June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Phenome-wide association analysis on risk variants for age-related macular degeneration reveals shared genetic influences with a wide range of disorders: the Million Veteran Program
Author Affiliations & Notes
  • Robert Igo
    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States
    Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States
  • Tyler G Kinzy
    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States
    Epidemiology and Biostatistics, Case Western Reserve University, 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
    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States
    Epidemiology and Biostatistics, Case Western Reserve University, 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 M. 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
    Ophalmology, 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
  • Helene Choquet
    Division of Research, Kaiser Permanente Northern California, Oakland, California, United States
  • Karina Patasova
    Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
  • Eric Jorgenson
    Division of Research, Kaiser Permanente Northern California, Oakland, California, United States
  • Pirro G Hysi
    Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
  • Andrew J Lotery
    Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
  • Jessica Cooke Bailey
    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States
    Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States
  • Neal S. Peachey
    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • Sudha K Iyengar
    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States
    Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States
  • Footnotes
    Commercial Relationships   Robert Igo, None; Tyler Kinzy, None; Christopher Halladay, None; Dana Crawford, None; Paul Greenberg, None; Jack Sullivan, None; Steven Fliesler, None; Wen-Chih Wu, None; Helene Choquet, None; Karina Patasova, None; Eric Jorgenson, None; Pirro Hysi, None; Andrew Lotery, None; Jessica Cooke Bailey, None; Neal Peachey, None; Sudha Iyengar, None
  • Footnotes
    Support  VA (I01 BX004557); Research to Prevent Blindness
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 3518. doi:
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      Robert Igo, Tyler G Kinzy, Christopher W. Halladay, Dana C. Crawford, Paul B Greenberg, Jack M. Sullivan, Steven J. Fliesler, Wen-Chih Wu, Helene Choquet, Karina Patasova, Eric Jorgenson, Pirro G Hysi, Andrew J Lotery, Jessica Cooke Bailey, Neal S. Peachey, Sudha K Iyengar; Phenome-wide association analysis on risk variants for age-related macular degeneration reveals shared genetic influences with a wide range of disorders: the Million Veteran Program. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3518.

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

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Abstract

Purpose : Age-related macular degeneration (AMD) is a leading cause of irreversible blindness with complex causes and a prominent heritable component. Here, we applied phenome-wide association analysis (PheWAS) to a large sample of US Veterans of European ancestry from the Million Veteran Program (MVP), scanning 907 common disorders for 50 AMD-associated risk loci that we recently identified by genome-wide association meta-analysis of MVP and several other AMD cohorts.

Methods : Our sample comprised 275,104 unrelated European American Veterans (≥ 30 years old at enrollment in the MVP), with ≥ 2 separate visits to the VA Healthcare System in each of the two years immediately prior to enrollment. Association analysis was performed with each marker using 907 PheCodes as outcomes, collections of ICD9 codes representing a given disease or phenotype, from 1,007 previously obtained PheCodes (Klarin et al., 2018, Nat Genet 50, 1514), with prevalence ≥ 0.25% in our sample. Analyses used the PheWAS package for the R statistical programming language (v3.2.0), with adjustment for age at enrollment, sex and five European-specific principal components of ancestry, assuming an additive inheritance model.

Results : A total of 222 marker/phenotype pairs, representing 104 unique phenotypes, were significantly associated (nominal p < 1.1 × 10–6 after Bonferroni correction for 907 traits and 50 markers). Ocular traits related to retinal diseases were common (24 traits; 102 associations with 25 markers), as were cardiovascular disease (14 traits), diabetes and lipid metabolic diseases (22 traits), dementia-related disorders (12 traits) and neoplasms/cancers (11 traits). Marker rs429358 in APOE, had the largest number of significant associations (42 traits). Relaxing the significance to a suggestive level, p < 1 × 10–4 yielded 361 associations over 160 unique traits.

Conclusions : PheWAS analysis revealed additional evidence for a genetic link between AMD and traits related to lipid metabolism and angiogenesis, which were previously implicated through physiological studies. Novel links between AMD and a wide range of other disorders were revealed through strongly associated genetic variants. Closer examination of the shared genetics may reveal new causal pathways for AMD.

This is a 2020 ARVO Annual Meeting abstract.

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