Three susceptible loci associated with primary open-angle glaucoma identified by genome-wide association study in a Japanese population
Masakazu Nakano,Yoko Ikeda,Takazumi Taniguchi,Tomohito Yagi,Masahiro Fuwa,Natsue Omi,Yuichi Tokuda,Masami Tanaka,Kengo Yoshii,Masaaki Kageyama,Shigeta Naruse,Akira Matsuda,Kazuhiko Mori,Shigeru Kinoshita,Kei Tashiro +14 more
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TLDR
It turned out that 3 genetic loci probably associated with POAG have been identified, and these findings would provide the foundation for future studies to build on, such as for the metaanalysis, to reveal the molecular mechanism of the POAG pathogenesis.Abstract:
Primary open-angle glaucoma (POAG) is the major type of glaucoma. To discover genetic markers associated with POAG, we examined a total of 1,575 Japanese subjects in a genome-wide association study (stage 1) and a subsequent study (stage 2). Both studies were carried out at a single institution. In the stage 1 association study, we compared SNPs between 418 POAG patients and 300 control subjects. First, low-quality data were eliminated by a stringent filter, and 331,838 autosomal SNPs were selected for analysis. Poorly clustered SNPs were eliminated by a visual assessment, leaving 255 that showed a significant deviation (P < 0.001) in the allele frequency comparison. In the stage 2 analysis, we tested these 255 SNPs for association in DNA samples from a separate group of 409 POAG and 448 control subjects. High-quality genotype data were selected and used to calculate the combined P values of stages 1 and 2 by the Mantel-Haenszel test. These analyses yielded 6 SNPs with P < 0.0001. All 6 SNPs showed a significant association (P < 0.05) in stage 2, demonstrating a confirmed association with POAG. Although we could not link the SNPs to the annotated gene(s), it turned out that we have identified 3 genetic loci probably associated with POAG. These findings would provide the foundation for future studies to build on, such as for the metaanalysis, to reveal the molecular mechanism of the POAG pathogenesis.read more
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Journal ArticleDOI
Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma
Gudmar Thorleifsson,G. Bragi Walters,Alex W. Hewitt,Alex W. Hewitt,Gisli Masson,Agnar Helgason,Agnar Helgason,Andrew T. DeWan,Asgeir Sigurdsson,Adalbjorg Jonasdottir,Sigurjon A. Gudjonsson,Kristinn P. Magnusson,Hreinn Stefansson,Dennis S.C. Lam,Pancy O. S. Tam,Gudrun J Gudmundsdottir,Laura Southgate,Kathryn P. Burdon,Maria Soffia Gottfredsdottir,Micheala A. Aldred,Paul Mitchell,David St Clair,David A. Collier,David A. Collier,Nelson L.S. Tang,Orn Sveinsson,Stuart MacGregor,Nicholas G. Martin,Angela J. Cree,Jane Gibson,Alex MacLeod,Aby Jacob,Sarah Ennis,Terri L. Young,Juliana C.N. Chan,W Karwatowski,Christopher J Hammond,Kristjan Thordarson,Mingzhi Zhang,Claes Wadelius,Andrew J. Lotery,Richard C. Trembath,Chi Pui Pang,Josephine Hoh,Jamie E Craig,Augustine Kong,David A. Mackey,David A. Mackey,David A. Mackey,Fridbert Jonasson,Unnur Thorsteinsdottir,Unnur Thorsteinsdottir,Kari Stefansson,Kari Stefansson +53 more
TL;DR: The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.
