Deep learning models predict regulatory variants in pancreatic islets and refine type 2 diabetes association signals
- University of Oxford, United Kingdom
- Genentech, United States
Abstract
Genome-wide association analyses have uncovered multiple genomic regions associated with T2D, but identification of the causal variants at these remains a challenge. There is growing interest in the potential of deep learning models - which predict epigenome features from DNA sequence - to support inference concerning the regulatory effects of disease-associated variants. Here, we evaluate the advantages of training convolutional neural network (CNN) models on a broad set of epigenomic features collected in a single disease-relevant tissue – pancreatic islets in the case of type 2 diabetes (T2D) - as opposed to models trained on multiple human tissues. We report convergence of CNN-based metrics of regulatory function with conventional approaches to variant prioritization – genetic fine-mapping and regulatory annotation enrichment. We demonstrate that CNN-based analyses can refine association signals at T2D-associated loci and provide experimental validation for one such signal. We anticipate that these approaches will become routine in downstream analyses of GWAS.
Data availability
The datasets analysed during the current study are available in the public repositories under accessions listed in STable 1.
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Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility lociEuropean Genome-Phenome Archive, EGAS00001002592.
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Integration of ATAC-seq and RNA-seq Identifies Human Alpha Cell and Beta Cell Signature GenesNCBI Gene Expression Omnibus, GSE76268.
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Duke_DnaseSeq_PanIsletsNCBI Gene Expression Omnibus, GSM816660.
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UNC_FaireSeq_PanIsletsNCBI Gene Expression Omnibus, GSM864346.
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DNaseI/FAIRE/ChIP Synthesis from ENCODE/OpenChrom(Duke/UNC/UTA)NCBI Gene Expression Omnibus, GSE40833.
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BI Human Reference Epigenome Mapping Project: ChIP-Seq in human subjectNCBI Gene Expression Omnibus, GSE19465.
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UCSF-UBC Human Reference Epigenome Mapping ProjectNCBI Gene Expression Omnibus, GSE16368.
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Epigenomic plasticity enables human pancreatic alpha to beta cell reprogrammingNCBI Gene Expression Omnibus, GSE50386.
Article and author information
Author details
Agata Wesolowska-Andersen
Funding
Wellcome (099673/Z/12/Z)
- Matthias Thurner
Horizon 2020 Framework Programme (T2D Systems)
- Anna L Gloyn
NIH Clinical Center (U01-DK105535)
- Anna L Gloyn
- Mark I McCarthy
NIH Clinical Center (U01-DK085545)
- Anna L Gloyn
National Institute for Health Research (NF-SI-0617-10090)
- Anna L Gloyn
Wellcome (090532)
- Mark I McCarthy
Wellcome (106130)
- Anna L Gloyn
- Mark I McCarthy
Wellcome (098381)
- Mark I McCarthy
Wellcome (203141)
- Anna L Gloyn
- Mark I McCarthy
Wellcome (212259)
- Mark I McCarthy
Wellcome (095101)
- Anna L Gloyn
Wellcome (200837)
- Anna L Gloyn
Medical Research Council (MR/L020149/1)
- Anna L Gloyn
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Wesolowska-Andersen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Deep learning models predict regulatory variants in pancreatic islets and refine type 2 diabetes association signals
eLife 9:e51503.
https://doi.org/10.7554/eLife.51503
Further reading
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Untranslated regions (UTRs) contain crucial regulatory elements for RNA stability, translation and localization, so their integrity is indispensable for gene expression. Approximately 3.7% of genetic variants associated with diseases occur in UTRs, yet a comprehensive understanding of UTR variant functions remains limited due to inefficient experimental and computational assessment methods. To systematically evaluate the effects of UTR variants on RNA stability, we established a massively parallel reporter assay on 6555 UTR variants reported in human disease databases. We examined the RNA degradation patterns mediated by the UTR library in two cell lines, and then applied LASSO regression to model the influential regulators of RNA stability. We found that UA dinucleotides and UA-rich motifs are the most prominent destabilizing element. Gain of UA dinucleotide outlined mutant UTRs with reduced stability. Studies on endogenous transcripts indicate that high UA-dinucleotide ratios in UTRs promote RNA degradation. Conversely, elevated GC content and protein binding on UA dinucleotides protect high-UA RNA from degradation. Further analysis reveals polarized roles of UA-dinucleotide-binding proteins in RNA protection and degradation. Furthermore, the UA-dinucleotide ratio of both UTRs is a common characteristic of genes in innate immune response pathways, implying a coordinated stability regulation through UTRs at the transcriptomic level. We also demonstrate that stability-altering UTRs are associated with changes in biobank-based health indices, underscoring the importance of precise UTR regulation for wellness. Our study highlights the importance of RNA stability regulation through UTR primary sequences, paving the way for further exploration of their implications in gene networks and precision medicine.
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