A Genome-Wide Association Study of Optic Disc Parameters
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 = 6.72×10−19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67×10−33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15×10−11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93×10−10) 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.
Vyšlo v časopise:
A Genome-Wide Association Study of Optic Disc Parameters. PLoS Genet 6(6): e32767. doi:10.1371/journal.pgen.1000978
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1000978
Souhrn
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 = 6.72×10−19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67×10−33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15×10−11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93×10−10) 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.
Zdroje
1. NangiaV
MatinA
BhojwaniK
KulkarniM
YadavM
2008 Optic disc size in a population-based study in central India: the Central India Eye and Medical Study (CIEMS). Acta Ophthalmol 86 103 104
2. HealeyPR
MitchellP
1999 Optic disk size in open-angle glaucoma: the Blue Mountains Eye Study. Am J Ophthalmol 128 515 517
3. BellezzaAJ
HartRT
BurgoyneCF
2000 The optic nerve head as a biomechanical structure: initial finite element modeling. Invest Ophthalmol Vis Sci 41 2991 3000
4. HoffmannEM
ZangwillLM
CrowstonJG
WeinrebRN
2007 Optic disk size and glaucoma. Surv Ophthalmol 52 32 49
5. KwonYH
FingertJH
KuehnMH
AlwardWL
2009 Primary open-angle glaucoma. N Engl J Med 360 1113 1124
6. QuigleyHA
1993 Open-angle glaucoma. N Engl J Med 328 1097 1106
7. KeltnerJL
JohnsonCA
AndersonDR
LevineRA
FanJ
2006 The association between glaucomatous visual fields and optic nerve head features in the Ocular Hypertension Treatment Study. Ophthalmology 113 1603 1612
8. MigliorS
PfeifferN
TorriV
ZeyenT
Cunha-VazJ
2007 Predictive factors for open-angle glaucoma among patients with ocular hypertension in the European Glaucoma Prevention Study. Ophthalmology 114 3 9
9. KleinBE
KleinR
LeeKE
2004 Heritability of risk factors for primary open-angle glaucoma: the Beaver Dam Eye Study. Invest Ophthalmol Vis Sci 45 59 62
10. van KoolwijkLM
DesprietDD
van DuijnCM
Pardo CortesLM
VingerlingJR
2007 Genetic contributions to glaucoma: heritability of intraocular pressure, retinal nerve fiber layer thickness, and optic disc morphology. Invest Ophthalmol Vis Sci 48 3669 3676
11. ChangTC
CongdonNG
WojciechowskiR
MunozB
GilbertD
2005 Determinants and heritability of intraocular pressure and cup-to-disc ratio in a defined older population. Ophthalmology 112 1186 1191
12. SchwartzJT
ReulingFH
FeinleibM
1975 Size of the physiologic cup of the optic nerve head. hereditary and environmental factors. Arch Ophthalmol 93 776 778
13. BrownNL
DagenaisSL
ChenCM
GlaserT
2002 Molecular characterization and mapping of ATOH7, a human atonal homolog with a predicted role in retinal ganglion cell development. Mamm Genome 13 95 101
14. BrownNL
KanekarS
VetterML
TuckerPK
GemzaDL
1998 Math5 encodes a murine basic helix-loop-helix transcription factor expressed during early stages of retinal neurogenesis. Development 125 4821 4833
15. QiuF
JiangH
XiangM
2008 A comprehensive negative regulatory program controlled by Brn3b to ensure ganglion cell specification from multipotential retinal precursors. J Neurosci 28 3392 3403
16. BrownNL
PatelS
BrzezinskiJ
GlaserT