Journal ArticleDOI
Common genetic determinants of intraocular pressure and primary open-angle glaucoma
Leonieke M E van Koolwijk,Wishal D. Ramdas,M. Kamran Ikram,Nomdo M. Jansonius,Nomdo M. Jansonius,Francesca Pasutto,Pirro G. Hysi,Stuart MacGregor,Sarah F. Janssen,Alex W. Hewitt,Ananth C. Viswanathan,Jacoline B. ten Brink,S. Mohsen Hosseini,Najaf Amin,Dominiek D. G. Despriet,Jacqueline J. M. Willemse-Assink,Rogier Kramer,Fernando Rivadeneira,Maksim Struchalin,Yurii S. Aulchenko,Nicole Weisschuh,Matthias Zenkel,Christian Y. Mardin,Eugen Gramer,Ulrich Welge-Lussen,Grant W. Montgomery,Francis Carbonaro,Terri L. Young,Céline Bellenguez,Peter McGuffin,Paul J. Foster,Fotis Topouzis,Paul Mitchell,Jie Jin Wang,Jie Jin Wang,Tien Yin Wong,Monika A. Czudowska,Albert Hofman,André G. Uitterlinden,Roger C. W. Wolfs,Paulus T. V. M. de Jong,Ben A. Oostra,Andrew D. Paterson,David A. Mackey,Arthur A. B. Bergen,André Reis,Christopher J Hammond,Johannes R. Vingerling,Hans G Lemij,Caroline C W Klaver,Cornelia M. van Duijn +50 more
TL;DR: GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina, and both genes functionally interact with known glaucoma disease genes.
Journal ArticleDOI
The vast complexity of primary open angle glaucoma: disease genes, risks, molecular mechanisms and pathobiology.
Sarah F. Janssen,Theo G. M. F. Gorgels,Wishal D. Ramdas,Caroline C W Klaver,Cornelia M. van Duijn,Nomdo M. Jansonius,Arthur A.B. Bergen +6 more
TL;DR: The data presented are essential to comprehend the role of genetic variation in POAG, and may provide leads to understand the pathophysiology of POAG as well as other neurodegenerative disorders, such as Alzheimer's disease.
Journal ArticleDOI
Common variants near ABCA1 and in PMM2 are associated with primary open-angle glaucoma
Yuhong Chen,Ying Lin,Eranga N. Vithana,Liyun Jia,Xianbo Zuo,Tien Yin Wong,Li Jia Chen,Xianjun Zhu,Pancy O. S. Tam,Bo Gong,Shaohong Qian,Zheng Li,Xiaoqi Liu,Baskaran Mani,Qian Luo,Celeste Guzman,Christopher Kai-Shun Leung,Xiaobo Li,Wenjun Cao,Quanyao Yang,Clement C Y Tham,Yilian Cheng,Xuejun Zhang,Ningli Wang,Tin Aung,Chiea Chuen Khor,Chi Pui Pang,Xinghuai Sun,Zhenglin Yang +28 more
TL;DR: Both ABCA1 and PMM2 are expressed in the trabecular meshwork, optic nerve and other ocular tissues, a finding consistent with it having a role in the development of glaucoma.
Journal ArticleDOI
Common genetic variants associated with open-angle glaucoma
Wishal D. Ramdas,Leonieke M E van Koolwijk,Hans G Lemij,Francesca Pasutto,Angela J. Cree,Gudmar Thorleifsson,Sarah F. Janssen,Ten Brink Jacoline,Najaf Amin,Fernando Rivadeneira,Roger C. W. Wolfs,G. Bragi Walters,Fridbert Jonasson,Nicole Weisschuh,Christian Y. Mardin,Jane Gibson,Richard H C Zegers,Albert Hofman,Paulus T. V. M. de Jong,André G. Uitterlinden,Ben A. Oostra,Unnur Thorsteinsdottir,Eugen Gramer,Ulrich C Welgen-Lüssen,James F Kirwan,Arthur A.B. Bergen,André Reis,Kari Stefansson,Andrew J. Lotery,Johannes R. Vingerling,Nomdo M. Jansonius,Caroline C W Klaver,Cornelia M. van Duijn +32 more
TL;DR: Consistent evidence is found for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma that may shed new light on the pathophysiological protein pathways leading to glau coma, and point to pathways involved in the growth and development of the optic nerve.
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