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

Abstract

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.

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Figure 1: LOXL1 p.Tyr407Phe regulates ECM synthesis and improves cellular adhesion.
Figure 2: Manhattan plot of the results from the GWAS discovery plus replication meta-analysis comprising 13,620 XFS cases and 109,837 controls.
Figure 3: Expression of POMP protein in ocular tissues of normal human donor eyes and donor eyes with XFS, as determined by immunoblotting and immunohistochemistry.
Figure 4: Expression of TMEM136 protein in the ocular tissues of normal human donor eyes and donor eyes with XFS, as determined by immunoblotting and immunohistochemistry.

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Acknowledgements

This research is supported by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore (to C.C.K.), by the Glaucoma Foundation of New York (to C.C.K.), by grants from the National Medical Research Council, Singapore NMRC/TCR/008-SERI/2013 and NMRC/STAR/0023/2014 to T.A. and NMRC/CBRG/0032/2013 to E.N.V.), by the Interdisziplinäres Zentrum für Klinische Forschung (IZKF-E23) from Germany to F.P. and U.S.-S., and by grants from the US National Institutes of Health: UM1 CA186107, R01 CA49449, R01 AR056291, R01 CA131332, P01 CA055075, R01 CA134958 and R01 EY015473 to J.L.W. For XFS cases in the US GWAS data set, genotyping services were provided through a grant to J.L.W. (HG008597) by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the US National Institutes of Health to The Johns Hopkins University, contract HHSN268201200008I. The Beijing, China, collection was supported by funding from the National Natural Science Foundation of China (81030016 and 81570837), the Program of Beijing Scholars (2013), the National Major Scientific and Technological Special Project for Significant New Drugs Development (2011ZX09302-007-05) and Leading Talents–High-Level Talents of the Health System of Beijing (2009-1-05) to N. Wang. We dedicate this article to the ophthalmologist Eva Forsman from Finland who passed away after diagnosing all of the exfoliation syndrome cases from Finland.

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