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PMID: 20548946 Published · epublish English Journal Article Meta-Analysis Research Support, Non-U.S. Gov't

A genome-wide association study of optic disc parameters.

PLoS genetics ·Vol. 6 ·No. 6 ·2010-06-10 ·Pages e1000978

Ramdas WD, van Koolwijk LM, Ikram MK, Jansonius NM, de Jong PT, Bergen AA, Isaacs A, Amin N, Aulchenko YS, Wolfs RC, Hofman A, Rivadeneira F, Oostra BA, Uitterlinden AG, Hysi P, Hammond CJ, Lemij HG, Vingerling JR, Klaver CC, van Duijn CM

Abstract

The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72x10(-19)) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67x10(-33)) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15x10(-11)) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93x10(-10)) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.

MeSH Terms
Adolescent Adult Aged Aged, 80 and over Female Genetic Variation Genome-Wide Association Study Humans Male Middle Aged Optic Disk/metabolism Young Adult
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Ramdas Wishal D
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
van Koolwijk Leonieke M E
Ikram M Kamran
Jansonius Nomdo M
de Jong Paulus T V M
Bergen Arthur A B
Isaacs Aaron
Amin Najaf
Aulchenko Yurii S
Wolfs Roger C W
Hofman Albert
Rivadeneira Fernando
Oostra Ben A
Uitterlinden Andre G
Hysi Pirro
Hammond Christopher J
Lemij Hans G
Vingerling Johannes R
Klaver Caroline C W
van Duijn Cornelia M
Conflict of Interest

The authors have declared that no competing interests exist.

