Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.
基金:
National Institutes of Health/National Eye Institute (NIH/NEI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Eye Institute (NEI) [1R01EY018246-01]; NIH/NEIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Eye Institute (NEI) [R01 EY014685]; Research to Prevent Blindness, Inc.Research to Prevent Blindness (RPB); University of Wisconsin School of Medicine and Public Health Centennial Scholars Fund; Australian National Health & Medical Research Council (NH&MRC), Canberra Australia [974159, 211069, 457349, 512423, 475604, 529912]; Centre for Clinical Research Excellence (Translational Clinical Research in Major Eye Diseases) [519923]; NH&MRC research fellowships [358702, 632909]; Wellcome Trust, UK as part of Wellcome Trust Case Control Consortium 2Wellcome Trust [085475/B/08/Z, 085475/Z/08/Z, 076113]; UK and Eire Glaucoma Society; International Glaucoma Association; Royal College of Ophthalmologists; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIH R01 EY022305]; NEIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Eye Institute (NEI) [K08EY022943]; MRC HGU "QTL in Health and Disease" core programme; National Institute for Health ResearchNational Institute for Health Research (NIHR) [SRF/01/010] Funding Source: researchfish; Fight for Sight [1895/96, 1738/39] Funding Source: researchfish; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [UM1CA186107] Funding Source: NIH RePORTER; NATIONAL EYE INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Eye Institute (NEI) [R01EY014685, R01EY023512, R01EY018246, R01EY022305, P30EY014104, K08EY022943] Funding Source: NIH RePORTER; NATIONAL HUMAN GENOME RESEARCH INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [U01HG004728] Funding Source: NIH RePORTER
通讯机构:[4]Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Stat Genet, Brisbane, Qld, Australia[*1]Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Stuart MacGregor Stat Genet, Brisbane, Qld, Australia
推荐引用方式(GB/T 7714):
Springelkamp Henriet,Iglesias Adriana I.,Mishra Aniket,et al.New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics[J].HUMAN MOLECULAR GENETICS.2017,26(2):438-453.doi:10.1093/hmg/ddw399.
APA:
Springelkamp, Henriet,Iglesias, Adriana I.,Mishra, Aniket,Hoehn, Rene,Wojciechowski, Robert...&MacGregor, Stuart.(2017).New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.HUMAN MOLECULAR GENETICS,26,(2)
MLA:
Springelkamp, Henriet,et al."New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics".HUMAN MOLECULAR GENETICS 26..2(2017):438-453