July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Evidence for novel risk loci for age-related macular degeneration on the X chromosome: the VA Million Veteran Program
Author Affiliations & Notes
  • Robert P. Igo
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States
  • Christopher W. Halladay
    Center for Innovation in Long Term Services and Supports, Providence VA Medical Center, Providence, Rhode Island, United States
  • Dana C. Crawford
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States
  • Tamer Hadi
    Ophthalmology and Visual Sciences, Case Western Reserve University, University Hospitals Eye Institute, Cleveland, Ohio, United States
  • Paul B 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
  • Jack Sullivan
    Research Service, VA Western NY Healthcare System, Buffalo, New York, United States
    Ophthalmology, SUNY-University at Buffalo, Buffalo, New York, United States
  • Steven J. Fliesler
    Research Service, VA Western NY Healthcare System, Buffalo, New York, United States
    Ophthalmology, Biochemistry and Neuroscience Program, SUNY-University at Buffalo, Buffalo, New York, United States
  • Wen-Chih Wu
    Section of Cardiology, Medical Service, Providence VA Medical Center, Providence, Rhode Island, United States
    Division of Cardiology, Alpert Medical School, Brown University, Providence, Rhode Island, United States
  • P. Eric Konicki
    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States
    Psychiatry, Case Western Reserve University, Cleveland, Ohio, United States
  • Neal S. Peachey
    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States
    Ophthalmology, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States
  • Sudha K Iyengar
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States
  • Footnotes
    Commercial Relationships   Robert Igo, None; Christopher Halladay, None; Dana Crawford, None; Tamer Hadi, None; Paul Greenberg, None; Jack Sullivan, None; Steven Fliesler, None; Wen-Chih Wu, None; P. Konicki, None; Neal Peachey, None; Sudha Iyengar, None
  • Footnotes
    Support  VA Grant I01 BX003364; Research to Prevent Blindness
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2958. doi:
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      Robert P. Igo, Christopher W. Halladay, Dana C. Crawford, Tamer Hadi, Paul B Greenberg, Jack Sullivan, Steven J. Fliesler, Wen-Chih Wu, P. Eric Konicki, Neal S. Peachey, Sudha K Iyengar; Evidence for novel risk loci for age-related macular degeneration on the X chromosome: the VA Million Veteran Program. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2958.

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

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Abstract

Purpose : Genes on the X chromosome play a role in diseases of the retina, but thus far no X-linked risk factors for age-related macular degeneration (AMD) have been discovered by genomewide association studies. The Million Veteran Program (MVP) comprises one of the world’s most successful biobanks, with genotypes available for > 480K participants, most of whom are men. Using individual survey data and electronic health records (EHR) from the MVP, we conducted a male-specific X-chromosome association analysis for AMD, the results of which are more readily interpreted than an analysis including both men and women.

Methods : The MVP sample was genotyped for a custom Affymetrix Biobank chip including about 725,000 genome-wide genetic variants. We selected male Veterans > 50 years of age, who had ICD9/ICD10 codes for AMD from at least two eye clinic visits, as AMD cases, and male Veterans > 65 years of age with no AMD codes or no eye clinic visits as AMD controls. We carried out association analysis on 9,355 common, X-linked DNA variants (minor allele frequency ≥ 0.5%) in European American men (17,124 AMD cases and 136,053 controls) by logistic regression, adjusting for 10 principal components of population structure. The two pseudoautosomal regions at the termini of the X chromosome were omitted (human genome build GRCh37 regions < 2,699,645 and > 154,930,230 bp).

Results : The Affymetrix Biobank panel yielded two major association peaks: near PRKX (rs111602303, OR = 1.094, p = 3.0 × 10–13) and a broad peak with chromosome-wide significant results (p < 5.3 × 10–6, Bonferroni adjusted for 9,355 tests) across a 3.2-megabasepair (Mb) region (88.9-92.1 Mb) with index SNP rs73535318 (OR = 1.72, p = 7.1 × 10–70). PRKX is a subunit of a developmentally regulated serine/threonine protein kinase that may be involved in fluid regulation and angiogenesis in the retina. The broad association region contains three protein-coding genes, TGIF2LX, PABPC5 and PCDH11X, and spans the X-transposed region, a region in Xq21.3 of high similarity between X and Y chromosomes. PCDH11X, a member of the cadherin superfamily, may be involved in the development of the central nervous system.

Conclusions : We have identified two novel potential AMD risk loci with moderate effect on the X chromosome in US Veterans, the largest male-only cohort studied to date.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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