneration in Hungarian patients. Acta Ophthalmol (Copenh) 89(3):255–262Google Scholar
  75. 75.
    Cui L, Zhou H, Yu J, Sun E, Zhang Y, Jia W, Jiao Y, Snellingen T, Liu X, Lim A, Wang N, Liu N (2010) Noncoding variant in the complement factor H gene and risk of exudative age-related macular degeneration in a Chinese population. Invest Ophthalmol Vis Sci 51(2):1116–1120PubMedGoogle Scholar
  76. 76.
    Scholl HPN, Fleckenstein M, Fritsche LG, Schmitz-Valckenberg S, Göbel A, Adrion C, Herold C, Keilhauer CN, Mackensen F, Mössner A, Pauleikhoff D, Weinberger AWA, Mansmann U, Holz FG, Becker T, Weber BHF (2009) CFH, C3 and ARMS2 are significant risk loci for susceptibility but not for disease progression of geographic atrophy due to AMD. PLoS One 4(10):e7418PubMedCentralPubMedGoogle Scholar
  77. 77.
    Ricci F, Zampatti S, D’Abbruzzi F, Missiroli F, Martone C, Lepre T, Pietrangeli I, Sinibaldi C, Peconi C, Novelli G, Giardina E (2009) Typing of ARMS2 and CFH in age-related macular degeneration: case-control study and assessment of frequency in the Italian population. Arch Ophthalmol 127(10):1368–1372PubMedGoogle Scholar
  78. 78.
    Zerbib J, Seddon JM, Richard F, Reynolds R, Leveziel N, Benlian P, Borel P, Feingold J, Munnich A, Soubrane G, Kaplan J, Rozet J-M, Souied EH (2009) rs5888 variant of SCARB1 gene is a possible susceptibility factor for age-related macular degeneration. PLoS One 4(10):e7341PubMedCentralPubMedGoogle Scholar
  79. 79.
    Chen M, Muckersie E, Robertson M, Forrester JV, Xu H (2008) Up-regulation of complement factor B in retinal pigment epithelial cells is accompanied by complement activation in the aged retina. Exp Eye Res 87(6):543–550PubMedGoogle Scholar
  80. 80.
    Chen M, Forrester JV, Xu H (2007) Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Exp Eye Res 84(4):635–645PubMedGoogle Scholar
  81. 81.
    Lee K-T, Byun M-J, Kang K-S, Park E-W, Lee S-H, Cho S, Kim H, Kim K-W, Lee T, Park J-E, Park W, Shin D, Park H-S, Jeon J-T, Choi B-H, Jang G-W, Choi S-H, Kim D-W, Lim D, Park H-S, Park M-R, Ott J, Schook LB, Kim T-H, Kim H (2011) Neuronal genes for subcutaneous fat thickness in human and pig are identified by local genomic sequencing and combined SNP association study. PLoS One 6(2):e16356PubMedCentralPubMedGoogle Scholar
  82. 82.
    Rajasekharan S, Kennedy TE (2009) The netrin protein family. Genome Biol 10(9):239PubMedCentralPubMedGoogle Scholar
  83. 83.
    Masuda T, Watanabe K, Sakuma C, Ikenaka K, Ono K, Yaginuma H (2008) Netrin-1 acts as a repulsive guidance cue for sensory axonal projections toward the spinal cord. J Neurosci Off J Soc Neurosci 28(41):10380–10385Google Scholar
  84. 84.
    Livesey FJ, Hunt SP (1997) Netrin and netrin receptor expression in the embryonic mammalian nervous system suggests roles in retinal, striatal, nigral, and cerebellar development. Mol Cell Neurosci 8(6):417–429PubMedGoogle Scholar
  85. 85.
    de la Torre JR, Höpker VH, Ming GL, Poo MM, Tessier-Lavigne M, Hemmati-Brivanlou A, Holt CE (1997) Turning of retinal growth cones in a netrin-1 gradient mediated by the netrin receptor DCC. Neuron 19(6):1211–1224PubMedGoogle Scholar
  86. 86.
