Genetic Architecture of Primary Open Angle Glaucoma in Individuals of African Descent: The African Descent & Glaucoma Evaluation Study (ADAGES) III

Details

• Alternative Title:
  Ophthalmology
• Personal Author:
  Taylor, Kent D. ; Guo, Xiuqing ; Zangwill, Linda M. ; Liebmann, Jeffrey M. ; Girkin, Christopher A. ; Feldman, Robert M. ; Dubiner, Harvey ; Hai, Yang ; Samuels, Brian C. ; Panarelli, Joseph F. ; Mitchell, John P. ; Al-Aswad, Lama A. ; Park, Sung Chul ; Tello, Celso ; Cotliar, Jeremy ; Bansal, Rajendra ; Sidoti, Paul A. ; Cioffi, George A. ; Blumberg, Dana ; Ritch, Robert ; Bell, Nicholas P. ; Blieden, Lauren S. ; Davis, Garvin ; Medeiros, Felipe A. ; Das, Swapan K. ; Divers, Jasmin ; Langefeld, Carl D. ; Palmer, Nicholette D. ; Freedman, Barry I. ; Bowden, Donald W. ; Ng, Maggie C. Y. ; Chen, Yii-Der Ida ; Ayyagari, Radha ; Rotter, Jerome I. ; Weinreb, Robert N.
• Corporate Authors:
  ADAGES III Genomics Study Group
• 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.
  
  
• Subjects:
  Aged Black Or African American Case-Control Studies Cross-Sectional Studies Female Gene Frequency Genetic Predisposition To Disease Genome-Wide Association Study Genotype Glaucoma, Open-Angle Humans Intraocular Pressure Male Middle Aged Phosphopyruvate Hydratase Polymorphism, Single Nucleotide ROC Curve

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• Source:
  Ophthalmology. 126(1):38-48
• Pubmed ID:
  30352225
• Pubmed Central ID:
  PMC6309605
• Document Type:
  Journal Article
• Funding:
  R01 DK070941/DK/NIDDK NIH HHSUnited States/ ; R01 EY011008/EY/NEI NIH HHSUnited States/ ; U01 DK105556/DK/NIDDK NIH HHSUnited States/ ; R01 EY023704/EY/NEI NIH HHSUnited States/ ; P30 EY022589/EY/NEI NIH HHSUnited States/ ; R01 DK087914/DK/NIDDK NIH HHSUnited States/ ; R01 AI056266/AI/NIAID NIH HHSUnited States/ ; R01 DK053591/DK/NIDDK NIH HHSUnited States/ ; UL1 TR001881/TR/NCATS NIH HHSUnited States/ ; R01 EY019869/EY/NEI NIH HHSUnited States/ ; R21 EY029605/EY/NEI NIH HHSUnited States/ ; R01 EY021818/EY/NEI NIH HHSUnited States/ ; U01 DP006436/DP/NCCDPHP CDC HHSUnited States/ ; P30 DK063491/DK/NIDDK NIH HHSUnited States/ ; R01 DK066358/DK/NIDDK NIH HHSUnited States/
• Place as Subject:
  Africa
• Volume:
  126
• Issue:
  1
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:ae19358ce70e34734865ced073e8e26a9c7365564f5730199313fd13c7195035
• Download URL:
  https://stacks.cdc.gov/view/cdc/114358/cdc_114358_DS1.pdf
• File Type:
  [PDF - 1.36 MB ]