ORE identifies extreme expression effects enriched for rare variants.
ORE identifies extreme expression effects enriched for rare variants.
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ORE 识别了稀有变异丰富的极端表达效应。
DOI：
10.1093/bioinformatics/btz202
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Gelb,BD
中科院分区：
文献类型：
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作者：
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
非编码罕见变异（RV）可能导致孟德尔疾病，但由于样本量小，遗传异质性和相关非编码特征的不确定性，研究一直具有挑战性。以前的研究确定了与表达离群值的RV，但不同的离群值的定义，并没有全面的开源software developed.ResultsWe开发的离群RV富集（ORE），以确定生物学意义的非编码RV。我们实施了ORE，将来自儿科心脏基因组学联盟的先天性心脏缺陷患者和来自基因型-组织表达的已故成人的全基因组测序和心脏RNAseq相结合。使用基于秩的离群值最大化灵敏度，而最极端的离群值方法最大化特异性。罕见的变异有更强的关联，这表明它们处于负选择压力下，并为调查它们对孟德尔疾病的贡献提供了基础。可用性和实施ORE，源代码和文档可以在MIT许可下在https://pypi.python.org/pypi/ore上获得。补充信息补充数据可以在Bioinformaticsonline上获得。
MotivationNon-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.ResultsWe 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 implementationORE, source code, and documentation are available at https://pypi.python.org/pypi/ore under the MIT license.Supplementary informationSupplementary data are available atBioinformaticsonline.