title: Genome-wide association study identifies genetic risk underlying primary rhegmatogenous retinal detachment.
abstract: Rhegmatogenous retinal detachment (RRD) is an important cause of vision loss and can potentially lead to blindness. The underlying pathogenesis is complex and incompletely understood. We applied a two-stage genetic association discovery phase followed by a replication phase in a combined total of 2833 RRD cases and 7871 controls. The discovery phase involved a genome-wide association scan of 867 affected individuals and 1953 controls from Scotland, followed by genotyping and testing 4347 highest ranking or candidate single nucleotide polymorphisms (SNPs) in independent sets of cases (1000) and controls (2912) of Dutch and British origin. None of the SNPs selected reached a Bonferroni-corrected threshold for significance (P < 1.27 × 10(-7)). The strongest association, for rs12960119 (P = 1.58 × 10(-7)) located within an intron of the SS18 gene. Further testing was carried out in independent case-control series from London (846 cases) and Croatia (120 cases). The combined meta-analysis identified one association reaching genome-wide significance for rs267738 (OR = 1.29, P = 2.11 × 10(-8)), a missense coding SNP and eQTL for CERS2 encoding the protein ceramide synthase 2. Several of the top signals showing suggestive significance in the combined meta-analysis encompassed genes with a documented role in cell adhesion or migration, including SS18, TIAM1, TSTA3 and LDB2, which warrant further investigation. This first genetic association study of RRD supports a polygenic component underlying RRD risk since 27.4% of the underlying RRD liability could be explained by the collective additive effects of the genotyped SNP from the discovery genome-wide scan.
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH89AG, UK.
authors.forename: Mirna
authors.initials: M
authors.lastname: Kirin
authors.forename: Aman
authors.initials: A
authors.lastname: Chandra
authors.forename: David G
authors.initials: DG
authors.lastname: Charteris
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Susan
authors.initials: S
authors.lastname: Campbell
authors.forename: Ivana
authors.initials: I
authors.lastname: Celap
authors.forename: Goran
authors.initials: G
authors.lastname: Bencic
authors.forename: Zoran
authors.initials: Z
authors.lastname: Vatavuk
authors.forename: Iva
authors.initials: I
authors.lastname: Kirac
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Richards
authors.forename: Albert
authors.initials: A
authors.lastname: Tenesa
authors.forename: Martin P
authors.initials: MP
authors.lastname: Snead
authors.forename: Brian W
authors.initials: BW
authors.lastname: Fleck
authors.forename: Jaswinder
authors.initials: J
authors.lastname: Singh
authors.forename: Steven
authors.initials: S
authors.lastname: Harsum
authors.forename: Robert E
authors.initials: RE
authors.lastname: Maclaren
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Dunlop
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.forename: Danny
authors.initials: D
authors.lastname: Mitry
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015201:Meta-Analysis as Topic; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012163:Retinal Detachment / Q000235:genetics*