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Quantitative Trait for Glaucoma

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Advances in Vision Research, Volume II

Part of the book series: Essentials in Ophthalmology ((ESSENTIALS))

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Abstract

Dissecting the genetic architecture of complex or multifactorial disorders always demanded different strategies in addition to the classical gene mapping methods, due to the high level of clinical and genetic heterogeneity. An endophenotype or intermediate phenotype is a measurable trait with a strong genetic component (determined by heritability and twin studies) which associates with a disease. Endophenotypes for POAG include intraocular pressure (IOP), central corneal thickness (CCT), cup area (CA), vertical cup-disc ratio (VCDR) and disc area (DA). The loci fo these genetic determinants are called as quantitative trait loci (QTLs). Identifying the QTLs for the clinical risk factors is considered as an effective strategy for mapping the genes contributing to the overall disease pathology. We review the various ocular QTs and the insights gained into the pathogenesis of glaucoma through QTL mapping.

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References

  1. Wang H-M, Hsiao C-L, Hsieh A-R, Lin Y-C, Fann CSJ. Constructing endophenotypes of complex diseases using non-negative matrix factorization and adjusted rand index. PLoS One. 2012;7(7):e40996.

    Article  CAS  Google Scholar 

  2. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160(4):636–45.

    Article  Google Scholar 

  3. Aung T, Rezaie T, Okada K, Viswanathan AC, Child AH, Brice G, Bhattacharya SS, Lehmann OJ, Sarfarazi M, Hitchings RA. Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene. Invest Ophthalmol Vis Sci. 2005;46(8):2816–22.

    Article  Google Scholar 

  4. Fingert JH, Robin AL, Stone JL, Roos BR, Davis LK, Scheetz TE, Bennett SR, Wassink TH, Kwon YH, Alward WL, Mullins RF, Sheffield VC, Stone EM. Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. Hum Mol Genet. 2011;20(12):2482–94.

    Article  CAS  Google Scholar 

  5. He L, Chen L, Li L. The TBK1-OPTN axis mediates crosstalk between mitophagy and the innate immune response: a potential therapeutic target for neurodegenerative diseases. Neurosci Bull. 2017;33:354.

    Article  Google Scholar 

  6. Monemi S, Spaeth G, DaSilva A, Popinchalk S, Ilitchev E, Liebmann J, Ritch R, Héon E, Crick RP, Child A, Sarfarazi M. Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1. Hum Mol Genet. 2005;14(6):725–33.

    Article  CAS  Google Scholar 

  7. Pasutto F, Mardin CY, Michels-Rautenstrauss K, Weber BH, Sticht H, Chavarria-Soley G, Rautenstrauss B, Kruse F, Reis A. Profiling of WDR36 missense variants in German patients with glaucoma. Invest Ophthalmol Vis Sci. 2008;49(1):270–4.

    Article  Google Scholar 

  8. Gordon RA, Donzis PB. Refractive development of the human eye. Arch Ophthalmol. 1985;103(6):785–9.

    Article  CAS  Google Scholar 

  9. Lyhne N, et al. The importance of genes and environment for ocular refraction and its determiners: a population based study among 20-45 year old twins. Br J Ophthalmol. 2001;85(12):1470–6.

    Article  CAS  Google Scholar 

  10. Seiler T, Wollensak J. The resistance of the trabecular meshwork to aqueous humor outflow. Graefes Arch Clin Exp Ophthalmol. 1985;223(2):88–91.

    Article  CAS  Google Scholar 

  11. van Koolwijk LM, Despriet DD, van Duijn CM, Pardo Cortes LM, Vingerling JR, Aulchenko YS, Oostra BA, Klaver CC, Lemij HG. Genetic contributions to glaucoma: heritability of intraocular pressure, retinal nerve fiber layer thickness, and optic disc morphology.Invest Ophthalmol Vis Sci. 2007;48(8):3669–76.

