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PLOS Genetics  2012 

Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma

DOI: 10.1371/journal.pgen.1002611

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Abstract:

Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4×10?8), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6×10?8). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4×10?2 for rs11656696 and p = 9.1×10?4 for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.

References

[1]  Resnikoff S, Pascolini D, Etya'ale D, Kocur I, Pararajasegaram R, et al. (2004) Global data on visual impairment in the year 2002. Bull World Health Organ 844–851.
[2]  van Koolwijk LME, Bunce C, Viswanathan AC (2009) Genetic Epidemiology. In: Shaarawy TM, Sherwood MB, Hitchings RA, Crowston JG, editors. Glaucoma. Saunders Elsevier. pp. 277–289.
[3]  Monemi S, Spaeth G, DaSilva A, Popinchalk S, Ilitchev E, et al. (2005) Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1. Hum Mol Genet 725–733.
[4]  Rezaie T, Child A, Hitchings R, Brice G, Miller L, et al. (2002) Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 1077–1079.
[5]  Stone EM, Fingert JH, Alward WL, Nguyen TD, Polansky JR, et al. (1997) Identification of a gene that causes primary open angle glaucoma. Science 668–670.
[6]  Fingert JH, Heon E, Liebmann JM, Yamamoto T, Craig JE, et al. (1999) Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet 899–905.
[7]  Alward WL, Kwon YH, Kawase K, Craig JE, Hayreh SS, et al. (2003) Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma. Am J Ophthalmol 904–910.
[8]  Hauser MA, Allingham RR, Linkroum K, Wang J, LaRocque-Abramson K, et al. (2006) Distribution of WDR36 DNA sequence variants in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci 2542–2546.
[9]  Thorleifsson G, Walters GB, Hewitt AW, Masson G, Helgason A, et al. (2010) Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet 906–909.
[10]  Nakano M, Ikeda Y, Taniguchi T, Yagi T, Fuwa M, et al. (2009) Three susceptible loci associated with primary open-angle glaucoma identified by genome-wide association study in a Japanese population. Proc Natl Acad Sci U S A 12838–12842.
[11]  Burdon KP, Macgregor S, Hewitt AW, Sharma S, Chidlow G, et al. (2011) Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet 574–578.
[12]  Ramdas WD, van Koolwijk LM, Ikram MK, Jansonius NM, de Jong PT, et al. (1998) A genome-wide association study of optic disc parameters. PLoS Genet e1000978. doi:10.1371/journal.pgen.1000978.
[13]  Jiao X, Yang Z, Yang X, Chen Y, Tong Z, et al. (2009) Common variants on chromosome 2 and risk of primary open-angle glaucoma in the Afro-Caribbean population of Barbados. Proc Natl Acad Sci U S A 17105–17110.
[14]  Coleman AL, Miglior S (2008) Risk factors for glaucoma onset and progression. Surv Ophthalmol S3–10.
[15]  Carbonaro F, Andrew T, Mackey DA, Spector TD, Hammond CJ (2008) Heritability of intraocular pressure: a classical twin study. Br J Ophthalmol 1125–1128.
[16]  Chang TC, Congdon NG, Wojciechowski R, Munoz B, Gilbert D, et al. (2005) Determinants and heritability of intraocular pressure and cup-to-disc ratio in a defined older population. Ophthalmology 1186–1191.
[17]  Klein BE, Klein R, Lee KE (2004) Heritability of risk factors for primary open-angle glaucoma: the Beaver Dam Eye Study. Invest Ophthalmol Vis Sci 59–62.
[18]  van Koolwijk LM, Despriet DD, van Duijn CM, Pardo Cortes LM, Vingerling JR, et al. (2007) Genetic contributions to glaucoma: heritability of intraocular pressure, retinal nerve fiber layer thickness, and optic disc morphology. Invest Ophthalmol Vis Sci 3669–3676.
[19]  Zheng Y, Xiang F, Huang W, Huang G, Yin Q, et al. (2009) Distribution and heritability of intraocular pressure in chinese children: the Guangzhou twin eye study. Invest Ophthalmol Vis Sci 2040–2043.
[20]  Charlesworth JC, Dyer TD, Stankovich JM, Blangero J, Mackey DA, et al. (2005) 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 3723–3729.
[21]  Duggal P, Klein AP, Lee KE, Iyengar SK, Klein R, et al. (2005) A genetic contribution to intraocular pressure: the beaver dam eye study. Invest Ophthalmol Vis Sci 555–560.
[22]  Duggal P, Klein AP, Lee KE, Klein R, Klein BE, et al. (2007) Identification of novel genetic loci for intraocular pressure: a genomewide scan of the Beaver Dam Eye Study. Arch Ophthalmol 74–79.