    Meriane M, Tcherkezian J, Webber CA, Danek EI, Triki I, McFarlane S, Bloch-Gallego E, Lamarche-Vane N (2004) Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance. J Cell Biol 167(4):687–698PubMedCentralPubMedGoogle Scholar
  87. 87.
    Jarjour AA, Bull S-J, Almasieh M, Rajasekharan S, Baker KA, Mui J, Antel JP, Di Polo A, Kennedy TE (2008) Maintenance of axo-oligodendroglial paranodal junctions requires DCC and netrin-1. J Neurosci Off J Soc Neurosci 28(43):11003–11014Google Scholar
  88. 88.
    Spassky N, de Castro F, Le Bras B, Heydon K, Quéraud-LeSaux F, Bloch-Gallego E, Chédotal A, Zalc B, Thomas J-L (2002) Directional guidance of oligodendroglial migration by class 3 semaphorins and netrin-1. J Neurosci Off J Soc Neurosci 22(14):5992–6004Google Scholar
  89. 89.
    Manitt C, Nikolakopoulou AM, Almario DR, Nguyen SA, Cohen-Cory S (2009) Netrin participates in the development of retinotectal synaptic connectivity by modulating axon arborization and synapse formation in the developing brain. J Neurosci Off J Soc Neurosci 29(36):11065–11077Google Scholar
  90. 90.
    Oster SF, Deiner M, Birgbauer E, Sretavan DW (2004) Ganglion cell axon pathfinding in the retina and optic nerve. Semin Cell Dev Biol 15(1):125–136PubMedGoogle Scholar
  91. 91.
    Smith CJ, Watson JD, VanHoven MK, Colón-Ramos DA, Iii DMM (2012) Netrin (UNC-6) mediates dendritic self-avoidance. Nat Neurosci 15(5):731–737PubMedCentralPubMedGoogle Scholar
  92. 92.
    Shi M, Zheng M-H, Liu Z-R, Hu Z-L, Huang Y, Chen J-Y, Zhao G, Han H, Ding Y-Q (2010) DCC is specifically required for the survival of retinal ganglion and displaced amacrine cells in the developing mouse retina. Dev Biol 348(1):87–96PubMedGoogle Scholar
  93. 93.
    Xu H, Liu J, Xiong S, Y-z L, Xia X (2012) Suppression of retinal neovascularization by lentivirus-mediated netrin-1 small Hairpin RNA. Ophthalmic Res 47(3):163–169PubMedCentralPubMedGoogle Scholar
  94. 94.
    Tian X-F, Xia X-B, Xiong S-Q, Jiang J, Liu D, Liu J-L (2011) Netrin-1 overexpression in oxygen-induced retinopathy correlates with breakdown of the blood-retina barrier and retinal neovascularization. Ophthalmologica 226(2):37–44PubMedGoogle Scholar
  95. 95.
    Bányai L, Patthy L (1999) The NTR module: domains of netrins, secreted frizzled related proteins, and type I procollagen C-proteinase enhancer protein are homologous with tissue inhibitors of metalloproteases. Protein Sci 8(8):1636–1642PubMedCentralPubMedGoogle Scholar
  96. 96.
    Kaur I, Rathi S, Chakrabarti S (2010) Variations in TIMP3 are associated with age-related macular degeneration. Proc Natl Acad Sci U S A 107(28):E112–E113PubMedCentralPubMedGoogle Scholar
  97. 97.
    Strunnikova NV, Maminishkis A, Barb JJ, Wang F, Zhi C, Sergeev Y, Chen W, Edwards AO, Stambolian D, Abecasis G, Swaroop A, Munson PJ, Miller SS (2010) Transcriptome analysis and molecular signature of human retinal pigment epithelium. Hum Mol Genet 19(12):2468–2486PubMedCentralPubMedGoogle Scholar
  98. 98.
    Bekhouche M, Kronenberg D, Vadon-Le Goff S, Bijakowski C, Lim NH, Font B, Kessler E, Colige A, Nagase H, Murphy G, Hulmes DJS, Moali C (2010) Role of the netrin-like domain of procollagen C-proteinase enhancer-1 in the control of metalloproteinase activity. J Biol Chem 285(21):15950–15959PubMedCentralPubMedGoogle Scholar
  99. 99.
