ORE identifies extreme expression effects enriched for rare variants

• DOI: 10.1093/bioinformatics/btz202
• Publication Date: 2019-03-20T20:23:04Z
• Authors: 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
• Keywords: 0303 health sciences; 03 medical and health sciences; Whole Genome Sequencing; Uncertainty; Humans; Documentation; Genomics; Child; Software; 3. Good health

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.