2001 Math5 is required for retinal ganglion cell and optic nerve formation. Development 128 2497 2508
17. WangY
XuL
ZhangL
YangH
MaY
2006 Optic disc size in a population based study in northern China: the Beijing Eye Study. Br J Ophthalmol 90 353 356
18. MaW
YanRT
XieW
WangSZ
2004 A role of ath5 in inducing neuroD and the photoreceptor pathway. J Neurosci 24 7150 7158
19. KimJ
WuHH
LanderAD
LyonsKM
MatzukMM
2005 GDF11 controls the timing of progenitor cell competence in developing retina. Science 308 1927 1930
20. MuX
BeremandPD
ZhaoS
PershadR
SunH
2004 Discrete gene sets depend on POU domain transcription factor Brn3b/Brn-3.2/POU4f2 for their expression in the mouse embryonic retina. Development 131 1197 1210
21. HannonGJ
BeachD
1994 p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371 257 261
22. DrexlerHG
1998 Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. Leukemia 12 845 859
23. MatsumuraY
NishigoriC
YagiT
ImamuraS
TakebeH
1998 Mutations of p16 and p15 tumor suppressor genes and replication errors contribute independently to the pathogenesis of sporadic malignant melanoma. Arch Dermatol Res 290 175 180
24. LiuY
El-NaggarS
DarlingDS
HigashiY
DeanDC
2008 Zeb1 links epithelial-mesenchymal transition and cellular senescence. Development 135 579 588
25. ZegginiE
WeedonMN
LindgrenCM
FraylingTM
ElliottKS
2007 Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316 1336 1341
26. EngelsS
KohlhaseJ
McGaughranJ
2000 A SALL1 mutation causes a branchio-oto-renal syndrome-like phenotype. J Med Genet 37 458 460
27. OlavarrietaL
Morales-AnguloC
del CastilloI
MorenoF
Moreno-PelayoMA
2008 Stickler and branchio-oto-renal syndromes in a patient with mutations in EYA1 and COL2A1 genes. Clin Genet 73 262 267
28. ChaiL
YangJ
DiC
CuiW
KawakamiK
2006 Transcriptional activation of the SALL1 by the human SIX1 homeodomain during kidney development. J Biol Chem 281 18918 18926
29. KochharA
OrtenDJ
SorensenJL
FischerSM
CremersCW
2008 SIX1 mutation screening in 247 branchio-oto-renal syndrome families: a recurrent missense mutation associated with BOR. Hum Mutat 29 565
30. LiX
PerissiV
LiuF
RoseDW
RosenfeldMG
2002 Tissue-specific regulation of retinal and pituitary precursor cell proliferation. Science 297 1180 1183
31. GallardoME
Lopez-RiosJ
Fernaud-EspinosaI
GranadinoB
SanzR
1999 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 61 82 91
32. NolenLD
AmorD
HaywoodA
St HeapsL
WillcockC
2006 Deletion at 14q22-23 indicates a contiguous gene syndrome comprising anophthalmia, pituitary hypoplasia, and ear anomalies. Am J Med Genet A 140 1711 1718
33. JeanD
BernierG
GrussP
1999 Six6 (Optx2) is a novel murine Six3-related homeobox gene that demarcates the presumptive pituitary/hypothalamic axis and the ventral optic stalk. Mech Dev 84 31 40
34. ToyJ
SundinOH
1999 Expression of the optx2 homeobox gene during mouse development. Mech Dev 83 183 186
35. SchmidtWM
KrausC
HogerH
HochmeisterS
OberndorferF
2007 Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration. EMBO Rep 8 691 697
36. AliM
McKibbinM
BoothA
ParryDA
JainP
2009 Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet 84 664 671
37. Narooie-NejadM
PaylakhiSH
ShojaeeS
FazlaliZ
Rezaei KanaviM
2009 Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma. Hum Mol Genet 18 3969 3977
38. Capes-DavisA
TolhurstO
DunnJM
JeffreyPL
2005 Expression of doublecortin (DCX) and doublecortin-like kinase (DCLK) within the developing chick brain. Dev Dyn 232 457 467
39. Meijers-HeijboerH
van den OuwelandA