    Google Scholar 

  12. Charlesworth JC, et al. Linkage to 10q22 for maximum intraocular pressure and 1p32 for maximum cup-to-disc ratio in an extended primary open-angle glaucoma pedigree. Invest Ophthalmol Vis Sci. 2005;46(10):3723–9.

    Article  Google Scholar 

  13. Nag A, et al. A genome-wide association study of intra-ocular pressure suggests a novel association in the gene FAM125B in the TwinsUK cohort. Hum Mol Genet. 2014;23(12):3343–8.

    Article  CAS  Google Scholar 

  14. Cao D, et al. CDKN2B polymorphism is associated with primary open-angle glaucoma (POAG) in the Afro-Caribbean population of Barbados, West Indies. PLoS One. 2012;7(6):e39278.

    Article  CAS  Google Scholar 

  15. van Koolwijk LM, et al. Common genetic determinants of intraocular pressure and primary openangle glaucoma. PLoS Genet. 2012;8(5):e1002611.

    Article  Google Scholar 

  16. Ozel AB, et al. Genome-wide association study and meta-analysis of intraocular pressure. Hum Genet. 2014;133(1):41–57.

    Google Scholar 

  17. Hysi PG, Cheng CY, Springelkamp H, Macgregor S, Bailey JN, Wojciechowski R, Vitart V, Nag A, Hewitt AW, Hohn R, et al. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma. Nat Genet. 2014;46:1126–30. https://doi.org/10.1038/ng.3087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen F, Klein AP, Klein BE, Lee KE, Truitt B, Klein R, Iyengar SK, Duggal P. Exome array analysis identifies cav1/cav2 as a susceptibility locus for intraocular pressure. Investig Ophthalmol Vis Sci. 2015;56:544–51.

    Article  CAS  Google Scholar 

  19. Chang TC, Congdon NG, Wojciechowski R, et al. Determinants and heritability of intraocular pressure and cup-to-disc ratio in a defined older population. Ophthalmology. 2005;112(7):1186–91. 

    Google Scholar 

  20. Ramdas WD, van Koolwijk LM, Lemij HG, Pasutto F, Cree AJ, Thorleifsson G, Janssen SF, Jacoline TB, Amin N, Rivadeneira F, et al. Common genetic variants associated with open-angle glaucoma. Hum Mol Genet. 2011;20:2464–71.

    Article  CAS  Google Scholar 

  21. Iglesias AI, Springelkamp H, van der Linde H, Severijnen LA, Amin N, Oostra B, Kockx CE, van den Hout MC, van Ijcken WF, Hofman A, et al. Exome sequencing and functional analyses suggest that six6 is a gene involved in an altered proliferation-differentiation balance early in life and optic nerve degeneration at old age. Hum Mol Genet. 2014;23:1320–32.

    Article  CAS  Google Scholar 

  22. Ramdas WD, et al. A genome-wide association study of optic disc parameters. PLoS Genet. 2010;6(6):e1000978.

    Article  Google Scholar 

  23. Macgregor S, et al. Genome-wide association identifies ATOH7 as a major gene determining human optic disc size. Hum Mol Genet. 2010;19(13):2716–24.

    Article  CAS  Google Scholar 

  24. Khor CC, et al. Genome-wide association studies in Asians confirm the involvement of ATOH7 and TGFBR3, and further identify CARD10 as a novel locus influencing optic disc area. Hum Mol Genet. 2011;20(9):1864–72.

    Article  CAS  Google Scholar 

  25. Abu-Amero K, Kondkar AA, Chalam KV. An updated review on the genetics of primary open angle Glaucoma. Alexov E, ed. Int J Mol Sci. 2015;16(12):28886–28911. https://doi.org/10.3390/ijms161226135.

  26. Mabuchi F, Sakurada Y, Kashiwagi K, Yamagata Z, Iijima H, Tsukahara S. Association between genetic variants associated with vertical cup-to-disc ratio and phenotypic features of primary open-angle glaucoma. Ophthalmology. 2012;119:1819–25.

