Purpose: 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 imputation to dense genetic markers and combining data from CREAM and 23andMe. Methods: 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 and a 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. Results: Approximately 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 new loci include genes with functions in known pathways, such as extracellular matrix, and ion channel acitivy, but also revealed new pathways, such as angiogenesis, Wnt signaling pathway, and TGF-? signaling pathway. Conclusions: Our study represents the largest meta-analysis of any refractive phenotype to date. The results highlight the important pathways involved in refractive error and myopia development.
Genome-wide Mega-Analysis on Myopia and Refractive Error in CREAM and 23andMe
2014
Abstract
Purpose: 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 imputation to dense genetic markers and combining data from CREAM and 23andMe. Methods: 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 and a 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. Results: Approximately 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 new loci include genes with functions in known pathways, such as extracellular matrix, and ion channel acitivy, but also revealed new pathways, such as angiogenesis, Wnt signaling pathway, and TGF-? signaling pathway. Conclusions: Our study represents the largest meta-analysis of any refractive phenotype to date. The results highlight the important pathways involved in refractive error and myopia development.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
