Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma
Megan U. Carnes,Yangfan P. Liu,R. Rand Allingham,Benjamin T. Whigham,Shane J. Havens,Melanie E. Garrett,Chunyan Qiao,Chunyan Qiao,Nicholas Katsanis,Janey L. Wiggs,Louis R. Pasquale,Allison E. Ashley-Koch,Edwin C. Oh,Michael A. Hauser,Murray H. Brilliant,Donald L. Budenz,Hemin R. Chin,Jessica N. Cooke Bailey,John H. Fingert,David S. Friedman,Douglas E. Gaasterland,Terry Gaasterland,Jonathan L. Haines,Jae H. Kang,Richard K. Lee,Paul R. Lichter,Yutao Liu,Stephanie Loomis,Cathy Essentia McCarty,Sayoko E. Moroi,Margaret A. Pericak-Vance,Anthony Realini,Julia E. Richards,Joel S. Schuman,William K. Scott,Kuldev Singh,Arthur J. Sit,Douglas Vollrath,Robert N. Weinreb,Gadi Wollstein,Brian L. Yaspan,Donald J. Zack,Kang Zhang +42 more
TLDR
It is hypothesized that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.Abstract:
Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10(-11)). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10)) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.read more
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Journal ArticleDOI
Primary open-angle glaucoma.
Robert N. Weinreb,Christopher Kai-Shun Leung,Jonathan G Crowston,Felipe A. Medeiros,David S. Friedman,Janey L. Wiggs,Keith R Martin +6 more
TL;DR: Primary open-angle glaucoma (POAG) is the most common type and management of POAG includes topical drug therapies and surgery to reduce IOP, although new therapies targeting neuroprotection of RGCs and axonal regeneration are under development.
Journal ArticleDOI
Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy
Claudia Gonzaga-Jauregui,Claudia Gonzaga-Jauregui,Tamar Harel,Tomasz Gambin,Maria Kousi,Laurie B. Griffin,Ludmila Francescatto,Burcak Ozes,Ender Karaca,Shalini N. Jhangiani,Matthew N. Bainbridge,Kim Lawson,Davut Pehlivan,Yuji Okamoto,Marjorie Withers,Pedro Mancias,Anne Slavotinek,Pamela J. Reitnauer,Meryem Tuba Goksungur,Michael E. Shy,Thomas O. Crawford,Michel Koenig,Michel Koenig,Jason R. Willer,Brittany N. Flores,Igor Pediaditrakis,Onder Us,Wojciech Wiszniewski,Yesim Parman,Anthony Antonellis,Donna M. Muzny,Nicholas Katsanis,Esra Battaloglu,Eric Boerwinkle,Eric Boerwinkle,Richard A. Gibbs,James R. Lupski +36 more
TL;DR: Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, suggesting that mutation burden potentially contributes to phenotypic variability.
