1. ORE identifies extreme expression effects enriched for rare variants.
- Author
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Richter, F, Hoffman, G E, Manheimer, K B, Patel, N, Sharp, A J, McKean, D, Morton, S U, DePalma, S, Gorham, J, Kitaygorodksy, A, Porter, G A, Giardini, A, Shen, Y, Chung, W K, Seidman, J G, Seidman, C E, Schadt, E E, and Gelb, B D
- Subjects
INTERNET servers ,CONGENITAL heart disease ,ORES ,SOURCE code ,CARDIAC patients ,EXOMES - Abstract
Motivation Non-coding rare variants (RVs) may contribute to Mendelian disorders but have been challenging to study due to small sample sizes, genetic heterogeneity and uncertainty about relevant non-coding features. Previous studies identified RVs associated with expression outliers, but varying outlier definitions were employed and no comprehensive open-source software was developed. Results We developed Outlier-RV Enrichment (ORE) to identify biologically-meaningful non-coding RVs. We implemented ORE combining whole-genome sequencing and cardiac RNAseq from congenital heart defect patients from the Pediatric Cardiac Genomics Consortium and deceased adults from Genotype-Tissue Expression. Use of rank-based outliers maximized sensitivity while a most extreme outlier approach maximized specificity. Rarer variants had stronger associations, suggesting they are under negative selective pressure and providing a basis for investigating their contribution to Mendelian disorders. Availability and implementation ORE, source code, and documentation are available at https://pypi.python.org/pypi/ore under the MIT license. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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