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Tiarnan D Keenan, Michael Simmons, Freekje Van Asten, Ayush Singhal, Rinki Ratnapriya, Elvira Agron, Anand Swaroop, Zhiyong Lu, Emily Chew; Deep Phenotype Association Study in AREDS2 Suggests Pleiotropic Genetic Associations with Ocular and Systemic Disease. Invest. Ophthalmol. Vis. Sci. 2017;58(8):177.
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© ARVO (1962-2015); The Authors (2016-present)
The aim was to investigate for novel pleiotropic associations between genetic variants and both ocular and systemic disease. Using a novel literature-mining tool to help select genetic variants, we performed a Deep Phenotype Association Study (DeePAS) on AREDS2 participants in order to study potential associations between these genetic variants and diverse medical conditions.
The AREDS2 documented 138 phenotypes including AMD features, other ocular conditions, cognitive function and cardiovascular, neurological, gastrointestinal and endocrine disease. Genotype data was available for 1826 AREDS2 participants. A literature-mining tool (PubTator) was used to aid selection of SNPs (24 total). The DeePAS analysis was performed by assessing correlation between SNPs and phenotypes in the AREDS2 dataset.
The ε2 allele of the APOE genotype was inversely and significantly associated with both hyperlipidemia (OR 0.51; p=2.1x10-9) and use of statin medication (OR 0.60; p=4.2x10-6). Other results met the nominal but not Bonferroni-corrected significance level, as follows. A very common variant in PON1 (rs662) was associated with increased risk of diabetes mellitus (OR 1.36; p=0.001) but decreased risk of multiple AMD phenotypes including geographic atrophy (OR 0.76; p=0.001) and neovascular AMD (OR 0.46; p=0.002). A common variant in MTHFR (rs1801133) was linked to decreased risk of cognitive dysfunction (OR 0.59; p=0.0007) but to increased risk of positive cardiac stress test (OR 2.9; p=0.002). A variant in HFE (rs1800562), the hemochromatosis gene, was inversely associated with cortical lens opacity (OR= 0.59; p=0.0005).
Genotype-phenotype analysis in AREDS2 participants, aided by automatic literature mining, can suggest novel pleiotropic associations between genetic variants and diverse ocular and systemic diseases. In the context of understanding AMD pathophysiology, the potentially protective effects of PON1 variants merit further study.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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