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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.
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© 2017 Association for Research in Vision and Ophthalmology.
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.
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.
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.
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.
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