April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
Cross-Phenotype Associations and Pleiotropy in Age-Related Macular Degeneration
Author Affiliations & Notes
  • Tanya Glaser
    NEI, National Institutes of Health, Bethesda, MD
  • Emily Y Chew
    NEI, National Institutes of Health, Bethesda, MD
  • John Paul P SanGiovanni
    NEI, National Institutes of Health, Bethesda, MD
  • Footnotes
    Commercial Relationships Tanya Glaser, None; Emily Chew, None; John Paul SanGiovanni, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 2225. doi:
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      Tanya Glaser, Emily Y Chew, John Paul P SanGiovanni; Cross-Phenotype Associations and Pleiotropy in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2225.

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

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Purpose: A number of age-related macular degeneration (AMD)-associated DNA sequence variants also reach genome-wide significance in association studies for other complex traits and diseases. In this report we describe cross-phenotype associations and putative pleiotropy in AMD.

Methods: We filtered estimates of advanced AMD-gene relationships (P < 1.0 x10-8) from a 77,000-person study using a set of disease- and trait-associated SNPs (P < 5.0 x10-8) available in an open-access NIH-based catalog. We annotated findings with data from ENCODE, 1000 Genomes Project, and dbSNP to make inferences in the context of evidence on AMD pathobiology, while considering the potential influence of co-inherited SNPs from adjacent genes.

Results: Cross-phenotype associations existed for 23 SNPs from 16 different genes on 6 different chromosomes. A number of SNPs yielding cross-phenotype relationships were highly conserved, overlapped regulatory elements in a human RPE cell line, or were in linkage disequilibrium (LD) with DNA coding variants. An AMD- and HIV-related SNP in TNXB (rs12198173) was in complete LD with a missense coding variant (rs1221140) in the same gene. A conserved missense variant (rs6905572) was in nearly complete LD with an AMD-associated SNP in SNORD48 (rs4711279). A conserved synonymous AMD-associated SNP in SLC44A4 (rs494620), demonstrating DNase hypersensitivity in human RPE cells, was also associated with age of menopause. TOMM40 carried a variant (rs157582), associated with both AMD and metabolic syndrome, that was in complete LD with a SNP (rs184017) in a DNase hypersensitivity cluster in human RPE cells. A number of SNPs with cross-phenotype associations did not show LD with any other variants tested in the 1000 Genomes Pilot Study. These included rs592229 (SKIVL2, IgG glycosylation), rs6857 (PRVL2, Alzheimer’s Disease), rs4821083 and rs5749482 (SYN3, height), and rs2269426 (TNXB, eosinophil counts).

Conclusions: Our findings may shed light on common underlying biology of AMD with other complex diseases and streamline the process of identifying promising preventative and therapeutic interventions.

Keywords: 412 age-related macular degeneration • 539 genetics  

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