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Mariusz Butkiewicz, Rebecca J Sardell, Patrice Whitehead, William K. Scott, Dwight Stambolian, Margaret A Pericak-Vance, Jonathan Haines; Whole Exome Sequencing in the Amish identifies candidate rare variants for AMD. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2643.
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© 2017 Association for Research in Vision and Ophthalmology.
Previous studies have demonstrated that the genetic architecture of age-related macular degeneration (AMD) in the Amish shares some but not all risk loci with the general population. Thus, novel risk or protective variants for AMD may be uniquely detectable in the Amish. Here, motivated by the need to populate a novel Exome Chip with custom content for the Amish, we conducted whole exome sequencing (WES) on 89 Amish individuals ascertained for a longitudinal study of AMD.
We selected the relatively isolated Amish populations from Ohio, Indiana, and Pennsylvania for study as they are descended from a small number of founders and their continued cultural isolation restricts the introduction of additional genetic variation. They have large and stable pedigrees ideal for genetic studies. Individuals were selected from widely dispersed sibships with at least one AMD case to optimize rare variant discovery. The WES identified a total of 116,811,848 called nucleotide base pair variants before quality control (QC). After applying multiple QC filters, 292,162 variants remained. These variants were analyzed with respect to two criteria: 1) variants that are present yet rare in the general population using the Exome Aggregation Consortium (ExAC) database and 2) variants that are not present in ExAC but are novel in the Amish.
Based on the outlined filtering criteria, we identified 19,371 variants that are present in the Amish but rare in the general population (minor allele frequency < 0.01). 8,477 variants differed significantly in frequency between the Amish and the general population. Further, we found 115,668 variants that are novel and did not appear among variants in the general population (ExAC). We examined the possible phenome-wide impact of these variants by examining the ClinVar database, but found no evidence of association.
The ultimate goal of this study is to evaluate genetic determinates of AMD progression. This first study demonstrates that the Amish carry numerous rare and novel variants that are candidate for variants influencing AMD. These variants have the potential to identify new target genes relevant to AMD.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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