April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
Pathway Analysis of Age-Related Macular Degeneration Exome Chip Data
Author Affiliations & Notes
  • Jonathan L Haines
    Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH
  • Footnotes
    Commercial Relationships Jonathan Haines, None
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Investigative Ophthalmology & Visual Science April 2014, Vol.55, 2215. doi:
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      Jonathan L Haines, ; Pathway Analysis of Age-Related Macular Degeneration Exome Chip Data. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2215.

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

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Purpose: Age-related macular degeneration (AMD) is a complex heterogeneous disease that is a leading cause of blindness in elderly individuals worldwide. Risk for AMD is mediated by genetic and environmental factors. While several genetic risk loci are known, these account for less than 2/3 of the heritability of AMD. To further elucidate AMD genetic susceptibility factors, we utilized pathway analysis, a hypothesis-free approach to explore candidate regions as well as genome-wide association data for overrepresentation of association signals within any particular biological pathway or gene set in the International AMD Genomics Consortium (IAMDGC) dataset.

Methods: We applied INGENUITY Pathway Analysis (IPA), Interval-based Enrichment Analysis for Genome-wide Association Studies (INRICH), and Pathway Analysis by Randomization Incorporating Structure (PARIS) with curated pathway databases, including Gene Ontology, Reactome, and Kyoto Encyclopedia of Genes and Genomes. We analyzed all available data for novel findings and also specifically evaluated pathwas previously implicated in AMD and those specific to AMD subtypes.

Results: Pathways previously implicated in AMD, including complement, LXR/RXR activation, and atherosclerosis signaling, were implicated by all methods. For the INRICH analysis, in our initial conservative setup, i.e. limiting the analysis to the 27 linkage disequilibrium regions with genome-wide significant signals (P<5x10-8) from single variant analysis (unrelated, European late AMD cases [N=13423] and controls [N=14397], we detected an overrepresentation of several gene sets, e.g. complement regulation, lipid particle remodeling and transport, regulation of immune response, and extracellular matrix organization. While the role of complement genes C2, C3, C9, CFB, CFH, CFI is well documented in AMD, our analysis also indicated a possible involvement of complement component genes C4A, C4B on chromosome 6 and additional immune regulatory process genes (PLA2G6, TNF, LTA).

Conclusions: Pathway analysis of extensive genome-wide exome data is a useful method for detecting biologically relevant signals that might otherwise be overlooked by traditional analysis methods. These analyses confirm established AMD pathways and also highlight interesting candidate genes within these pathways. Ongoing analyses with less conservative thresholds may uncover additional AMD or subphenotype-specific pathways for functional follow-up.

Keywords: 539 genetics • 412 age-related macular degeneration  

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