    Sanchez-Ramos C, Vega JA, Del Valle ME, Fernandez-Balbuena A, Bonnin-Arias C, Benitez-Del Castillo JM (2010) Role of metalloproteases in retinal degeneration induced by violet and blue light. Adv Exp Med Biol 664:159–164PubMedGoogle Scholar
  100. 100.
    Hirano AA, Brandstätter JH, Morgans CW, Brecha NC (2011) SNAP25 expression in mammalian retinal horizontal cells. J Comp Neurol 519(5):972–988PubMedCentralPubMedGoogle Scholar
  101. 101.
    Mazelova J, Ransom N, Astuto-Gribble L, Wilson MC, Deretic D (2009) Syntaxin 3 and SNAP-25 pairing, regulated by omega-3 docosahexaenoic acid, controls the delivery of rhodopsin for the biogenesis of cilia-derived sensory organelles, the rod outer segments. J Cell Sci 122(Pt 12):2003–2013PubMedCentralPubMedGoogle Scholar
  102. 102.
    Morgans C, Brandstätter JH (2000) SNAP-25 is present on the Golgi apparatus of retinal neurons. Neuroreport 11(1):85–88PubMedGoogle Scholar
  103. 103.
    Yang H, Standifer KM, Sherry DM (2002) Synaptic protein expression by regenerating adult photoreceptors. J Comp Neurol 443(3):275–288PubMedGoogle Scholar
  104. 104.
    Greenlee MHW, Wilson MC, Sakaguchi DS (2002) Expression of SNAP-25 during mammalian retinal development: thinking outside the synapse. Semin Cell Dev Biol 13(2):99–106PubMedGoogle Scholar
  105. 105.
    Kono N, Inoue T, Yoshida Y, Sato H, Matsusue T, Itabe H, Niki E, Aoki J, Arai H (2008) Protection against oxidative stress-induced hepatic injury by intracellular type II platelet-activating factor acetylhydrolase by metabolism of oxidized phospholipids in vivo. J Biol Chem 283(3):1628–1636PubMedGoogle Scholar
  106. 106.
    Demos C, Bandyopadhyay M, Br R (2008) Identification of candidate genes for human retinal degeneration loci using differentially expressed genes from mouse photoreceptor dystrophy models. Mol Vis 14:1639–1649PubMedCentralPubMedGoogle Scholar
  107. 107.
    Burzynski GM, Delalande J-M, Shepherd I (2009) Characterization of spatial and temporal expression pattern of SCG10 during zebrafish development. Gene Expr Patterns 9(4):231–237PubMedCentralPubMedGoogle Scholar
  108. 108.
    Liedtke W, Leman EE, Fyffe REW, Raine CS, Schubart UK (2002) Stathmin-deficient mice develop an age-dependent axonopathy of the central and peripheral nervous systems. Am J Pathol 160(2):469–480PubMedCentralPubMedGoogle Scholar
  109. 109.
    Hasegawa A, Hisatomi O, Yamamoto S, Ono E, Tokunaga F (2007) Stathmin expression during newt retina regeneration. Exp Eye Res 85(4):518–527PubMedGoogle Scholar
  110. 110.
    Finnegan S, Robson J, Hocking PM, Ali M, Inglehearn CF, Stitt A, Curry WJ (2010) Proteomic profiling of the retinal dysplasia and degeneration chick retina. Mol Vis 16:7–17PubMedCentralPubMedGoogle Scholar
  111. 111.
    Kompass KS, Agapova OA, Li W, Kaufman PL, Rasmussen CA, Hernandez MR (2008) Bioinformatic and statistical analysis of the optic nerve head in a primate model of ocular hypertension. BMC Neurosci 9:93PubMedCentralPubMedGoogle Scholar
  112. 112.
    Wang A-G, Chen C-H, Yang C-W, Yen M-Y, Hsu W-M, Liu J-H, Fann M-J (2002) Change of gene expression profiles in the retina following optic nerve injury. Brain Res Mol Brain Res 101(1–2):82–92PubMedGoogle Scholar
  113. 113.
