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Bioinformatics. 2019 Mar 23. pii: btz202. doi: 10.1093/bioinformatics/btz202. [Epub ahead of print]

ORE Identifies Extreme Expression Effects Enriched for Rare Variants.

Author information

1
Graduate School of Biomedical Sciences, New York, NY, USA.
2
Icahn Institute for Genomics and Multiscale Biology, New York, NY, USA.
3
Genetics and Genomic Sciences and Pediatrics, 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, and Departments of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6
Department of Genetics, Harvard Medical School, Boston, MA, USA.
7
Departments 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
Biomedical Informatics, Columbia University, New York, NY, USA.
11
Pediatrics, and Medicine, Columbia University, New York, NY, USA.
12
Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Abstract

MOTIVATION:

Noncoding 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 noncoding 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 noncoding 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 GTEx. 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:

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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