Age-related macular degeneration (AMD) is one of the leading causes of blindness in the elderly. It has a significant impact on the independence, quality of life, and healthcare costs for those afflicted and the additional social cost on caregivers and family members is incalculable. There is substantial variability in the AMD phenotype and the primary treatment, to repeatedly inject anti-VEGF antibodies into the eye of those severely affected, is effective in only a subset of individuals. Thus a better understanding of the underlying causes of AMD is needed to help guide development of more universal and effective treatments and potential preventive measures for AMD. AMD is strongly influenced by genomic variation. Through the initial funding period of this proposal, we supported the development of the International AMD Genomics Consortium (IAMDGC), which brought together 26 research groups from around the world. The IAMDGC has increased the known genomic loci from 12 to 52 and successfully performed a new and larger genotyping study focused on rarer variation using a high-density genome-wide SNP chip with exome content. This collaborative effort has also spawned numerous additional interesting avenues of research that we now need to explore in more detail through the renewal of this highly successful project. While the current genotypic dataset of over 50,000 samples has much left to be mined, expansion of the available samples, with a particular focus on families and minority samples, is necessary if we are to achieve our stated goal of completely defining the genetic architecture of AMD. To address these unresolved issues we propose four specific aims: 1) Expand the IAMDGC resource with additional datasets and expansion of current datasets, with a focus on family data and diverse genetic ancestry; 2) Expand the range of clinical diagnostic measures (e.g. fundus photos, OCT measures), biomarker, comorbidity, and covariate data associated with the samples; 3) Use an analytical hub infrastructure to perform detailed analyses of these data; and 4) Support the logistics and administration of the IAMDGC.

Public Health Relevance

Age-related macular degeneration (AMD) is the most common cause of severe vision loss among elderly individuals. Variations in multiple genes strongly affect the risk of developing AMD but a substantial portion of the genetic architecture of risk, progression, response to treatment, and in different genetic ancestries remains unexplained. The International AMD Genomic Consortium (IAMDGC) was formed to address these gaps and to develop a complete understanding of the genetic underpinnings of AMD as a pathway to better treatments and preventions.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022310-05
Application #
9442788
Study Section
Special Emphasis Panel (ZEY1)
Program Officer
Shen, Grace L
Project Start
2012-04-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Genetics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Geerlings, Maartje J; Kersten, Eveline; Groenewoud, Joannes M M et al. (2018) Geographic distribution of rare variants associated with age-related macular degeneration. Mol Vis 24:75-82
Marouli, Eirini (see original citation for additional authors) (2017) Rare and low-frequency coding variants alter human adult height. Nature 542:186-190
Schulz, Heidi L; Grassmann, Felix; Kellner, Ulrich et al. (2017) Mutation Spectrum of the ABCA4 Gene in 335 Stargardt Disease Patients From a Multicenter German Cohort-Impact of Selected Deep Intronic Variants and Common SNPs. Invest Ophthalmol Vis Sci 58:394-403
Persad, Patrice J; Heid, Iris M; Weeks, Daniel E et al. (2017) Joint Analysis of Nuclear and Mitochondrial Variants in Age-Related Macular Degeneration Identifies Novel Loci TRPM1 and ABHD2/RLBP1. Invest Ophthalmol Vis Sci 58:4027-4038
Grassmann, Felix; Kiel, Christina; Zimmermann, Martina E et al. (2017) Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits. Genome Med 9:29
Sardell, Rebecca J; Persad, Patrice J; Pan, Samuel S et al. (2016) Progression Rate From Intermediate to Advanced Age-Related Macular Degeneration Is Correlated With the Number of Risk Alleles at the CFH Locus. Invest Ophthalmol Vis Sci 57:6107-6115
Cooke Bailey, Jessica N; Hoffman, Joshua D; Sardell, Rebecca J et al. (2016) The Application of Genetic Risk Scores in Age-Related Macular Degeneration: A Review. J Clin Med 5:
Fritsche, Lars G; Igl, Wilmar; Bailey, Jessica N Cooke et al. (2016) A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet 48:134-43
Grassmann, Felix; Cantsilieris, Stuart; Schulz-Kuhnt, Anja-Sabrina et al. (2016) Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD). J Neuroinflammation 13:81
Cuellar-Partida, Gabriel; Craig, Jamie E; Burdon, Kathryn P et al. (2016) Assessment of polygenic effects links primary open-angle glaucoma and age-related macular degeneration. Sci Rep 6:26885

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