Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.
Τίτλος | Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Aung, T., Ozaki M., Lee M. Chin, Schlötzer-Schrehardt U., Thorleifsson G., Mizoguchi T., et al. |
Journal | Nat Genet |
Volume | 49 |
Issue | 7 |
Pagination | 993-1004 |
Date Published | 2017 07 |
ISSN | 1546-1718 |
Λέξεις κλειδιά | Aged, 80 and over, Alleles, Amino Acid Oxidoreductases, Amino Acid Substitution, Asian Continental Ancestry Group, Calcium Channels, Cell Adhesion, Exfoliation Syndrome, Extracellular Matrix, Eye, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Humans, Male, Molecular Chaperones, Mutation, Missense, Point Mutation, RNA, Messenger, Spheroids, Cellular |
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) 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). 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. |
DOI | 10.1038/ng.3875 |
Alternate Journal | Nat Genet |
PubMed ID | 28553957 |
PubMed Central ID | PMC6685441 |
Grant List | UM1 CA186107 / CA / NCI NIH HHS / United States R01 EY015473 / EY / NEI NIH HHS / United States HHSN268201200008I / HL / NHLBI NIH HHS / United States HHSN268201200008C / HL / NHLBI NIH HHS / United States R01 EY020928 / EY / NEI NIH HHS / United States R01 CA049449 / CA / NCI NIH HHS / United States P30 EY014104 / EY / NEI NIH HHS / United States R01 EY023512 / EY / NEI NIH HHS / United States R01 EY013882 / EY / NEI NIH HHS / United States |