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

doi:10.1093/bioinformatics/btz202

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

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7 Scopus citations

Abstract

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 language	English
Pages (from-to)	3906-3912
Number of pages	7
Journal	Bioinformatics
Volume	35
Issue number	20
DOIs	https://doi.org/10.1093/bioinformatics/btz202
State	Published - 15 Oct 2019

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Richter, F., Hoffman, G. E., Manheimer, K. B., Patel, N., Sharp, A. J., McKean, D., Morton, S. U., Depalma, S., Gorham, J., Kitaygorodksy, A., Porter, G. A., Giardini, A., Shen, Y., Chung, W. K., Seidman, J. G., Seidman, C. E., Schadt, E. E., Gelb, B. D., & Stegle, O. (2019). ORE identifies extreme expression effects enriched for rare variants. Bioinformatics, 35(20), 3906-3912. https://doi.org/10.1093/bioinformatics/btz202

@article{d64125c0a9c24e34b2414ac38849f2c6,

title = "ORE identifies extreme expression effects enriched for rare variants",

abstract = "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.",

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

year = "2019",

month = oct,

day = "15",

doi = "10.1093/bioinformatics/btz202",

language = "English",

volume = "35",

pages = "3906--3912",

journal = "Bioinformatics",

issn = "1367-4803",

publisher = "Oxford University Press",

number = "20",

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Richter, F, Hoffman, GE, Manheimer, KB, Patel, N, Sharp, AJ, McKean, D, Morton, SU, Depalma, S, Gorham, J, Kitaygorodksy, A, Porter, GA, Giardini, A, Shen, Y, Chung, WK, Seidman, JG, Seidman, CE, Schadt, EE , Gelb, BD & Stegle, O 2019, 'ORE identifies extreme expression effects enriched for rare variants', Bioinformatics, vol. 35, no. 20, pp. 3906-3912. https://doi.org/10.1093/bioinformatics/btz202

TY - JOUR

T1 - ORE identifies extreme expression effects enriched for rare variants

AU - Richter, F.

AU - Hoffman, G. E.

AU - Manheimer, K. B.

AU - Patel, N.

AU - Sharp, A. J.

AU - McKean, D.

AU - Morton, S. U.

AU - Depalma, S.

AU - Gorham, J.

AU - Kitaygorodksy, A.

AU - Porter, G. A.

AU - Giardini, A.

AU - Shen, Y.

AU - Chung, W. K.

AU - Seidman, J. G.

AU - Seidman, C. E.

AU - Schadt, E. E.

AU - Gelb, B. D.

AU - Stegle, Oliver

PY - 2019/10/15

Y1 - 2019/10/15

N2 - 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.

AB - 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.

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DO - 10.1093/bioinformatics/btz202

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SN - 1367-4803

VL - 35

SP - 3906

EP - 3912

JO - Bioinformatics

JF - Bioinformatics

IS - 20

ER -

ORE identifies extreme expression effects enriched for rare variants

Abstract

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