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Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.
- Source :
-
Nature genetics [Nat Genet] 2017 Jul; Vol. 49 (7), pp. 993-1004. Date of Electronic Publication: 2017 May 29. - Publication Year :
- 2017
-
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 <superscript>-14</superscript> ) 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 <superscript>-8</superscript> ). 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.
- Subjects :
- Aged, 80 and over
Alleles
Amino Acid Oxidoreductases physiology
Amino Acid Substitution
Asian People genetics
Calcium Channels genetics
Cell Adhesion
Exfoliation Syndrome ethnology
Extracellular Matrix metabolism
Eye metabolism
Female
Gene Expression Profiling
Genetic Predisposition to Disease
Haplotypes
Humans
Male
Molecular Chaperones biosynthesis
Molecular Chaperones genetics
RNA, Messenger biosynthesis
Spheroids, Cellular
Amino Acid Oxidoreductases genetics
Exfoliation Syndrome genetics
Genome-Wide Association Study
Mutation, Missense
Point Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 49
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 28553957
- Full Text :
- https://doi.org/10.1038/ng.3875