Journal ArticleDOI
Genome-wide association analysis identifies TXNRD2 , ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma
Jessica N. Cooke Bailey,Stephanie Loomis,Jae H. Kang,R. Rand Allingham,Puya Gharahkhani,Chiea Chuen Khor,Chiea Chuen Khor,Kathryn P. Burdon,Kathryn P. Burdon,Hugues Aschard,Daniel I. Chasman,Robert P. Igo,Pirro G. Hysi,Craig A. Glastonbury,Allison E. Ashley-Koch,Murray H. Brilliant,Andrew A. Brown,Donald L. Budenz,Alfonso Buil,Ching-Yu Cheng,Ching-Yu Cheng,Hyon K. Choi,William G. Christen,Gary C. Curhan,Immaculata De Vivo,John H. Fingert,Paul J. Foster,Paul J. Foster,Charles S. Fuchs,Douglas E. Gaasterland,Terry Gaasterland,Alex W. Hewitt,Frank B. Hu,David J. Hunter,Anthony P Khawaja,Richard K. Lee,Zheng Li,Paul R. Lichter,David A. Mackey,David A. Mackey,Peter McGuffin,Paul Mitchell,Sayoko E. Moroi,Shamira A. Perera,Shamira A. Perera,Keating W. Pepper,Qibin Qi,Tony Realini,Julia E. Richards,Paul M. Ridker,Eric B. Rimm,Robert Ritch,Marylyn D. Ritchie,Joel S. Schuman,William K. Scott,Kuldev Singh,Arthur J. Sit,Yeunjoo E. Song,Rulla M. Tamimi,Fotis Topouzis,Ananth C. Viswanathan,Shefali S. Verma,Douglas Vollrath,Jie Jin Wang,Nicole Weisschuh,Bernd Wissinger,Gadi Wollstein,Tien Yin Wong,Tien Yin Wong,Brian L. Yaspan,Donald J. Zack,Kang Zhang,Robert N. Weinreb,Margaret A. Pericak-Vance,Kerrin S. Small,Christopher J Hammond,Tin Aung,Tin Aung,Yutao Liu,Eranga N. Vithana,Eranga N. Vithana,Stuart MacGregor,Jamie E Craig,Peter Kraft,Gareth R. Howell,Michael A. Hauser,Louis R. Pasquale,Jonathan L. Haines,Janey L. Wiggs +88 more
TL;DR: New pathways underlying POAG susceptibility are identified and new targets for preventative therapies are suggested, including TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head.
Journal ArticleDOI
New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics
Henriët Springelkamp,Adriana I Iglesias,Aniket Mishra,Aniket Mishra,René Höhn,Robert Wojciechowski,Anthony P Khawaja,Abhishek Nag,Ya Xing Wang,Jie Jin Wang,Gabriel Cuellar-Partida,Jane Gibson,Jessica N. Cooke Bailey,Eranga N. Vithana,Puya Gharahkhani,Thibaud Boutin,Wishal D. Ramdas,Tanja Zeller,Robert Luben,Ekaterina Yonova-Doing,Ananth C. Viswanathan,Seyhan Yazar,Angela J. Cree,Jonathan L. Haines,Jia Yu Koh,Emmanuelle Souzeau,James F. Wilson,Najaf Amin,Christian P. Müller,Cristina Venturini,Lisa S. Kearns,Jae H. Kang,Yih Chung Tham,Tiger Zhou,Elisabeth M. van Leeuwen,Stefan Nickels,Paul G. Sanfilippo,Paul G. Sanfilippo,Jiemin Liao,Herma C. van der Linde,Wanting Zhao,Leonieke M E van Koolwijk,Li Zheng,Fernando Rivadeneira,Mani Baskaran,Sven J. van der Lee,Shamira A. Perera,Paulus T. V. M. de Jong,Ben A. Oostra,André G. Uitterlinden,Qiao Fan,Albert Hofman,E. Shyong Tai,Johannes R. Vingerling,Xueling Sim,Roger C. W. Wolfs,Yik Ying Teo,Hans G Lemij,Chiea Chuen Khor,Rob Willemsen,Karl J. Lackner,Tin Aung,Nomdo M. Jansonius,Grant W. Montgomery,Philipp S. Wild,Terri L. Young,Kathryn P. Burdon,Pirro G. Hysi,Louis R. Pasquale,Louis R. Pasquale,Tien Yin Wong,Caroline C W Klaver,Alex W. Hewitt,Alex W. Hewitt,Jost B. Jonas,Paul Mitchell,Andrew J. Lotery,Paul J. Foster,Veronique Vitart,Norbert Pfeiffer,Jamie E Craig,David A. Mackey,David A. Mackey,Christopher J Hammond,Janey L. Wiggs,Ching-Yu Cheng,Cornelia M. van Duijn,Stuart MacGregor +87 more
TL;DR: Several novel genes influencing the major clinical risk predictors of POAG are identified and it is shown that genetic variation in CDKN1A is important in POAG risk.
Journal ArticleDOI
Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.
TL;DR: The authors conducted a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known.
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