June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Genome-wide association identified novel loci contributing to ROP
Author Affiliations & Notes
  • Leah Owen
    Ophthalmology and Visual Sciences, University of Utah Health, Salt Lake City, Utah, United States
    SUNY Buffalo State College, Buffalo, New York, United States
  • Xiaohui Li
    The Lundquist Institute, Torrance, California, United States
  • Kent Taylor
    The Lundquist Institute, Torrance, California, United States
  • Susan Ostmo
    Oregon Health & Science University Casey Eye Institute, Portland, Oregon, United States
  • Y.-D. Ida Chen
    The Lundquist Institute, Torrance, California, United States
  • Aaron S Coyner
    Oregon Health & Science University Casey Eye Institute, Portland, Oregon, United States
  • Kemal Sonmez
    Oregon Health & Science University Casey Eye Institute, Portland, Oregon, United States
  • Mary Elizabeth Hartnett
    Ophthalmology and Visual Sciences, University of Utah Health, Salt Lake City, Utah, United States
  • Robison Vernon Paul Chan
    University of Illinois Chicago, Chicago, Illinois, United States
  • Margaret M DeAngelis
    SUNY Buffalo State College, Buffalo, New York, United States
    Ophthalmology and Visual Sciences, University of Utah Health, Salt Lake City, Utah, United States
  • Michael F Chiang
    National Eye Institute, Bethesda, Maryland, United States
  • J. Peter Campbell
    Oregon Health & Science University Casey Eye Institute, Portland, Oregon, United States
  • Jerome I Rotter
    The Lundquist Institute, Torrance, California, United States
  • Footnotes
    Commercial Relationships   Leah Owen iVeena, Code C (Consultant/Contractor); Xiaohui Li None; Kent Taylor None; Susan Ostmo None; Y.-D. Chen None; Aaron Coyner Boston AI Lab, Code R (Recipient); Kemal Sonmez None; Mary Elizabeth Hartnett None; Robison Chan Alcon, Code C (Consultant/Contractor), Genentech, Code F (Financial Support), Siloam, Code O (Owner), Boston AI Lab, Code R (Recipient); Margaret DeAngelis Genentech, Code F (Financial Support); Michael Chiang None; J. Peter Campbell Boston AI Lab, Code C (Consultant/Contractor), Genentech, Code F (Financial Support), Siloam Vision, Code O (Owner), Boston AI Lab, Code R (Recipient); Jerome Rotter None
  • Footnotes
    Support  This work is funded by the NEI, 1K08EY031800; L. Owen PI. This work is also supported by National Institutes of Health Core Grant (EY014800), and an Unrestricted Grant from Research to Prevent Blindness (RPB), New York, NY, to the Department of Ophthalmology & Visual Sciences, University of Utah. Unrestricted RPB support is also present for Oregon Health Sciences and for RVP Chan, University of Illinois Chicago. Support also includes: Clinical and Genetic Analysis of Retinopathy of Prematurity, National Eye Institute. Oregon Health & Science University. R01EY19474 Principal Investigator(s): Peter Campbell
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2855. doi:
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    • Get Citation

      Leah Owen, Xiaohui Li, Kent Taylor, Susan Ostmo, Y.-D. Ida Chen, Aaron S Coyner, Kemal Sonmez, Mary Elizabeth Hartnett, Robison Vernon Paul Chan, Margaret M DeAngelis, Michael F Chiang, J. Peter Campbell, Jerome I Rotter; Genome-wide association identified novel loci contributing to ROP. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2855.

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

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Abstract

Purpose : Retinopathy of prematurity (ROP) is a major cause of childhood visual loss and significantly contributes to social burdens stemming from infancy-acquired blindness. Clinical risk factors inform current ROP screening paradigms, though have low specificity; twin studies suggest that genetic factors may contribute to disease risk. To identify genetic susceptibility loci for ROP, we conducted a genome-wide association study (GWAS).

Methods : Infants with genotype and phenotype data within the multi-ethnic iROP consortium cohort were identified; 920 of the total 4929 infants met these criteria. Genotyping was performed using the Illumina Global Screening Array and genotypes were imputed using the Michigan Imputation Server with the reference panel from the 1000 Genome Project. Primary outcome measure was ROP severity as defined by ROP Stage; phenotype was determined as previously published by our group. Expression profiling from human donor eye tissue collected using the Utah Protocol was used to determine retinal and retinal pigment epithelial (RPE) expression.

Results : The GWAS cohort included 44.5% Hispanic American, 35.4% White, 12.1% African-American and 8% unidentified race individuals. All ROP phenotypes are represented, including 197 with ROP Stage ≥3. Using the most severe ROP stage, we identified 2 loci at GWAS significance level (p<5 × 10-8) and 7 suggestive significant loci (p < 5 × 10-6). The most significant locus at rs2058019 on chromosome 7 reached genome-wide significance within the full multiethnic cohort (p = 4.96 × 10-9) and showed a trend of the association in the same direction for both Hispanic and Caucasian infants. The lead single nucleotide polymorphism (SNP) falls in an intronic region within the Glioma-associated oncogene family zinc finger 3 (GLI3) gene, a transcription factor in the sonic hedgehog pathway. Some SNP-associations at the GLI3 gene were replicated in an independent Hispanic diabetic retinopathy cohort and relevance for GLI3 to human ocular disease substantiated through identified expression in normal human donor retinal and RPE tissues. Genetic ROP risk is further substantiated as genetic risk scores, representing risk associated with set of significant SNPs, were highly associated with ROP.

Conclusions : We report the largest ROP GWAS to date, which identified a novel locus at GLI3 on chromosome 7 with relevance to retinal biology and potential genetic susceptibilities for ROP risk.

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

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