    Nakazawa T, Nakano I, Furuyama T, Morii H, Tamai M, Mori N (2000) The SCG10-related gene family in the developing rat retina: persistent expression of SCLIP and stathmin in mature ganglion cell layer. Brain Res 861(2):399–407PubMedGoogle Scholar
  114. 114.
    Yanagisawa H, Komuta Y, Kawano H, Toyoda M, Sango K (2010) Pleiotrophin induces neurite outgrowth and up-regulates growth-associated protein (GAP)-43 mRNA through the ALK/GSK3[beta]/[beta]-catenin signaling in developing mouse neurons. Neurosci Res 66(1):111–116PubMedGoogle Scholar
  115. 115.
    Perez-Pinera P, Zhang W, Chang Y, Vega JA, Deuel TF (2007) Anaplastic Lymphoma Kinase Is Activated Through the Pleiotrophin/Receptor Protein-tyrosine Phosphatase β/ζ Signaling Pathway. Journal of Biological Chemistry 282:28683 –28690. doi: 10.1074/jbc.M704505200PubMedGoogle Scholar
  116. 116.
    Chen H, Campbell RA, Chang Y, Li M, Wang CS, Li J, Sanchez E, Share M, Steinberg J, Berenson A, Shalitin D, Zeng Z, Gui D, Perez-Pinera P, Berenson RJ, Said J, Bonavida B, Deuel TF, Berenson JR (2009) Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: a novel mechanism of tumor-induced vasculogenesis. Blood 113(9):1992–2002PubMedCentralPubMedGoogle Scholar
  117. 117.
    Yeh HJ, He YY, Xu J, Hsu CY, Deuel TF (1998) Upregulation of pleiotrophin gene expression in developing microvasculature, macrophages, and astrocytes after acute ischemic brain injury. J Neurosci Off J Soc Neurosci 18(10):3699–3707Google Scholar
  118. 118.
    Rao KN, Nagireddy S, Chakrabarti S (2011) Complex genetic mechanisms in glaucoma: an overview. Indian J Ophthalmol 59(Suppl):S31–S42PubMedCentralPubMedGoogle Scholar
  119. 119.
    Tamm ER (2011) Development of the iridocorneal angle and congenital glaucoma. Ophthalmologe 108(7):610–617PubMedGoogle Scholar
  120. 120.
    Yu-Wai-Man P, Griffiths PG, Chinnery PF (2011) Mitochondrial optic neuropathies—Disease mechanisms and therapeutic strategies. Prog Retin Eye Res 30(2):81–114PubMedCentralPubMedGoogle Scholar
  121. 121.
    Tang Y, Scheef EA, Gurel Z, Sorenson CM, Jefcoate CR, Sheibani N (2010) CYP1B1 and endothelial nitric oxide synthase combine to sustain proangiogenic functions of endothelial cells under hyperoxic stress. Am J Physiol Cell Physiol 298(3):C665–C678PubMedCentralPubMedGoogle Scholar
  122. 122.
    Lin H, Xu H, Liang F-Q, Liang H, Gupta P, Havey AN, Boulton ME, Godley BF (2011) Mitochondrial DNA damage and repair in RPE associated with aging and age-related macular degeneration. Invest Ophthalmol Vis Sci 52(6):3521–3529PubMedCentralPubMedGoogle Scholar
  123. 123.
    Schrier SA, Falk MJ (2011) Mitochondrial disorders and the eye. Curr Opin Ophthalmol 22(5):325–331PubMedCentralPubMedGoogle Scholar
  124. 124.
    Blasiak J, Szaflik JP (2011) DNA damage and repair in age-related macular degeneration. Front Biosci 16:1291–1301Google Scholar
  125. 125.
    Epand RF, Maekawa S, Epand RM (2003) Specificity of membrane binding of the neuronal protein NAP-22. J Membr Biol 193(3):171–176PubMedGoogle Scholar
  126. 126.
