A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

• DOI: 10.1038/ng.3226
• Publication Date: 2015-02-23T17:57:15Z
• Authors: Tin Aung; ; Mineo Ozaki; Takanori Mizoguchi; R Rand Allingham; Zheng Li; Aravind Haripriya; Satoko Nakano; Steffen Uebe; Jeffrey M Harder; Anita S Y Chan; Mei Chin Lee; Kathryn P Burdon; Yury S Astakhov; Khaled K Abu-Amero; Juan C Zenteno; Yildirim Nilgün; Tomasz Zarnowski; Mohammad Pakravan; Leen Abu Safieh; Liyun Jia; Ya Xing Wang; Susan Williams; Daniela Paoli; Patricio G Schlot...; Lulin Huang; Kar Seng Sim; Jia Nee Foo; Masakazu Nakano; Yoko Ikeda; Rajesh S Kumar; Morio Ueno; Shin-ichi Manabe; Ken Hayashi; Shigeyasu Kazama; Ryuichi Ideta; Yosai Mori; Kazunori Miyata; Kazuhisa Sugiyama; Tomomi Higashide; Etsuo Chihara; Kenji Inoue; Satoshi Ishiko; Akitoshi Yoshida; Masahide Yanagi; Yoshiaki Kiuchi; Makoto Aihara; Tsutomu Ohashi; Toshiya Sakurai; Takako Sugimoto; Hideki Chuman; Fumihiko Matsuda; Kenji Yamashiro; Norimoto Gotoh; Masahiro Miyake; Sergei Y Astakhov; Essam A Osman; Saleh A Al-Obeidan; Ohoud Owaidhah; Leyla Al-Jasim; Sami Al Shahwan; Rhys A Fogarty; Paul Leo; Yaz Yetkin; Çilingir Oğuz; Mozhgan Rezaei Ka...; Afsaneh Naderi Beni; Shahin Yazdani; Evgeny L Akopov; Kai-Yee Toh; Gareth R Howell; Andrew C Orr; Yufen Goh; Wee Yang Meah; Su Qin Peh; Ewa Kosior-Jarecka; Urszula Lukasik; Mandy Krumbiegel; Eranga N Vithana; Tien Yin Wong; Yutao Liu; Allison E Ashley ...; Pratap Challa; Robyn M Rautenbach; David A Mackey; Alex W Hewitt; Paul Mitchell; Jie Jin Wang; Ari Ziskind; Trevor Carmichael; Rangappa Ramakris...; Kalpana Narendran; Rangaraj Venkatesh; Saravanan Vijayan; Peiquan Zhao; Xueyi Chen; Dalia Guadarrama-...; Ching Yu Cheng; Shamira A Perera; Rahat Husain; Su-Ling Ho; Ulrich-Christoph ...; Christian Mardin; Ursula Schloetzer...; Axel M Hillmer; Stefan Herms; Susanne Moebus; Markus M Nöthen; Nicole Weisschuh; Rohit Shetty; Arkasubhra Ghosh; Yik Ying Teo; Matthew A Brown; Ignacio Lischinsky; Jonathan G Crowston; Michael Coote; Bowen Zhao; Jinghong Sang; Nihong Zhang; Qisheng You; Vera Vysochinskaya; Panayiota Founti; Anthoula Chatziky...; Alexandros Lambro...; Eleftherios Anast...; Anne L Coleman; M Roy Wilson; Douglas J Rhee; Jae Hee Kang; Inna May-Bolchakova; Steffen Heegaard; Kazuhiko Mori; Wallace L M Alward; Jost B Jonas; Liang Xu; Jeffrey M Liebmann; Balram Chowbay; Elke Schaeffeler; Matthias Schwab; Fabian Lerner; Ningli Wang; Zhenglin Yang; Paolo Frezzotti; Shigeru Kinoshita; John H Fingert; Masaru Inatani; Kei Tashiro; André Reis; Deepak P Edward; Louis R Pasquale; Toshiaki Kubota; Janey L Wiggs; Francesca Pasutto; Fotis Topouzis; Michael Dubina; Jamie E Craig; Nagahisa Yoshimura; Periasamy Sundaresan; Simon W M John; Robert Ritch; Michael A Hauser; Chiea-Chuen Khor
• Keywords: 0301 basic medicine; Medizin; HeLa Cell; Inbred C57BL; Exfoliation Syndrome; Medical and Health Sciences; Mice; MCF-7 Cell; Animals; Asian Continental Ancestry Group; Calcium Channels; Case-Control Studies; Chromosome Mapping; Exfoliation Syndrome; Genetic Predisposition to Disease; Genome-Wide Association Study; Glaucoma, Open-Angle; HEK293 Cells; HeLa Cells; Humans; Japan; MCF-7 Cells; Mice; Mice, Inbred C57BL; Tumor Cells, Cultured; Polymorphism, Single Nucleotide; Genetics; HEK293 Cell; Japan; HEK293 cells; Open-angle; Medicine and Health Sciences; Tumor Cells, Cultured; GWAS; 2.1 Biological and endogenous factors; XFS; MCF-7 cells; Aetiology; Cultured; Japanese population; Life Sciences; Chromosome Mapping; Single Nucleotide; Biological Sciences; Bioinformatics and computational biology; Tumor Cells; 3. Good health; Pseudoexfoliation syndrome; Open-Angle; MCF-7 Cells; Blue Mountains Eye Study GWAS Team; Case-Control Studie; Glaucoma, Open-Angle; Human; Asian Continental Ancestry Group; Chromosome mapping; Exfoliation syndrome; Agricultural biotechnology; open-angle glaucoma; 610; Case-control studies; CACNA1A; Tumor cells; Calcium Channel; Polymorphism, Single Nucleotide; Sequence variants; 03 medical and health sciences; Rare Diseases; 1311 Genetics; Asian People; Genetics; Animals; Humans; Genetic Predisposition to Disease; HeLa cells; Polymorphism; Genome-wide association Study; Animal; Prevention; Human Genome; Wellcome Trust Case Control Consortium 2; Genetic predisposition to Disease; Glaucoma; Mice, Inbred C57BL; Calcium channels; HEK293 Cells; Hela Cells; Case-Control Studies; Loxl1 gene polymorphisms; Calcium Channels; Developmental Biology; Genome-Wide Association Study; HeLa Cells

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.