    Article  Google Scholar 

  27. Dimasi DP, Burdon KP, Hewitt AW, Fitzgerald J, Wang JJ, Healey PR, Mitchell P, Mackey DA, Craig JE. Genetic investigation into the endophenotypic status of central corneal thickness and optic disc parameters in relation to open-angle glaucoma. Am J Ophthalmol. 2012;154:833–42.

    Article  Google Scholar 

  28. Chen JH, Wang D, Huang C, Zheng Y, Chen H, Pang CP, Zhang M. Interactive effects of atoh7 and rftn1 in association with adult-onset primary open-angle glaucoma. Investig Ophthalmol Vis Sci. 2012;53:779–85.

    Article  CAS  Google Scholar 

  29. Burdon KP, Crawford A, Casson RJ, Hewitt AW, Landers J, Danoy P, Mackey DA, Mitchell P, Healey PR, Craig JE. Glaucoma risk alleles at cdkn2b-as1 are associated with lower intraocular pressure, normal-tension glaucoma, and advanced glaucoma. Ophthalmology. 2012;119:1539–45.

    Article  Google Scholar 

  30. Fan BJ, et al. Genetic variants associated with optic nerve vertical cup-to-disc ratio are risk factors for primary open angle glaucoma in a US Caucasian population. Invest Ophthalmol Vis Sci. 2011;52(3):1788–92.

    Article  Google Scholar 

  31. Jarman AP, et al. Atonal is a proneural gene that directs chordotonal organ formation in the Drosophila peripheral nervous system. Cell. 1993;73(7):1307–21.

    Article  CAS  Google Scholar 

  32. Brown NL, et al. Molecular characterization and mapping of ATOH7, a human atonal homolog with a predicted role in retinal ganglion cell development. Mamm Genome. 2002;13(2):95–101.

    Article  CAS  Google Scholar 

  33. Brown NL, et al. Math5 is required for retinal ganglion cell and optic nerve formation. Development. 2001;128(13):2497–508.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang SW, et al. Requirement for math5 in the development of retinal ganglion cells. Genes Dev. 2001;15(1):24–9.

    Article  CAS  Google Scholar 

  35. Philomenadin FS, et al. Genetic association of SNPs near ATOH7, CARD10, CDKN2B, CDC7 and SIX1/SIX6 with the endophenotypes of primary open angle glaucoma in Indian population. PLoS One. 2015;10(3):e0119703.

    Article  Google Scholar 

  36. Khan K, et al. Next generation sequencing identifies mutations in atonal homolog 7 (ATOH7) in families with global eye developmental defects. Hum Mol Genet. 2012;21(4):776–83.

    Article  CAS  Google Scholar 

  37. Carnes MU, et al. Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma. PLoS Genet. 2014;10(5):e1004372.

    Article  Google Scholar 

  38. Li X, et al. Tissue-specific regulation of retinal and pituitary precursor cell proliferation. Science. 2002;297(5584):1180–3.

    CAS  PubMed  Google Scholar 

  39. Zuber ME, et al. Giant eyes in Xenopus laevis by overexpression of XOptx2. Cell. 1999;98(3):341–52.

    Article  CAS  Google Scholar 

  40. Bernier G, et al. Expanded retina territory by midbrain transformation upon overexpression of Six6 (Optx2) in Xenopus embryos. Mech Dev. 2000;93(1–2):59–69.

    Article  CAS  Google Scholar 

  41. Wiggs JL, et al. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet. 2012;8(4):e1002654.

    Article  CAS  Google Scholar 

  42. Skarie JM, Link BA. The primary open-angle glaucoma gene WDR36 functions in ribosomal RNA processing and interacts with the p53 stress-response pathway. Hum Mol Genet. 2008;17(16):2474–85.

    Article  CAS  Google Scholar 

  43. Toh T, et al. Central corneal thickness is highly heritable: the twin eye studies. Invest Ophthalmol Vis Sci. 2005;46(10):3718–22.

    Article  Google Scholar 

  44. Hong S, et al. Central corneal thickness and visual field progression in patients with chronic primary angle-closure glaucoma with low intraocular pressure. Am J Ophthalmol. 2007;143(2):362–3.

