Genome-wide Association Analyses Identify Three New Susceptibility Loci for Primary Angle Closure Glaucoma

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR)=1.22; P=5.33×10(-12)), rs3753841 in COL11A1 (per-allele OR=1.20; P=9.22×10(-10)) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR=1.50; P=3.29×10(-9)). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

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References

Awadalla M, Burdon K, Kuot A, Hewitt A, Craig J . Matrix metalloproteinase-9 genetic variation and primary angle closure glaucoma in a Caucasian population. Mol Vis. 2011; 17:1420-4. PMC: 3108894. View

Teo Y, Sim X, Ong R, Tan A, Chen J, Tantoso E . Singapore Genome Variation Project: a haplotype map of three Southeast Asian populations. Genome Res. 2009; 19(11):2154-62. PMC: 2775604. DOI: 10.1101/gr.095000.109. View

Sawcer S, Hellenthal G, Pirinen M, Spencer C, Patsopoulos N, Moutsianas L . Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011; 476(7359):214-9. PMC: 3182531. DOI: 10.1038/nature10251. View

Li H, Wang J, Wang C, Yu P, Zhou Q, Chen Y . Localization of a novel gene for congenital nonsyndromic simple microphthalmia to chromosome 2q11-14. Hum Genet. 2007; 122(6):589-93. DOI: 10.1007/s00439-007-0435-y. View

Mathieson I, McVean G . Differential confounding of rare and common variants in spatially structured populations. Nat Genet. 2012; 44(3):243-6. PMC: 3303124. DOI: 10.1038/ng.1074. View

Aptel F, Denis P . Optical coherence tomography quantitative analysis of iris volume changes after pharmacologic mydriasis. Ophthalmology. 2009; 117(1):3-10. DOI: 10.1016/j.ophtha.2009.10.030. View

Othman M, Sullivan S, Skuta G, Cockrell D, Stringham H, Downs C . Autosomal dominant nanophthalmos (NNO1) with high hyperopia and angle-closure glaucoma maps to chromosome 11. Am J Hum Genet. 1998; 63(5):1411-8. PMC: 1377551. DOI: 10.1086/302113. View

Quigley H, Friedman D, Congdon N . Possible mechanisms of primary angle-closure and malignant glaucoma. J Glaucoma. 2003; 12(2):167-80. DOI: 10.1097/00061198-200304000-00013. View

Ghoussaini M, Fletcher O, Michailidou K, Turnbull C, Schmidt M, Dicks E . Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet. 2012; 44(3):312-8. PMC: 3653403. DOI: 10.1038/ng.1049. View

10.

Kooner J, Saleheen D, Sim X, Sehmi J, Zhang W, Frossard P . Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat Genet. 2011; 43(10):984-9. PMC: 3773920. DOI: 10.1038/ng.921. View

11.

Awadalla M, Thapa S, Burdon K, Hewitt A, Craig J . The association of hepatocyte growth factor (HGF) gene with primary angle closure glaucoma in the Nepalese population. Mol Vis. 2011; 17:2248-54. PMC: 3164689. View

12.

Reveille J, Sims A, Danoy P, Evans D, Leo P, Pointon J . Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet. 2010; 42(2):123-7. PMC: 3224997. DOI: 10.1038/ng.513. View

13.

Klein R, Zeiss C, Chew E, Tsai J, Sackler R, Haynes C . Complement factor H polymorphism in age-related macular degeneration. Science. 2005; 308(5720):385-9. PMC: 1512523. DOI: 10.1126/science.1109557. View

14.

Diehn J, Diehn M, Marmor M, Brown P . Differential gene expression in anatomical compartments of the human eye. Genome Biol. 2005; 6(9):R74. PMC: 1242209. DOI: 10.1186/gb-2005-6-9-r74. View

15.

. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet. 2009; 41(7):824-8. DOI: 10.1038/ng.396. View

16.

Hornby S, Adolph S, Gilbert C, Dandona L, Foster A . Visual acuity in children with coloboma: clinical features and a new phenotypic classification system. Ophthalmology. 2000; 107(3):511-20. DOI: 10.1016/s0161-6420(99)00140-2. View

17.

Abecasis G, Altshuler D, Auton A, Brooks L, Durbin R, Gibbs R . A map of human genome variation from population-scale sequencing. Nature. 2010; 467(7319):1061-73. PMC: 3042601. DOI: 10.1038/nature09534. View

18.

Nalls M, Plagnol V, Hernandez D, Sharma M, Sheerin U, Saad M . Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet. 2011; 377(9766):641-9. PMC: 3696507. DOI: 10.1016/S0140-6736(10)62345-8. View

19.

Michael I, Shmoish M, Walton D, Levenberg S . Interactions between trabecular meshwork cells and lens epithelial cells: a possible mechanism in infantile aphakic glaucoma. Invest Ophthalmol Vis Sci. 2008; 49(9):3981-7. DOI: 10.1167/iovs.08-1674. View

20.

Michael S, Qamar R, Akhtar F, Khan W, Ahmed A . C677T polymorphism in the methylenetetrahydrofolate reductase gene is associated with primary closed angle glaucoma. Mol Vis. 2008; 14:661-5. PMC: 2277437. View