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Genetic Architecture of Primary Open Angle Glaucoma in Individuals of African Descent: The African Descent & Glaucoma Evaluation Study (ADAGES) III
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1 2019
Source: Ophthalmology. 126(1):38-48 -
Alternative Title:Ophthalmology
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Description:Objective:
Find genetic contributions to glaucoma in African Americans.
Design:
Cross-sectional, case-control study.
Participants:
1875 POAG cases and 1709 controls, self-identified as African Descent (AD), from the African Descent and Glaucoma Evaluation Study (ADAGESIII) and Wake Forest School of Medicine.
Methods:
MegaChip genotypes were imputed to Thousand Genomes data. Association of SNPs with POAG and advanced POAG was tested by linear mixed model correcting for relatedness and population stratification. Genetic risk scores were tested by Receiver Operator Characteristics (ROC-AUC).
Main Outcome:
POAG defined by visual field loss without other non-ocular conditions (N=1875). Advanced POAG was defined by age-based mean deviation of visual field (N=946).
Results:
18,281,920 SNPs met imputation quality r2>0.7 and minor allele frequency>0.005. Association of a novel locus, ENO4, was observed for advanced POAG (rs185815146 beta 0.36, SE 0.065, p<3×10−8). For POAG, an AD signal was observed at 9p21 ED POAG signal (rs79721419; p<6.5×10−5) independent of the previously observed 9p21 ED signal (rs2383204; p<2.3×10−5) by conditional analyses. An association with POAG in FNDC3B (rs111698934, p<3.9×10−5) was observed, not in LD with the previously reported ED SNP. Additional previously identified loci associated with POAG in AD were: 8q22, AFAP1, TMCO1. An AUC of 0.62 was observed with an unweighted genetic risk score composed of 11 SNPs in candidate genes. Two additional risk scores were studied by using a penalized matrix decomposition with cross-validation; risk scores of 50 and 400 SNPs were identified with ROC of AUC=0.74 and AUC=0.94, respectively.
Conclusions:
A novel association with advanced POAG in the ENO4 locus was putatively identified in subjects of African descent. In addition to this finding, this GWAS in AD POAG subjects contributes to POAG genetics by identification of novel signals in prior loci (9p21), as well as advancing the fine-mapping of regions due to shorter average linkage disequilibrium (FNDC3B). While not useful without confirmation and clinical trials, the use of genetic risk scores demonstrated that considerable AD-specific genetic information remains in these data.
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Pubmed ID:30352225
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Pubmed Central ID:PMC6309605
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