[23]  Lee MK, Woo SJ, Kim JI, Cho SI, Kim H, et al. (2010) Replication of a glaucoma candidate gene on 5q22.1 for intraocular pressure in mongolian populations: the GENDISCAN Project. Invest Ophthalmol Vis Sci 1335–1340.
[24]  Rotimi CN, Chen G, Adeyemo AA, Jones LS, Agyenim-Boateng K, et al. (2006) Genomewide scan and fine mapping of quantitative trait loci for intraocular pressure on 5q and 14q in West Africans. Invest Ophthalmol Vis Sci 3262–3267.
[25]  Pang CP, Fan BJ, Canlas O, Wang DY, Dubois S, et al. (2006) A genome-wide scan maps a novel juvenile-onset primary open angle glaucoma locus to chromosome 5q. Mol Vis 85–92.
[26]  Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O'Donnell CJ, et al. (2008) SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 2938–2939.
[27]  Wiggs JL, Allingham RR, Hossain A, Kern J, Auguste J, et al. (2000) Genome-wide scan for adult onset primary open angle glaucoma. Hum Mol Genet 1109–1117.
[28]  Liton PB, Luna C, Challa P, Epstein DL, Gonzalez P (2006) Genome-wide expression profile of human trabecular meshwork cultured cells, nonglaucomatous and primary open angle glaucoma tissue. Mol Vis 774–790.
[29]  Cherry TJ, Trimarchi JM, Stadler MB, Cepko CL (2009) Development and diversification of retinal amacrine interneurons at single cell resolution. Proc Natl Acad Sci U S A 9495–9500.
[30]  Ju YT, Chang AC, She BR, Tsaur ML, Hwang HM, et al. (1998) gas7: A gene expressed preferentially in growth-arrested fibroblasts and terminally differentiated Purkinje neurons affects neurite formation. Proc Natl Acad Sci U S A 11423–11428.
[31]  She BR, Liou GG, Lin-Chao S (2002) Association of the growth-arrest-specific protein Gas7 with F-actin induces reorganization of microfilaments and promotes membrane outgrowth. Exp Cell Res 34–44.
[32]  Chao CC, Chang PY, Lu HH (2005) Human Gas7 isoforms homologous to mouse transcripts differentially induce neurite outgrowth. J Neurosci Res 153–162.
[33]  Koga T, Shen X, Park JS, Qiu Y, Park BC, et al. (2010) Differential effects of myocilin and optineurin, two glaucoma genes, on neurite outgrowth. Am J Pathol 343–352.
[34]  Dijk F, Bergen AA, Kamphuis W (2007) GAP-43 expression is upregulated in retinal ganglion cells after ischemia/reperfusion-induced damage. Exp Eye Res 858–867.
[35]  Wentz-Hunter K, Kubota R, Shen X, Yue BY (2004) Extracellular myocilin affects activity of human trabecular meshwork cells. J Cell Physiol 45–52.
[36]  Bayer AU, Ferrari F, Erb C (2002) High occurrence rate of glaucoma among patients with Alzheimer's disease. Eur Neurol 165–168.
[37]  Wang WH, McNatt LG, Pang IH, Millar JC, Hellberg PE, et al. (2008) Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure. J Clin Invest 1056–1064.
[38]  Shyam R, Shen X, Yue BY, Wentz-Hunter KK (2010) Wnt gene expression in human trabecular meshwork cells. Mol Vis 122–129.
[39]  Russ PK, Kupperman AI, Presley SH, Haselton FR, Chang MS (2010) Inhibition of RhoA signaling with increased Bves in trabecular meshwork cells. Invest Ophthalmol Vis Sci 223–230.
[40]  Chang Y, Ueng SW, Lin-Chao S, Chao CC (2008) Involvement of Gas7 along the ERK1/2 MAP kinase and SOX9 pathway in chondrogenesis of human marrow-derived mesenchymal stem cells. Osteoarthritis Cartilage 1403–1412.
[41]  Ramdas WD, van Koolwijk LM, Ikram MK, Jansonius NM, de Jong PT, et al. (2010) A genome-wide association study of optic disc parameters. PLoS Genet e1000978. PLoS Genet: e1000978. doi:10.1371/journal.pgen.1000978.
[42]  Robertson J, Golesic E, Gauldie J, West-Mays JA (2009) Ocular Gene Transfer of Active TGF{beta} Induces Changes in Anterior Segment Morphology and Elevated IOP in Rats. Invest Ophthalmol Vis Sci.
[43]  Xin B, Puffenberger EG, Turben S, Tan H, Zhou A, et al. (2010) Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism, skeletal anomalies, and mental retardation. Proc Natl Acad Sci U S A 258–263.
[44]  Zhang Z, Mo D, Cong P, He Z, Ling F, et al. (2010) Molecular cloning, expression patterns and subcellular localization of porcine TMCO1 gene. Mol Biol Rep 1611–1618.
[45]  Ehret GB, O'Connor AA, Weder A, Cooper RS, Chakravarti A (2009) Follow-up of a major linkage peak on chromosome 1 reveals suggestive QTLs associated with essential hypertension: GenNet study. Eur J Hum Genet 1650–1657.
