Journal Article

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

Ueno, Morio, Aljasim, Leyla Ali, Kazama, Shigeyasu, Zompa, Tamara, Binder, Alexander, Chowbay, Balram, Wang, Jie Jin, Paoli, Daniela, Akhtar, Farah, Mardin, Christian, Chuman, Hideki, Pasquale, Louis R, Sugiyama, Kazuhisa, Pappas, Theofanis, Herms, Stefan, Kobakhidze, Nino, Chen, Xiao Yin, Grossmann, Rodolfo Perez, Greer, Wenda L, Anastasopoulos, Eleftherios, Crowston, Jonathan G, Reis, André, Qiao, Chunyan, Rautenbach, Robyn M, Berner, Daniel, Welge-Luessen, Ulrich-Christoph, Chaya, Craig J, Ideta, Ryuichi, Nguyn, Giang T T, Tamcelik, Nevbahar, Yang, Zhenglin, Chan, Anita S Y, Mizoguchi, Takanori, Ishiko, Satoshi, Khan, Muhammad Imran, Moebus, Susanne, García, Montserrat, Kitnarong, Naris, Järvelä, Irma, Mossböck, Georg, Ozaki, Mineo, Ramsay, Michele, Inatani, Masaru, Ahn, Jeeyun, Fornero, Pablo, Okeke, Suhanya, Shingleton, Bradford J, Ashaye, Adeyinka O, Hayashi, Ken, Hauser, Michael, Reynier, Pascal, Mills, Richard A, George, Ronnie, Founti, Panayiota, Yong, Victor H K, Wong, Tien Yin, Weisschuh, Nicole, Olawoye, Olusola O, Matsuda, Fumihiko, Nguyn, Trình V, Yanagi, Masahide, Chong, Yaan Fun, Nelson, Sar

2017

Overview

Chiea Chuen Khor, Tin Aung, Francesca Pasutto, Janey Wiggs and colleagues report a global genome-wide association study of exfoliation syndrome and a fine-mapping analysis of a previously identified disease-associated locus, LOXL1 . They identify a rare protective variant in LOXL1 exclusive to the Japanese population and five new common variant susceptibility loci. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 13/51 / 45 / 45/23 / 45/43 / 631/208/205/2138 / 631/208/212 / 692/699 / Aged, 80 and over / Agriculture / Alleles / Alzheimer's disease / Amino Acid Oxidoreductases - genetics / Amino Acid Oxidoreductases - physiology / Amino Acid Substitution / Analysis / Animal Genetics and Genomics / Asian Continental Ancestry Group - genetics / Bioinformatics / Biology / Biomedicine / Blindness / Calcium Channels - genetics / Cancer Research / Cardiovascular disease / Cell Adhesion / Collaboration / Computer Science / Disease susceptibility / Exfoliatins / Exfoliation / Exfoliation Syndrome - ethnology / Exfoliation Syndrome - genetics / Extracellular Matrix - metabolism / Eye - metabolism / Female / Gene Expression Profiling / Gene Function / Genes / Genetic aspects / Genetic Predisposition to Disease / Genetics / Genome-wide association studies / Genome-Wide Association Study / Genomes / Glaucoma / Haplotypes / Human Genetics / Humans / Life Sciences / Loci / Male / Microbiology and Parasitology / Molecular Chaperones - biosynthesis / Molecular Chaperones - genetics / Mutation, Missense / Parasitology / Point Mutation / Populations and Evolution / Principal components analysis / Quantitative Methods / Risk factors / RNA, Messenger - biosynthesis / Santé publique et épidémiologie / Spheroids, Cellular / Studies / Virology