F Richter1, G E Hoffman2,3, K B Manheimer4, N Patel5, A J Sharp3,5, D McKean6, S U Morton6, S DePalma6, J Gorham6, A Kitaygorodksy7, G A Porter8, A Giardini9, Y Shen7,10, W K Chung11, J G Seidman6, C E Seidman6, E E Schadt2,3,4, B D Gelb3,5,12. 1. Graduate School of Biomedical Sciences. 2. Icahn Institute for Genomics and Multiscale Biology. 3. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 4. Sema4, A Mount Sinai Venture, Stamford, CT, USA. 5. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 6. Department of Genetics, Harvard Medical School, Boston, MA, USA. 7. Department of Systems Biology, Columbia University, New York, NY, USA. 8. Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA. 9. Cardiorespiratory Unit, Great Ormond Street Hospital and University College London, London, UK. 10. Department of Biomedical Informatics, Columbia University, New York, NY, USA. 11. Department of Pediatrics and Medicine, Columbia University, New York, NY, USA. 12. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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.
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 defectpatients 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.
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