References (56)
56 references, click to expand
  1. Swollen optic discs in a patient with the chromosome 22q11.2 deletion syndrome.
    Br J Ophthalmol. 2004 Apr;88(4):591-2 PMID: 15031192
  2. Optic disc size in a population based study in northern China: the Beijing Eye Study.
    Br J Ophthalmol. 2006 Mar;90(3):353-6 PMID: 16488961
  3. The Rotterdam Study: objectives and design update.
    Eur J Epidemiol. 2007;22(11):819-29 PMID: 17955331
  4. A role of ath5 in inducing neuroD and the photoreceptor pathway.
    J Neurosci. 2004 Aug 11;24(32):7150-8 PMID: 15306648
  5. Expression of the optx2 homeobox gene during mouse development.
    Mech Dev. 1999 May;83(1-2):183-6 PMID: 10381579
  6. A comprehensive negative regulatory program controlled by Brn3b to ensure ganglion cell specification from multipotential retinal precursors.
    J Neurosci. 2008 Mar 26;28(13):3392-403 PMID: 18367606
  7. The heritability of optic disc parameters: a classic twin study.
    Invest Ophthalmol Vis Sci. 2008 Jan;49(1):77-80 PMID: 18172077
  8. Zeb1 links epithelial-mesenchymal transition and cellular senescence.
    Development. 2008 Feb;135(3):579-88 PMID: 18192284
  9. GDF11 controls the timing of progenitor cell competence in developing retina.
    Science. 2005 Jun 24;308(5730):1927-30 PMID: 15976303
  10. Primary open-angle glaucoma.
    N Engl J Med. 2009 Mar 12;360(11):1113-24 PMID: 19279343
  11. Family-based association tests for genomewide association scans.
    Am J Hum Genet. 2007 Nov;81(5):913-26 PMID: 17924335
  12. Predictive factors for open-angle glaucoma among patients with ocular hypertension in the European Glaucoma Prevention Study.
    Ophthalmology. 2007 Jan;114(1):3-9 PMID: 17070596
  13. Size of the physiologic cup of the optic nerve head. hereditary and environmental factors.
    Arch Ophthalmol. 1975 Sep;93(9):776-8 PMID: 1235482
  14. The association between glaucomatous visual fields and optic nerve head features in the Ocular Hypertension Treatment Study.
    Ophthalmology. 2006 Sep;113(9):1603-12 PMID: 16949445
  15. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies.
    Nat Genet. 2009 Nov;41(11):1199-206 PMID: 19801982
  16. Comparing ophthalmoscopy, slide viewing, and semiautomated systems in optic disc morphometry.
    Ophthalmology. 2002 Mar;109(3):486-93 PMID: 11874749
  17. Math5 is required for retinal ganglion cell and optic nerve formation.
    Development. 2001 Jul;128(13):2497-508 PMID: 11493566
  18. Causes of incident visual field loss in a general elderly population: the Rotterdam study.
    Arch Ophthalmol. 2005 Feb;123(2):233-8 PMID: 15710821
  19. Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells.
    Leukemia. 1998 Jun;12(6):845-59 PMID: 9639410
  20. Transcriptional activation of the SALL1 by the human SIX1 homeodomain during kidney development.
    J Biol Chem. 2006 Jul 14;281(28):18918-26 PMID: 16670092
  21. A third locus for dominant optic atrophy on chromosome 22q.
    J Med Genet. 2005 Jan;42(1):e1 PMID: 15635063
  22. GRIMP: a web- and grid-based tool for high-speed analysis of large-scale genome-wide association using imputed data.
    Bioinformatics. 2009 Oct 15;25(20):2750-2 PMID: 19700477
  23. Null mutations in LTBP2 cause primary congenital glaucoma.
    Am J Hum Genet. 2009 May;84(5):664-71 PMID: 19361779
  24. Tissue-specific regulation of retinal and pituitary precursor cell proliferation.
    Science. 2002 Aug 16;297(5584):1180-3 PMID: 12130660
  25. Molecular characterization and mapping of ATOH7, a human atonal homolog with a predicted role in retinal ganglion cell development.
    Mamm Genome. 2002 Feb;13(2):95-101 PMID: 11889557
  26. Measurement variability in digital analysis of optic discs.
    Doc Ophthalmol. 1994;85(3):211-22 PMID: 7924849
  27. Reproducibility of optic disk topographic measurements with the Topcon ImageNet and the Heidelberg Retina Tomograph.
    Ophthalmologica. 1998;212(2):95-8 PMID: 9486547
  28. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.
    Nature. 1994 Sep 15;371(6494):257-61 PMID: 8078588
  29. Six6 (Optx2) is a novel murine Six3-related homeobox gene that demarcates the presumptive pituitary/hypothalamic axis and the ventral optic stalk.
    Mech Dev. 1999 Jun;84(1-2):31-40 PMID: 10473118
  30. Linkage disequilibrium in young genetically isolated Dutch population.
    Eur J Hum Genet. 2004 Jul;12(7):527-34 PMID: 15054401
  31. Heritability of risk factors for primary open-angle glaucoma: the Beaver Dam Eye Study.
    Invest Ophthalmol Vis Sci. 2004 Jan;45(1):59-62 PMID: 14691154
  32. Comparison between laser scanning tomography and computerised image analysis of the optic disc.
    Br J Ophthalmol. 1999 Mar;83(3):295-8 PMID: 10365036
  33. Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration.
    EMBO Rep. 2007 Jul;8(7):691-7 PMID: 17571074
  34. Changing views on open-angle glaucoma: definitions and prevalences--The Rotterdam Study.
    Invest Ophthalmol Vis Sci. 2000 Oct;41(11):3309-21 PMID: 11006219
  35. Math5 encodes a murine basic helix-loop-helix transcription factor expressed during early stages of retinal neurogenesis.
    Development. 1998 Dec;125(23):4821-33 PMID: 9806930
  36. Optic disc size in a population-based study in central India: the Central India Eye and Medical Study (CIEMS).
    Acta Ophthalmol. 2008 Feb;86(1):103-4 PMID: 17662097
  37. Digital imaging of the optic nerve head: monoscopic and stereoscopic analysis.
    Br J Ophthalmol. 2005 Jul;89(7):879-84 PMID: 15965171
  38. Optic disk size and glaucoma.
    Surv Ophthalmol. 2007 Jan-Feb;52(1):32-49 PMID: 17212989
  39. Expression of doublecortin (DCX) and doublecortin-like kinase (DCLK) within the developing chick brain.
    Dev Dyn. 2005 Feb;232(2):457-67 PMID: 15614772
  40. Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma.
    Hum Mol Genet. 2009 Oct 15;18(20):3969-77 PMID: 19656777
  41. Mutations of p16 and p15 tumor suppressor genes and replication errors contribute independently to the pathogenesis of sporadic malignant melanoma.
    Arch Dermatol Res. 1998 Apr;290(4):175-80 PMID: 9617435
  42. Open-angle glaucoma.
    N Engl J Med. 1993 Apr 15;328(15):1097-106 PMID: 8455668
  43. Discrete gene sets depend on POU domain transcription factor Brn3b/Brn-3.2/POU4f2 for their expression in the mouse embryonic retina.
    Development. 2004 Mar;131(6):1197-210 PMID: 14973295
  44. Deletion at 14q22-23 indicates a contiguous gene syndrome comprising anophthalmia, pituitary hypoplasia, and ear anomalies.
    Am J Med Genet A. 2006 Aug 15;140(16):1711-8 PMID: 16835935
  45. Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies.
    Genomics. 1999 Oct 1;61(1):82-91 PMID: 10512683
  46. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations.
    Nat Genet. 2002 May;31(1):55-9 PMID: 11967536
  47. GenABEL: an R library for genome-wide association analysis.
    Bioinformatics. 2007 May 15;23(10):1294-6 PMID: 17384015
  48. Determinants and heritability of intraocular pressure and cup-to-disc ratio in a defined older population.
    Ophthalmology. 2005 Jul;112(7):1186-91 PMID: 15939473
  49. The optic nerve head as a biomechanical structure: initial finite element modeling.
    Invest Ophthalmol Vis Sci. 2000 Sep;41(10):2991-3000 PMID: 10967056
  50. Stickler and branchio-oto-renal syndromes in a patient with mutations in EYA1 and COL2A1 genes.
    Clin Genet. 2008 Mar;73(3):262-7 PMID: 18177466
  51. A SALL1 mutation causes a branchio-oto-renal syndrome-like phenotype.
    J Med Genet. 2000 Jun;37(6):458-60 PMID: 10928856
  52. The effect of genetic drift in a young genetically isolated population.
    Ann Hum Genet. 2005 May;69(Pt 3):288-95 PMID: 15845033
  53. Optic disk size in open-angle glaucoma: the Blue Mountains Eye Study.
    Am J Ophthalmol. 1999 Oct;128(4):515-7 PMID: 10577600
  54. SIX1 mutation screening in 247 branchio-oto-renal syndrome families: a recurrent missense mutation associated with BOR.
    Hum Mutat. 2008 Apr;29(4):565 PMID: 18330911
  55. Genetic contributions to glaucoma: heritability of intraocular pressure, retinal nerve fiber layer thickness, and optic disc morphology.
    Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3669-76 PMID: 17652737
  56. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
    Science. 2007 Jun 1;316(5829):1336-41 PMID: 17463249
Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1000978
Published
2010-06-10
Epub
2010-00-10
Pages
e1000978
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC2883590
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pgen.1000978 PMC Full Text View journal details
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