Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

• Main Authors: Aung T., Ozaki M., Lee M., Schlötzer-Schrehardt U., Thorleifsson G., Mizoguchi T., Igo R., Haripriya A., Williams S., Astakhov Y., Orr A., Burdon K., Nakano S., Mori K., Abu-Amero K., Hauser M., Li Z., Prakadeeswari G., Bailey J., Cherecheanu A., Kang J., Nelson S., Hayashi K., Manabe S., Kazama S., Zarnowski T., Inoue K., Irkec M., Coca-Prados M., Sugiyama K., Järvelä I., Schlottmann P., Lerner S., Lamari H., Nilgün Y., Bikbov M., Park K., Cha S., Yamashiro K., Zenteno J., Jonas J., Kumar R., Perera S., Chan A., Kobakhidze N., George R., Vijaya L., Do T., Edward D., De Juan Marcos L., Pakravan M., Moghimi S., Ideta R., Bach-Holm D., Kappelgaard P., Wirostko B., Thomas S., Gaston D., Bedard K., Greer W., Yang Z., Chen X., Huang L., Sang J., Jia H., Jia L., Qiao C., Zhang H., Liu X., Zhao B., Wang Y., Xu L., Leruez S., Reynier P., Chichua G., Tabagari S.
• Format: Journal
• Published: 2017
• Online Access: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85021706287&origin=inward; http://cmuir.cmu.ac.th/jspui/handle/6653943832/40352
• Institution: Chiang Mai University

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.