    Article  Google Scholar 

  45. Wang R, Wiggs JL. Common and rare genetic risk factors for Glaucoma. Cold Spring Harb Perspect Med. 2014;4(12):a017244.

    Article  Google Scholar 

  46. Lu Y, et al. Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus. Nat Genet. 2013;45(2):155–63.

    Article  CAS  Google Scholar 

  47. Vithana EN, et al. Collagen-related genes influence the glaucoma risk factor, central corneal thickness. Hum Mol Genet. 2011;20(4):649–58.

    Article  CAS  Google Scholar 

  48. Vitart V, et al. New loci associated with central cornea thickness include COL5A1, AKAP13 and AVGR8. Hum Mol Genet. 2010;19(21):4304–11.

    Article  CAS  Google Scholar 

  49. Cornes BK, et al. Identification of four novel variants that influence central corneal thickness in multi-ethnic Asian populations. Hum Mol Genet. 2012;21(2):437–45.

    Article  CAS  Google Scholar 

  50. Hoehn R, et al. Population-based meta-analysis in Caucasians confirms association with COL5A1 and ZNF469 but not COL8A2 with central corneal thickness. Hum Genet. 2012;131(11):1783–93.

    Article  Google Scholar 

  51. Ulmer M, et al. Genome-wide analysis of central corneal thickness in primary open-angle glaucoma cases in the NEIGHBOR and GLAUGEN consortia. Invest Ophthalmol Vis Sci. 2012;53(8):4468–74.

    Article  Google Scholar 

  52. Desronvil T, et al. Distribution of COL8A2 and COL8A1 gene variants in Caucasian primary open angle glaucoma patients with thin central corneal thickness. Mol Vis. 2010;16:2185–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Lehmann OJ, et al. Novel anterior segment phenotypes resulting from forkhead gene alterations: evidence for cross-species conservation of function. Invest Ophthalmol Vis Sci. 2003;44(6):2627–33.

    Article  Google Scholar 

  54. Abu A, et al. Deleterious mutations in the Zinc-Finger 469 gene cause brittle cornea syndrome. Am J Hum Genet. 2008;82(5):1217–22. 101

    Article  CAS  Google Scholar 

  55. Lu Y, et al. Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness. PLoS Genet. 2010;6(5):e1000947.

    Article  Google Scholar 

  56. Iglesias AI, et al. Genes, pathways, and animal models in primary open- angle glaucoma. Eye. 2015;29:1285–98.

    Article  CAS  Google Scholar 

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Compliance with Ethical Requirements

This article does not contain any studies with human participants performed by any of the authors. This article does not contain any studies with animals performed by any of the authors. Sarangapani Sripriya, Ferdina Sharmila, Suganya Kandeepan and Ronnie George declare that they have no conflict of interest.

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Authors and Affiliations

  1. SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India

    Sarangapani Sripriya, Ferdina Sharmila & Suganya Kandeepan

  2. Smt. Jadhavbai Nathamal Singhvee Glaucoma Services, Medical Research Foundation, Chennai, India

    Ronnie George

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  1. Sarangapani Sripriya
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  2. Ferdina Sharmila
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  3. Suganya Kandeepan
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  4. Ronnie George
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Correspondence to Ronnie George .

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Editors and Affiliations

  1. National Eye Institute, National Institutes of Health, Bethesda, MD, USA

    Gyan Prakash

  2. National Institute of Sensory Organs Tokyo Medical Center, National Hospital Organization, Tokyo, Japan

    Takeshi Iwata

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Sripriya, S., Sharmila, F., Kandeepan, S., George, R. (2019). Quantitative Trait for Glaucoma. In: Prakash, G., Iwata, T. (eds) Advances in Vision Research, Volume II. Essentials in Ophthalmology. Springer, Singapore. https://doi.org/10.1007/978-981-13-0884-0_30

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  • DOI: https://doi.org/10.1007/978-981-13-0884-0_30

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