June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
From Genome to Phenome: Novel Cross-Ancestry Evaluation of Glaucoma Genetic Risk in the Million Veteran Program
Author Affiliations & Notes
  • Andrea R Waksmunski
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States
  • Tyler G Kinzy
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    VA Northeast Ohio Healthcare System, Cleveland, Ohio, United States
  • Lauren A Cruz
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States
  • Cari L Nealon
    VA Northeast Ohio Healthcare System, Cleveland, Ohio, United States
  • Christopher W Halladay
    Center of Innovation in Long Term Services and Supports, Providence VA Medical Center, Providence, Rhode Island, United States
  • Paul Greenberg
    Section of Ophthalmology, Providence VA Medical Center, Providence, Rhode Island, United States
    Division of Ophthalmology, Alpert Medical School, Brown University, Providence, Rhode Island, United States
  • Wen-Chih Wu
    Section of Cardiology, Medical Service, Providence VA Medical Center, Providence, Rhode Island, United States
  • Sudha K Iyengar
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    VA Northeast Ohio Healthcare System, Cleveland, Ohio, United States
  • Dana C Crawford
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    VA Northeast Ohio Healthcare System, Cleveland, Ohio, United States
  • Neal S Peachey
    VA Northeast Ohio Healthcare System, Cleveland, Ohio, United States
    Cleveland Clinic Cole Eye Institute, Cleveland, Ohio, United States
  • Jessica Cooke Bailey
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    VA Northeast Ohio Healthcare System, Cleveland, Ohio, United States
  • Footnotes
    Commercial Relationships   Andrea Waksmunski None; Tyler Kinzy None; Lauren Cruz None; Cari Nealon None; Christopher Halladay None; Paul Greenberg None; Wen-Chih Wu None; Sudha Iyengar None; Dana Crawford None; Neal Peachey None; Jessica Cooke Bailey None
  • Footnotes
    Support  VA Office of Research Development (I01 BX004557), NIH Core Grants (P30 EY025585, P30 EY011373), CWRU Clinical and Translational Scientist Training Program (TL1 TR 002549-04), National Heart, Lung, and Blood Institute (T32 HL 0075-67), Clinical and Translational Science Collaborative of Cleveland (UL1TR0002548), Cleveland Institute for Computational Biology, Research to Prevent Blindness
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 491. doi:
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      Andrea R Waksmunski, Tyler G Kinzy, Lauren A Cruz, Cari L Nealon, Christopher W Halladay, Paul Greenberg, Wen-Chih Wu, Sudha K Iyengar, Dana C Crawford, Neal S Peachey, Jessica Cooke Bailey; From Genome to Phenome: Novel Cross-Ancestry Evaluation of Glaucoma Genetic Risk in the Million Veteran Program. Invest. Ophthalmol. Vis. Sci. 2023;64(8):491.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Genome-wide association studies (GWAS) leveraging biobanks with genomic data linked to electronic health records have facilitated novel risk loci discovery. Phenome-wide association studies (PheWAS) can expand understanding of the implications of genomic variants in other traits. We performed a GWAS and subsequent PheWAS of primary open-angle glaucoma (POAG) variants to evaluate association between POAG-associated variants and other traits in the Million Veteran Program (MVP).

Methods : We performed GWAS on 64429 European-descent (EUR; 5618 cases, 58811 controls), 9586 African-descent (AFR; 3921 cases, 5665 controls), and 3600 Hispanic-descent (HIS; 634 cases, 2966 controls) MVP Veterans. Lead variants from each ancestry group were used in PheWAS, restricting analyses to unrelated EUR, AFR, and HIS Veterans (n=446306, 114324, and 49437, respectively). PheWAS were performed using logistic regression models for each lead variant and phecode using the PheWAS R package, adjusting for age, sex, and 5 principal components (calculated for each ancestry group). Phecodes were based on PheMap version 1.2beta with ICD-clinically modified codes.

Results : We identified multiple POAG risk loci in EUR, AFR, and HIS Veterans (n=23, 4, and 2, respectively), including 2 novel hits each in AFR (FREM1, IGFL1/IGFL2) and HIS (PBLD, CPED1). For all 3 ancestry groups, the most significant PheWAS hits occurred with glaucoma-related phecodes (p<2x10-5). The lead HIS GWAS PBLD variant was associated with glaucoma-related phecodes in both HIS and EUR PheWAS. While not genome-wide significant in the HIS GWAS, variants from CDKN2B-AS1, TMCO1, and CHEK2 were associated with glaucoma-related phecodes in the HIS PheWAS. We observed a similar trend in the AFR-specific analysis. The EUR PheWAS had 188 variant-phecode associations involving various conditions (e.g., sensory, cancer, metabolic, circulatory, and digestive).

Conclusions : We identified novel POAG risk variants in AFR and HIS MVP Veterans. Most lead GWAS variants were associated with glaucoma-related phecodes in PheWAS of EUR, AFR, and HIS. Associations between lead variants from ancestry-specific GWAS and glaucoma-related phecodes in PheWAS of other ancestries suggest that additional loci should be interrogated further to understand influence on disease risk.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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