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: ORA allele = 9.87, P = 2.13 × 10−217; non-Japanese: ORA 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.
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NCBI Reference Sequence
The authors thank the staff and participants of all studies for their important contributions. We thank K.-K. Heng, X.-Y. Chen, H.-M. Soo, S.-Q. Mok, A. Jamuth, N. Foxworth and M. Elbl for technical assistance. This research was funded by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore. J.L.W. acknowledges support from US National Institutes of Health/National Eye Institute grants (NIH/NEI R01 EY020928 and NIH/NEI P30 EY014104). S.W.M.J. acknowledges support from grant EY11721 from the US National Institutes of Health/National Eye Institute and is an investigator of the Howard Hughes Medical Institute. L.R.P. acknowledges support from a Harvard Medical School Distinguished Ophthalmology Scholar Award and the Harvard Glaucoma Center of Excellence. J.H.F. acknowledges support from US National Institutes of Health/National Eye Institute grants (EY023512 and EY018825). Z.Y. acknowledges support from the National Natural Science Foundation of China (81025006 and 81170883), as well as from the Department of Science and Technology of Sichuan Province, China (2012SZ0219 and 2011jtd0020). M.S. acknowledges support from Robert Bosch Stiftung (Stuttgart, Germany) and the German Cancer Consortium (DKTK), Germany. The Australian case cohort was funded by grants from the Ophthalmic Research Institute of Australia and National Health and Medical Research Council (NHMRC) project 535044. The Thessaloniki Eye Study was cofunded by the European Union (European Social Fund) and Greek national funds under act ‘Aristia’ of the operational program ‘Education and Lifelong Learning’ (Supplementary Note). Blue Mountains Eye Study (BMES) GWAS and genotyping costs were supported by the Australian NHMRC (Canberra, Australia; NHMRC project grants 512423, 475604 and 529912) and the Wellcome Trust, UK, as part of the Wellcome Trust Case Control Consortium 2 (A. Viswanathan, P. McGuffin, P. Mitchell, F. Topouzis, P. Foster; grants 085475/B/08/Z and 085475/08/Z). K.P.B. is an NHMRC Senior Research Fellow, and J.E.C. is an NHMRC Practitioner Fellow. M.A.B. is an NHMRC Principal Research Fellow. A.W.H. is an NHMRC Peter Doherty Fellow.
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Supplementary Figures 1–13, Supplementary Tables 1–10 and Supplementary Note.
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De novo variants in an extracellular matrix protein coding gene, fibulin-5 (FBLN5) are associated with pseudoexfoliation
European Journal of Human Genetics (2019)