April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Whole Genome Sequencing Scan of 2,099 Samples in Age-related Macular Degeneration Study
Author Affiliations & Notes
  • Xiaowei Zhan
    Department of Biostatistics, University of Michigan, Ann Arbor, MI
    Center of Statistical Genetics, University of Michigan, Ann Arbor, MI
  • Jennifer Bragg-Gresham
    Department of Biostatistics, University of Michigan, Ann Arbor, MI
    Center of Statistical Genetics, University of Michigan, Ann Arbor, MI
  • Lars G Fritsche
    Department of Biostatistics, University of Michigan, Ann Arbor, MI
    Center of Statistical Genetics, University of Michigan, Ann Arbor, MI
  • Kari E Branham
    Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, MI
  • Dwight Stambolian
    Department of Ophthalmology and Human Genetics, University of Pennsylvania Medical School, Philadelphia, PA
  • Emily Y Chew
    Division of Epidemiology and Clinical Applications, National Eye Institute/National Institutes of Health, Bethesda, MD
  • Anand Swaroop
    Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute/National Institutes of Health, Bethesda, MD
  • Goncalo Abecasis
    Department of Biostatistics, University of Michigan, Ann Arbor, MI
    Center of Statistical Genetics, University of Michigan, Ann Arbor, MI
  • Footnotes
    Commercial Relationships Xiaowei Zhan, None; Jennifer Bragg-Gresham, None; Lars Fritsche, None; Kari Branham, None; Dwight Stambolian, None; Emily Chew, None; Anand Swaroop, None; Goncalo Abecasis, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 4571. doi:
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      Xiaowei Zhan, Jennifer Bragg-Gresham, Lars G Fritsche, Kari E Branham, Dwight Stambolian, Emily Y Chew, Anand Swaroop, Goncalo Abecasis; Whole Genome Sequencing Scan of 2,099 Samples in Age-related Macular Degeneration Study. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4571.

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

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Abstract
 
Purpose
 

Age-related Macular Degeneration (AMD) is a leading cause of blindness among the elderly. Over the past several years, genetic studies of common variation have provided many clues about disease biology. Due to assay limitations, these studies have typically ignored rare variants or examined them only in a small set of candidate regions. Here, we set out to systematically study the contribution of rare variants to disease.

 
Methods
 

We assembled a collection of 2,099 cases and controls with advanced AMD (67% neovascularization, 33% geographic atrophy) from Kellogg Eye Center at University of Michigan, Age-Related Eye Disease Study and University of Pennsylvania. We matched case and control according to age, gender and ethnicity. We sequenced the genome of all individuals to characterize genetic variation systematically.

 
Results
 

As of today, 2,099 samples have been sequenced, representing >39 Terabytes (3.9 x 1013 bytes) of sequence data. This corresponds to a total genomic coverage of 9,237x and an average coverage of 4.4x per sample. In an initial analysis, we discovered and genotyped ~31 million variants. The set includes many previously studied variants, such as the complement factor H variants Y402H (fcase = 0.44, fcontrol= 0.63, p-value = 3.2x10-34) and R1210C (fcase = 0.0048, fcontrol = 0, p-value = 1.5x10-3), but also many new functionally interesting variants, such as 20 missense and 1 nonsense mutations that are very rare (median minor allele frequency = 0.05 %) and missing from previous studies.

 
Conclusions
 

We provide a first detailed look at the genetic of AMD, through whole genome sequencing of more than 2,000 individuals. Our data will enable a systematic genomewide search for rare risk alleles and should allow us to evaluate the effect of nonsense variants in many previously associated genes.

 
Keywords: 412 age-related macular degeneration • 539 genetics  
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