Purchase this article with an account.
John Paul P. SanGiovanni, Traci E. Clemons, Lois E. Smith, Przemyslaw Mike Sapieha, Elvira Agron, Emily Y. Chew; Genomic Systems Approach to Study of Mitochondria-Related Genes in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3306.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
To examine the association of DNA sequence variation with advanced AMD in the context of genes and pathways related to mitochondrial (mt) structure and function.
We applied microarray data from three independent cohorts to interrogate ~4100 sequence variants resident in ~1000 nuclear genes encoding mt-associated proteins. The mt gene set was constructed from a protein inventory validated with mass spectrometry, GFP tagging, and machine learning methods. Meta-analytic techniques were used to compute combined estimates of association in single markers showing concordance across cohorts. These AMD-and-mt-associated polymorphisms were first examined for enrichment in over 400 metabolic and signaling pathways and subsequently assessed for relationships at levels of the pathway, gene, and SNP. We further examined enriched pathways by populating them with data from all resident molecules tested in our genome-wide association study. This approach was developed to permit: 1) interpretation of mt-AMD findings in the context of other AMD-associated genes/pathways; and, 2) identification of meaningful ligands and molecular targets existing in the enriched pathways.
Nearly 350 sequence variants resident in ~200 mt-related genes yielded associations with advanced AMD in meta-analysis on results from age-, sex-, and smoking-adjusted logistic regression models. Pathways selectively enriched with these genes drive propanoate (P ≤ 8.1 x 10-16) and branched chain amino acid metabolism (P ≤ 1.3 x 10-12). We were intrigued to learn that these two pathways, and our strongest AMD-associated empirical network of sequence variants (representing polymorphisms in 26 genes), contain genes encoding targets of FDA-approved compounds.
Applying a systems-based approach, we extend our genome-wide investigations of mt DNA to elucidate evidence that mt-and-AMD-associated nuclear DNA sequence variants are resident in genes of pathways driving specific aspects carbohydrate and amino acid metabolism. As products of a number of these genes are known targets of available compounds, our approach may show value as an early step in identifying promising ligands and molecular targets for applied clinical research and clinical trials on AMD.
This PDF is available to Subscribers Only