    Epand RM, Braswell EH, Yip CM, Epand RF, Maekawa S (2003) Quaternary structure of the neuronal protein NAP-22 in aqueous solution. Biochim Biophys Acta 1650(1–2):50–58PubMedGoogle Scholar
  127. 127.
    Khan TK, Yang B, Thompson NL, Maekawa S, Epand RM, Jacobson K (2003) Binding of NAP-22, a calmodulin-binding neuronal protein, to raft-like domains in model membranes. Biochemistry 42(17):4780–4786PubMedGoogle Scholar
  128. 128.
    de las-Heras R, Depaz I, Jaquet V, Kroon P, Wilce PA (2007) Neuronal protein 22 colocalises with both the microtubule and microfilament cytoskeleton in neurite-like processes. Brain Res 1128(1):12–20PubMedGoogle Scholar
  129. 129.
    Depaz IM, Wilce PA (2006) The novel cytoskeleton-associated protein Neuronal protein 22: elevated expression in the developing rat brain. Brain Res 1081(1):59–64PubMedGoogle Scholar
  130. 130.
    Neale BM, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S, Tan PL, Oh EC, Merriam JE, Souied E, Bernstein PS, Li B, Frederick JM, Zhang K, Brantley MA, Lee AY, Zack DJ, Campochiaro B, Campochiaro P, Ripke S, Smith RT, Barile GR, Katsanis N, Allikmets R, Daly MJ, Seddon JM (2010) Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci 107(16):7395–7400PubMedCentralPubMedGoogle Scholar
  131. 131.
    Krumbiegel M, Pasutto F, Schlötzer-Schrehardt U, Uebe S, Zenkel M, Mardin CY, Weisschuh N, Paoli D, Gramer E, Becker C, Ekici AB, Weber BHF, Nürnberg P, Kruse FE, Reis A (2011) Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome. Eur J Hum Genet 19(2):186–193PubMedCentralPubMedGoogle Scholar
  132. 132.
    Schlötzer-Schrehardt U (2011) Genetics and genomics of pseudoexfoliation syndrome/glaucoma. Middle East Afr J Ophthalmol 18(1):30–36PubMedCentralPubMedGoogle Scholar
  133. 133.
    Sharon D, Yamamoto H, McGee TL, Rabe V, Szerencsei RT, Winkfein RJ, Prinsen CFM, Barnes CS, Andreasson S, Fishman GA, Schnetkamp PPM, Berson EL, Dryja TP (2002) Mutated alleles of the rod and cone Na-Ca + K-exchanger genes in patients with retinal diseases. Invest Ophthalmol Vis Sci 43(6):1971–1979PubMedGoogle Scholar
  134. 134.
    Wilson PM, Fryer RH, Fang Y, Hatten ME (2010) ASTN2, a novel member of the astrotactin gene family, regulates the trafficking of ASTN1 during glial-guided neuronal migration. J Neurosci Off J Soc Neurosci 30(25):8529–8540Google Scholar
  135. 135.
    Vallee RB, Seale GE, Tsai J-W (2009) Emerging roles for myosin II and cytoplasmic dynein in migrating neurons and growth cones. Trends Cell Biol 19(7):347–355PubMedCentralPubMedGoogle Scholar
  136. 136.
    Tuo J, Ning B, Bojanowski CM, Lin Z-N, Ross RJ, Reed GF, Shen D, Jiao X, Zhou M, Chew EY, Kadlubar FF, Chan C-C (2006) Synergic effect of polymorphisms in ERCC6 5 flanking region and complement factor H on age-related macular degeneration predisposition. Proc Natl Acad Sci 103(24):9256–9261PubMedCentralPubMedGoogle Scholar
  137. 137.
    Kramerov AA, Saghizadeh M, Pan H, Kabosova A, Montenarh M, Ahmed K, Penn JS, Chan CK, Hinton DR, Grant MB, Ljubimov AV (2006) Expression of protein kinase CK2 in astroglial cells of normal and neovascularized retina. Am J Pathol 168(5):1722–1736PubMedCentralPubMedGoogle Scholar
  138. 138.
