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Virginie JM Verhoeven, Pirro G Hysi, Robert Wojciechowski, Qiao Fan, Amy K Kiefer, Caroline C W Klaver, Christopher J Hammond, Nick Eriksson, Consortium for Refractive Error and Myopia; Genome-wide Mega-Analysis on Myopia and Refractive Error in CREAM and 23andMe. Invest. Ophthalmol. Vis. Sci. 2014;55(13):839.
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Myopia is widely recognized as a multifactorial, complex genetic disorder. Recently, multiple loci for refractive phenotypes were identified separately by the Consortium for Refractive Error and Myopia (CREAM) and investigators from 23andMe, Inc. We aimed to identify additional genetic loci that explain the genetic architecture of refractive error using higher power and denser imputation by meta-analyzing data from CREAM and 23andMe.
We conducted a genome-wide association study (GWAS) meta-analysis of refractive error including 61,888 individuals (47,999 Caucasians; 13,899 Asians) from the CREAM consortium using a linear regression model. Age-at-onset of myopia for 104,293 individuals from the 23andMe dataset was analyzed using survival analysis (Cox proportional hazards model). GWAS regression results from both studies were meta-analyzed by z-scores using a fixed effects model. We performed pathway analyses using Panther.
Over 80 regions across the genome reached a genome-wide significance at P-value < 5.0x10-8. The most significant P-value was 3.6x10-63 for rs524952 near the known refractive error gene GJD2. We also confirmed association with 26 other previously reported genes. The results confirm over-representation of known pathways, such as extracellular matrix, and ion channel activity, but also suggested potentially new mechanisms, such as angiogenesis, Wnt signaling and TGF-β signaling pathways.
This study is one of the largest meta-GWAS ever and the largest meta-analysis of any refractive phenotype to date. This greatly-increased catalogue of genetic variants conferring susceptibility to myopia reveals new pathways that influence refractive development, including unexpected additions such as angiogenesis.
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