My area of research focuses on elucidating the genetic and epidemiological factors that may underlie hereditary eye diseases including age-related macular degeneration (AMD). Genomic convergence of our gene expression and linkage data has identified additional genomic regions (other than 1q32 and 10q26, the most consistently associated AMD regions) that may harbor AMD susceptibility genes. Using high-throughput chip assays we our characterizing both single nucleotide polymorphisms and copy number variations (insertions/deletions) associated with genes in these regions. We are also studying the pathways in which these genes function at the DNA, RNA and protein level For example we have begun serum analysis in an effort to correlate significant genetic findings with corresponding circulating proteins to identify quantifiable biomarkers for progression to advanced AMD. By utilizing a systems level approach, that is converging genomics (including SNPs, copy number variation and linkage data), gene expression data, with phenomic data (including standardized clinical and epidemiological information) we hope to identify sets of genes (biomarkers) and their functional pathways/networks that not only contribute to AMD onset and progression but therapeutic response as well. The success of this project, in large part, has involved building strong collaborations between scientists and clinicians across several institutions not only in the Harvard Community but outside as well. This work was funded initially by a National Research Service Award from the National Institutes of Health during my post-doctoral training which provided the impetus for my current work. Since it is widely agreed that AMD is a multifactorial disease, we believe that the sibpair method is one of the most powerful approaches for revealing weak genetic effects. We applied this method to not only genetic but epidemiological studies of neovascular AMD as well. We hypothesize that if siblings with highly contrasting phenotypes are likely to carry different alleles at one or more genetically predisposing loci, then they may have different exposures to environmental factor such as cigarette smoking, hypertension, life-time body mass index, alcohol consumption, use of aspirin and vitamins. Since recruitment has increased due to an R01 funded by the National Eye Institute in 2003 we have been able to conduct genetic studies as well. The success of our work is in part due to a strong collaborative effort between the Department of Ophthalmology here (Drs. Miller, Kim and myself), the Rockefeller Institute in New York City (Drs. Ott and Ji) and Boston University (Dr. Lindsay Farrer). Concurrently, we also have collected bloods to create cell lines for gene expression microarray analysis which has resulted in preliminary findings. Using these complementary approaches, our ultimate goal is to identify quantifiable biomarkers that could serve as preventive and/or therapeutic targets for advanced AMD. In collaboration with Dr. Debra Schaumberg at the Harvard School of Public Health we are replicating and validating our findings on large nested case control cohorts which include the Nurses Health Study, Health Professionals Follow-up Study, Women’s Health Study and Physicians Health Study. Similarly, we are replicating and validating our findings on unrelated case-controls from central Greece in collaboration with Dr. Maria Kotoula. Additionally, I am working with Drs. Gregory Hageman, Anand Swaroop (National Eye Institute) and Neena Haider (University of Nebraska) on the biochemistry and pathophysiology of retinal diseases characterized by neovascularization. Furthermore in collaboration with Dr. Rui Chen at Baylor University School of Medicine Genome Center we are elucidating structural variants (copy number variation) that cause complex ocular diseases using high through put innovative molecular methods.