[46]  Klein BE, Klein R, Knudtson MD (2005) Intraocular pressure and systemic blood pressure: longitudinal perspective: the Beaver Dam Eye Study. Br J Ophthalmol 284–287.
[47]  Kohlhaas M, Boehm AG, Spoerl E, Pursten A, Grein HJ, et al. (2006) Effect of central corneal thickness, corneal curvature, and axial length on applanation tonometry. Arch Ophthalmol 471–476.
[48]  Gordon MO, Beiser JA, Brandt JD, Heuer DK, Higginbotham EJ, et al. (2002) The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 714–720.
[49]  Shimmyo M, Ross AJ, Moy A, Mostafavi R (2003) Intraocular pressure, Goldmann applanation tension, corneal thickness, and corneal curvature in Caucasians, Asians, Hispanics, and African Americans. Am J Ophthalmol 603–613.
[50]  Gunvant P, Baskaran M, Vijaya L, Joseph IS, Watkins RJ, et al. (2004) Effect of corneal parameters on measurements using the pulsatile ocular blood flow tonograph and Goldmann applanation tonometer. Br J Ophthalmol 518–522.
[51]  Foster PJ, Baasanhu J, Alsbirk PH, Munkhbayar D, Uranchimeg D, et al. (1998) Central corneal thickness and intraocular pressure in a Mongolian population. Ophthalmology 969–973.
[52]  Foster PJ, Machin D, Wong TY, Ng TP, Kirwan JF, et al. (2003) Determinants of intraocular pressure and its association with glaucomatous optic neuropathy in Chinese Singaporeans: the Tanjong Pagar Study. Invest Ophthalmol Vis Sci 3885–3891.
[53]  Charlesworth J, Kramer PL, Dyer T, Diego V, Samples JR, et al. (2010) The path to open-angle glaucoma gene discovery: endophenotypic status of intraocular pressure, cup-to-disc ratio, and central corneal thickness. Invest Ophthalmol Vis Sci 3509–3514.
[54]  Landers JA, Hewitt AW, Dimasi DP, Charlesworth JC, Straga T, et al. (2009) Heritability of central corneal thickness in nuclear families. Invest Ophthalmol Vis Sci 4087–4090.
[55]  Toh T, Liew SH, MacKinnon JR, Hewitt AW, Poulsen JL, et al. (2005) Central corneal thickness is highly heritable: the twin eye studies. Invest Ophthalmol Vis Sci 3718–3722.
[56]  Lu Y, Dimasi DP, Hysi PG, Hewitt AW, Burdon KP, et al. (2010) Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness. PLoS Genet e1000947. doi:10.1371/journal.pgen.1000947.
[57]  Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, et al. (2009) Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet 666–676.
[58]  Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, et al. (2009) Genome-wide association study of blood pressure and hypertension. Nat Genet 677–687.
[59]  van der Valk R, Webers CA, Schouten JS, Zeegers MP, Hendrikse F, et al. (2005) Intraocular pressure-lowering effects of all commonly used glaucoma drugs: a meta-analysis of randomized clinical trials. Ophthalmology 1177–1185.
[60]  Gabelt BT, Kaufman PL (2005) Changes in aqueous humor dynamics with age and glaucoma. Prog Retin Eye Res 612–637.
[61]  (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 977–986.
[62]  Hofman A, Breteler MM, van Duijn CM, Krestin GP, Pols HA, et al. (2007) The Rotterdam Study: objectives and design update. Eur J Epidemiol 819–829.
[63]  Aulchenko YS, Heutink P, Mackay I, Bertoli-Avella AM, Pullen J, et al. (2004) Linkage disequilibrium in young genetically isolated Dutch population. Eur J Hum Genet 527–534.
[64]  Dielemans I, Vingerling JR, Hofman A, Grobbee DE, de Jong PT (1994) Reliability of intraocular pressure measurement with the Goldmann applanation tonometer in epidemiological studies. Graefes Arch Clin Exp Ophthalmol 141–144.
[65]  Aulchenko YS, Ripke S, Isaacs A, van Duijn CM (2007) GenABEL: an R library for genome-wide association analysis. Bioinformatics 1294–1296.
[66]  Amin N, van Duijn CM, Aulchenko YS (2007) A genomic background based method for association analysis in related individuals. PLoS ONE e1274. doi:10.1371/journal.pone.0001274.
[67]  Chen WM, Abecasis GR (2007) Family-based association tests for genomewide association scans. Am J Hum Genet 913–926.
[68]  Bacanu SA, Devlin B, Roeder K (2000) The power of genomic control. Am J Hum Genet 1933–1944.
[69]  Hoggart CJ, Clark TG, De IM, Whittaker JC, Balding DJ (2008) Genome-wide significance for dense SNP and resequencing data. Genet Epidemiol 179–185.
[70]  Booij JC, van SS, Swagemakers SM, Essing AH, Verkerk AJ, et al. (2009) Functional annotation of the human retinal pigment epithelium transcriptome. BMC Genomics 164.

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