KlijnJ
WasielewskiM
de SnooA
2002 Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31 55 59
40. BarbetF
HakikiS
OrssaudC
GerberS
PerraultI
2005 A third locus for dominant optic atrophy on chromosome 22q. J Med Genet 42 e1
41. GirgisRA
McKeeHD
InnesJR
2004 Swollen optic discs in a patient with the chromosome 22q11.2 deletion syndrome. Br J Ophthalmol 88 591 592
42. Azuara-BlancoA
HarrisA
CantorLB
1998 Reproducibility of optic disk topographic measurements with the Topcon ImageNet and the Heidelberg Retina Tomograph. Ophthalmologica 212 95 98
43. Azuara-BlancoA
SpaethGL
NichollJ
LanzlIM
AugsburgerJJ
1999 Comparison between laser scanning tomography and computerised image analysis of the optic disc. Br J Ophthalmol 83 295 298
44. IkramMK
BorgerPH
AssinkJJ
JonasJB
HofmanA
2002 Comparing ophthalmoscopy, slide viewing, and semiautomated systems in optic disc morphometry. Ophthalmology 109 486 493
45. HofmanA
BretelerMM
van DuijnCM
KrestinGP
PolsHA
2007 The Rotterdam Study: objectives and design update. Eur J Epidemiol 22 819 829
46. AulchenkoYS
HeutinkP
MackayI
Bertoli-AvellaAM
PullenJ
2004 Linkage disequilibrium in young genetically isolated Dutch population. Eur J Hum Genet 12 527 534
47. PardoLM
MacKayI
OostraB
van DuijnCM
AulchenkoYS
2005 The effect of genetic drift in a young genetically isolated population. Ann Hum Genet 69 288 295
48. MorganJE
SheenNJ
NorthRV
ChoongY
AnsariE
2005 Digital imaging of the optic nerve head: monoscopic and stereoscopic analysis. Br J Ophthalmol 89 879 884
49. RolandoM
IesterM
CampagnaP
BorgiaL
TraversoC
1994 Measurement variability in digital analysis of optic discs. Doc Ophthalmol 85 211 222
50. HealeyP
CarbonaroF
TaylorB
SpectorTD
MitchellP
2008 The heritability of optic disc parameters: a classic twin study. Invest Ophthalmol Vis Sci 49 77 80
51. Skenduli-BalaE
de VoogdS
WolfsRC
van LeeuwenR
IkramMK
2005 Causes of incident visual field loss in a general elderly population: the Rotterdam study. Arch Ophthalmol 123 233 238
52. WolfsRC
BorgerPH
RamrattanRS
KlaverCC
HulsmanCA
2000 Changing views on open-angle glaucoma: definitions and prevalences–The Rotterdam Study. Invest Ophthalmol Vis Sci 41 3309 3321
53. RivadeneiraF
StyrkarsdottirU
EstradaK
HalldorssonBV
HsuYH
2009 Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet
54. EstradaK
AbuseirisA
GrosveldFG
UitterlindenAG
KnochTA
2009 GRIMP: a web- and grid-based tool for high-speed analysis of large-scale genome-wide association using imputed data. Bioinformatics 25 2750 2752
55. AulchenkoYS
RipkeS
IsaacsA
van DuijnCM
2007 GenABEL: an R library for genome-wide association analysis. Bioinformatics 23 1294 1296
56. ChenWM
AbecasisGR
2007 Family-based association tests for genomewide association scans. Am J Hum Genet 81 913 926
57. Sanchez-MecaJ
Marin-MartinezF
1998 Weighting by Inverse Variance or by Sample Size in Meta-Analysis: A Simulation Study. Educ Psychol Meas 58 211 220
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2010 Číslo 6
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- The IG-DMR and the -DMR at Human Chromosome 14q32.2: Hierarchical Interaction and Distinct Functional Properties as Imprinting Control Centers
- Copy Number Variation and Transposable Elements Feature in Recent, Ongoing Adaptation at the Locus
- Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene
- Amplification of a Cytochrome P450 Gene Is Associated with Resistance to Neonicotinoid Insecticides in the Aphid