ORE identifies extreme expression effects enriched for rare variants

F. Richter, G. E. Hoffman, K. B. Manheimer, N. Patel, A. J. Sharp, D. McKean, S. U. Morton, S. Depalma, J. Gorham, A. Kitaygorodksy, G. A. Porter, A. Giardini, Y. Shen, W. K. Chung, J. G. Seidman, C. E. Seidman, E. E. Schadt, B. D. Gelb, Oliver Stegle

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish
Pages (from-to)3906-3912
Number of pages7
Issue number20
StatePublished - 15 Oct 2019


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