Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Aung T

PROVIDER: S-EPMC4605818 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Aung Tin T Ozaki Mineo M Mizoguchi Takanori T Allingham R Rand RR Li Zheng Z Haripriya Aravind A Nakano Satoko S Uebe Steffen S Harder Jeffrey M JM Chan Anita S Y AS Lee Mei Chin MC Burdon Kathryn P KP Astakhov Yury S YS Abu-Amero Khaled K KK Zenteno Juan C JC Nilgün Yildirim Y Zarnowski Tomasz T Pakravan Mohammad M Safieh Leen Abu LA Jia Liyun L Wang Ya Xing YX Williams Susan S Paoli Daniela D Schlottmann Patricio G PG Huang Lulin L Sim Kar Seng KS Foo Jia Nee JN Nakano Masakazu M Ikeda Yoko Y Kumar Rajesh S RS Ueno Morio M Manabe Shin-ichi S Hayashi Ken K Kazama Shigeyasu S Ideta Ryuichi R Mori Yosai Y Miyata Kazunori K Sugiyama Kazuhisa K Higashide Tomomi T Chihara Etsuo E Inoue Kenji K Ishiko Satoshi S Yoshida Akitoshi A Yanagi Masahide M Kiuchi Yoshiaki Y Aihara Makoto M Ohashi Tsutomu T Sakurai Toshiya T Sugimoto Takako T Chuman Hideki H Matsuda Fumihiko F Yamashiro Kenji K Gotoh Norimoto N Miyake Masahiro M Astakhov Sergei Y SY Osman Essam A EA Al-Obeidan Saleh A SA Owaidhah Ohoud O Al-Jasim Leyla L Al Shahwan Sami S Fogarty Rhys A RA Leo Paul P Yetkin Yaz Y Oğuz Çilingir Ç Kanavi Mozhgan Rezaei MR Beni Afsaneh Nederi AN Yazdani Shahin S Akopov Evgeny L EL Toh Kai-Yee KY Howell Gareth R GR Orr Andrew C AC Goh Yufen Y Meah Wee Yang WY Peh Su Qin SQ Kosior-Jarecka Ewa E Lukasik Urszula U Krumbiegel Mandy M Vithana Eranga N EN Wong Tien Yin TY Liu Yutao Y Koch Allison E Ashley AE Challa Pratap P Rautenbach Robyn M RM Mackey David A DA Hewitt Alex W AW Mitchell Paul P Wang Jie Jin JJ Ziskind Ari A Carmichael Trevor T Ramakrishnan Rangappa R Narendran Kalpana K Venkatesh Rangaraj R Vijayan Saravanan S Zhao Peiquan P Chen Xueyi X Guadarrama-Vallejo Dalia D Cheng Ching Yu CY Perera Shamira A SA Husain Rahat R Ho Su-Ling SL Welge-Luessen Ulrich-Christoph UC Mardin Christian C Schloetzer-Schrehardt Ursula U Hillmer Axel M AM Herms Stefan S Moebus Susanne S Nöthen Markus M MM Weisschuh Nicole N Shetty Rohit R Ghosh Arkasubhra A Teo Yik Ying YY Brown Matthew A MA Lischinsky Ignacio I Crowston Jonathan G JG Coote Michael M Zhao Bowen B Sang Jinghong J Zhang Nihong N You Qisheng Q Vysochinskaya Vera V Founti Panayiota P Chatzikyriakidou Anthoula A Lambropoulos Alexandros A Anastasopoulos Eleftherios E Coleman Anne L AL Wilson M Roy MR Rhee Douglas J DJ Kang Jae Hee JH May-Bolchakova Inna I Heegaard Steffen S Mori Kazuhiko K Alward Wallace L M WL Jonas Jost B JB Xu Liang L Liebmann Jeffrey M JM Chowbay Balram B Schaeffeler Elke E Schwab Matthias M Lerner Fabian F Wang Ningli N Yang Zhenglin Z Frezzotti Paolo P Kinoshita Shigeru S Fingert John H JH Inatani Masaru M Tashiro Kei K Reis André A Edward Deepak P DP Pasquale Louis R LR Kubota Toshiaki T Wiggs Janey L JL Pasutto Francesca F Topouzis Fotis F Dubina Michael M Craig Jamie E JE Yoshimura Nagahisa N Sundaresan Periasamy P John Simon W M SW Ritch Robert R Hauser Michael A MA Khor Chiea-Chuen CC

Nature genetics 20150223 4

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 (odd ...[more]

PMID: 25706626

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Project description:PURPOSE: Single nucleotide polymorphisms (SNPs) in the LOXL1 gene have been implicated in exfoliation syndrome (XFS) and exfoliation glaucoma (XFG). We have shown that these SNPs are not associated with the primary glaucomas such as primary open-angle (POAG) glaucoma and primary angle-closure glaucoma (PACG). To further establish the specificity of LOXL1 SNPs for XFS and XFG, we determined whether these SNPs were involved in pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG). METHODS: Three SNPs of LOXL1 (rs1048661, rs3825942, and rs2165241) were screened in a cohort of 78 unrelated and clinically well characterized glaucoma cases comprising of PG (n=44) and PDS (n=34) patients as well as 108 ethnically matched normal controls of Caucasian origin. The criteria for diagnosis of PDS/PG were Krukenberg spindle, hyperpigmentation of the trabecular meshwork, and wide open angle. Transillumination defects were detected by infrared pupillography, and the presence of a Zentmayer ring was considered as a confirmatory sign. All three SNPs were genotyped in cases and controls by resequencing the genomic region of LOXL1 harboring these variants and were further confirmed by polymerase chain reaction (PCR)-based restriction digestions. Haplotypes were generated from the genotype data, and the linkage disequilibrium (LD) and haplotype analysis were done with Haploview software that uses the expectation maximization (EM) algorithm. RESULTS: The LOXL1 SNPs showed no significant association with PDS or PG. There was no significant difference in the frequencies of the risk alleles of rs1048661 ('G' allele; p=0.309), rs3825942 ('G' allele' p=0.461), and rs2165241 ('T' allele; p=0.432) between PG/PDS cases and controls. Similarly, there was no involvement of the XFS/XFG-associated haplotypes, 'G-G' (p=0.643; [OR=1.08, 95%CI, 0.59-1.97]) and 'T-G' (p=0.266; [OR=1.35, 95%CI, 0.70-2.60]), with the PDS/PG phenotypes. The risk haplotype 'G-G' was observed in ~55% of the normal controls. CONCLUSIONS: There was no involvement of the LOXL1 SNPs in patients with PDS and PG. The results further indicate that the associations of these SNPs are specific to XFS/XFG.

Dataset Information

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

Publications

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

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