RESUMO
Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - "response to fluid shear stress" and "abnormal retina morphology" - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.
Assuntos
Glaucoma de Ângulo Aberto/etiologia , Glaucoma de Ângulo Aberto/genética , Idoso , Proteínas de Ligação ao Cálcio/genética , Estudos de Casos e Controles , Endofenótipos , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Glaucoma/etiologia , Glaucoma/genética , Glaucoma de Ângulo Aberto/metabolismo , Humanos , Pressão Intraocular/genética , Proteínas com Domínio LIM/genética , Proteínas com Homeodomínio LIM/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas Musculares/genética , Disco Óptico/fisiologia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Ácido Retinoico 4 Hidroxilase/genética , Fatores de Risco , Tonometria Ocular/métodos , Fatores de Transcrição/genética , Campos Visuais/genética , gama-Cristalinas/genéticaRESUMO
Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.