    Kramerov AA, Golub AG, Bdzhola VG, Yarmoluk SM, Ahmed K, Bretner M, Ljubimov AV (2010) Treatment of cultured human astrocytes and vascular endothelial cells with protein kinase CK2 inhibitors induces early changes in cell shape and cytoskeleton. Mol Cell Biochem 349(1–2):125–137PubMedCentralPubMedGoogle Scholar
  139. 139.
    Xie Y, Yeo TT, Zhang C, Yang T, Tisi MA, Massa SM, Longo FM (2001) The leukocyte common antigen-related protein tyrosine phosphatase receptor regulates regenerative neurite outgrowth in vivo. J Neurosci Off J Soc Neurosci 21(14):5130–5138Google Scholar
  140. 140.
    Yu J, Becka S, Zhang P, Zhang X, Brady-Kalnay SM, Wang Z (2008) Tumor-derived extracellular mutations of PTPRT/PTPrho are defective in cell adhesion. Mol Cancer Res 6(7):1106–1113PubMedCentralPubMedGoogle Scholar
  141. 141.
    Zhang P, Becka S, Craig SEL, Lodowski DT, Brady-Kalnay SM, Wang Z (2009) Cancer-derived mutations in the fibronectin III repeats of PTPRT/PTPrho inhibit cell-cell aggregation. Cell Commun Adhes 16(5–6):146–153PubMedCentralPubMedGoogle Scholar
  142. 142.
    Lim S-H, Kwon S-K, Lee MK, Moon J, Jeong DG, Park E, Kim SJ, Park BC, Lee SC, Ryu S-E, Yu D-Y, Chung BH, Kim E, Myung P-K, Lee J-R (2009) Synapse formation regulated by protein tyrosine phosphatase receptor T through interaction with cell adhesion molecules and Fyn. EMBO J 28(22):3564–3578PubMedCentralPubMedGoogle Scholar
  143. 143.
    Kumar M, Agarwal T, Khokhar S, Kumar M, Kaur P, Roy TS, Dada R (2011) Mutation screening and genotype phenotype correlation of $-crystallin, $-crystallin and GJA8 gene in congenital cataract. Mol Vis 17:693–707PubMedCentralPubMedGoogle Scholar
  144. 144.
    Roshan M, Vijaya PH, Lavanya GR, Shama PK, Santhiya ST, Graw J, Gopinath PM, Satyamoorthy K (2010) A novel human CRYGD mutation in a juvenile autosomal dominant cataract. Mol Vis 16:887–896PubMedCentralPubMedGoogle Scholar
  145. 145.
    Zhang L-Y, Yam GH-F, Tam PO-S, Lai RY-K, Lam DS-C, Pang C-P, Fan DS-P (2009) An alphaA-crystallin gene mutation, Arg12Cys, causing inherited cataract-microcornea exhibits an altered heat-shock response. Mol Vis 15:1127–1138PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Carlos Riveros
    • 1
    • 2
    Email author
  • Renato Vimieiro
    • 1
    • 2
  • Elizabeth G. Holliday
    • 3
    • 4
  • Christopher Oldmeadow
    • 3
    • 4
  • Jie Jin Wang
    • 5
    • 6
  • Paul Mitchell
    • 6
  • John Attia
    • 3
    • 4
  • Rodney J. Scott
    • 1
    • 3
  • Pablo A. Moscato
    • 1
    • 2
  1. 1.Centre for Bioinformatics, Biomarker Discovery, and Information-Based MedicineHunter Medical Research InstituteNew Lambton HeightsAustralia
  2. 2.School of Electrical Engineering and Computer ScienceThe University of NewcastleCallaghanAustralia
  3. 3.School of Medicine and Public HealthThe University of NewcastleCallaghanAustralia
  4. 4.CREDITSS—Clinical Research Design, Information Technology and Statistical Support UnitHunter Medical Research InstituteNew Lambton HeightsAustralia
  5. 5.Centre for Eye Research Australia and Department of OphthalmologyUniversity of MelbourneMelbourneAustralia
  6. 6.Department of Ophthalmology, Centre for Vision Research, Westmead Millennium InstituteUniversity of SydneySydneyAustralia

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