ORE identifies extreme expression effects enriched for rare variants

Bioinformatics. 2019 Oct 15;35(20):3906-3912. doi: 10.1093/bioinformatics/btz202.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Child
  • Documentation
  • Genomics*
  • Humans
  • Software*
  • Uncertainty
  • Whole Genome Sequencing