Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

• Published in: Nature genetics Vol. 43; no. 6; pp. 574 - 578
• Main Authors: BURDON, Kathryn P, MACGREGOR, Stuart, LANDERS, John, HENDERS, Anjali K, WOOD, John, SOUZEAU, Emmanuelle, CRAWFORD, April, LEO, Paul, JIE JIN WANG, ROCHTCHINA, Elena, NYHOLT, Dale R, MARTIN, Nicholas G, HEWITT, Alex W, MONTGOMERY, Grant W, MITCHELL, Paul, BROWN, Matthew A, MACKEY, David A, CRAIG, Jamie E, SHARMA, Shiwani, CHIDLOW, Glyn, MILLS, Richard A, DANOY, Patrick, CASSON, Robert, VISWANATHAN, Ananth C, LIU, Jimmy Z
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing Group 01.06.2011
• Subjects: Aged; Aged, 80 and over; Animals; Biological and medical sciences; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cytoskeletal Proteins - genetics; Data collection; Disease; Disease susceptibility; Eye Proteins - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Genetic aspects; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genomes; Glaucoma; Glaucoma and intraocular pressure; Glaucoma, Open-Angle - genetics; Glycoproteins - genetics; Haplotypes; Humans; Male; Medical sciences; Open-angle glaucoma; Ophthalmology; Polymorphism, Single Nucleotide; Rats; Regression analysis; Retina - metabolism; Risk factors; Single nucleotide polymorphisms; Studies; Twins; Australia; Eye disease; Identification; Open angle glaucoma; Locus
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.824

We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.