September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Phenome-wide association study provides biologic insights into the etiology of age-related macular degeneration
Author Affiliations & Notes
  • scott hebbring
    marshfield clinic, Marshfield, Wisconsin, United States
    University of Wisconsin Madison, Madison, Wisconsin, United States
  • John Mayer
    marshfield clinic, Marshfield, Wisconsin, United States
  • Zhan Ye
    marshfield clinic, Marshfield, Wisconsin, United States
  • Jixia Liu
    marshfield clinic, Marshfield, Wisconsin, United States
  • Wei-hua Lee
    University of Wisconsin Madison, Madison, Wisconsin, United States
  • Brian Hoch
    marshfield clinic, Marshfield, Wisconsin, United States
  • Steven Schrodi
    marshfield clinic, Marshfield, Wisconsin, United States
  • Jeffrey Joyce
    marshfield clinic, Marshfield, Wisconsin, United States
  • Akihiro Ikeda
    University of Wisconsin Madison, Madison, Wisconsin, United States
  • Murray Brilliant
    marshfield clinic, Marshfield, Wisconsin, United States
  • Footnotes
    Commercial Relationships   scott hebbring, None; John Mayer, None; Zhan Ye, None; Jixia Liu, None; Wei-hua Lee, None; Brian Hoch, None; Steven Schrodi, None; Jeffrey Joyce, None; Akihiro Ikeda, None; Murray Brilliant, None
  • Footnotes
    Support  NIH grant K22LM011938, R01GM114128
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2623. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      scott hebbring, John Mayer, Zhan Ye, Jixia Liu, Wei-hua Lee, Brian Hoch, Steven Schrodi, Jeffrey Joyce, Akihiro Ikeda, Murray Brilliant; Phenome-wide association study provides biologic insights into the etiology of age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2623.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : Early stage age related macular degeneration (AMD) is characterized by medium sized extracellular deposits called drusen and loss of endothelial cells from the pillars of choriocapillaris, which serves as the vascular supply for the retinal pigmented epithelium (RPE). Numerous genome-wide association studies (GWASs) have demonstrated that AMD is a genetically complex disease with over 30 independent genetic loci. Conversely, it remains to be elucidated on how these genes increase AMD risk. To better understand the genetic contribution to AMD pathology and etiology, we conducted a comprehensive phenome-wide association study (PheWAS) using ten independent SNPs known to be associated with AMD. We hypothesized that other phenotypes may share a common genetic biology with AMD.

Methods : We genotyped ten AMD-associated SNPs on 3,887 Marshfield Clinic patients linked to an extensive electronic health record system. A PheWAS was then conducted by combining the effects of each SNP and associating those effects across 4,653 phenotypes defined by diagnostic ICD9 codes. Genetic association results were validated in 7,481 Marshfield Clinic patients. Follow-up studies included association studies in 1.4 million Marshfield Clinic patients and functional genomic studies in primary cardiac endothelial cells and clinical biopsy samples.

Results : As expected, these ten SNPs were strongly associated with AMD (P=5.5E-22). More importantly, these ten SNPs were also significantly associated with clinical conditions defined as “disorders of the arteries and arterioles” (DAA) (P=2.1E-7). This genetic association was validated in an independent population. In the larger clinic population, DAA was associated with AMD risk (P=1.9E-37, OR 1.5) and patients diagnosed with DAA tended to be diagnosed with AMD three years earlier compared to those never diagnosed with DAA (P<0.0001). Immunohistochemistry staining of two AMD candidate genes in endothelial cell and clinical DAA tissues demonstrate strong expression.

Conclusions : This study demonstrates an expanded application of the PheWAS approach to study complex diseases such as AMD. In conjunction with the known pathology of AMD, these results also provide strong evidence that AMD-predisposing SNPs may increase AMD risk by directly affecting blood vessels of the eye and that these genetic effects are not limited to the eye.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×