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bioRxiv · 10.1101/2020.09.17.301960

GREEN-DB: a framework for the annotation and prioritization of non-coding regulatory variants in whole-genome sequencing

Giacopuzzi, E.·Popitsch, N.·Taylor, J. C.
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Abstract

Non-coding variants have emerged as important contributors to the pathogenesis of human diseases, not only as common susceptibility alleles but also as rare high-impact variants. Despite recent advances in the study of regulatory elements and the availability of specialized data collections, the systematic annotation of non-coding variants from genome sequencing remains challenging. Here, we propose a new framework for the prioritization of non-coding regulatory variants that integrates information about regulatory regions with prediction scores and HPO-based prioritization. Firstly, we created a comprehensive collection of annotations for regulatory regions including a curated database of 2.4 million regulatory elements (GREEN-DB) annotated with controlled gene(s), tissue(s) and associated phenotype(s) where available. Secondly, we calculated a variation constraint metric and showed that constrained regulatory regions associate with disease-associated genes and essential genes from mouse knock-out screens. Thirdly, we compared 19 non-coding impact prediction scores providing suggestions for variant prioritization. Finally, we developed a VCF annotation tool (GREEN-VARAN) that can integrate all these elements to annotate variants for their potential regulatory impact. In our evaluation, we show that GREEN-DB can capture previously published disease-associated non-coding variants as well as identify additional candidate disease genes in WGS trio analyses.

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Giacopuzzi, E., Popitsch, N., Taylor, J. C.. 2020-09-19. GREEN-DB: a framework for the annotation and prioritization of non-coding regulatory variants in whole-genome sequencing. https://doi.org/10.1101/2020.09.17.301960

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