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Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals

View ORCID ProfileNicola Whiffin, View ORCID ProfileKonrad J Karczewski, Xiaolei Zhang, Sonia Chothani, View ORCID ProfileMiriam J Smith, View ORCID ProfileD Gareth Evans, View ORCID ProfileAngharad M Roberts, Nicholas M Quaife, Sebastian Schafer, View ORCID ProfileOwen Rackham, Jessica Alföldi, View ORCID ProfileAnne H O’Donnell-Luria, Laurent C Francioli, Genome Aggregation Database (gnomAD) Production Team, Genome Aggregation Database (gnomAD) Consortium, Stuart A Cook, View ORCID ProfilePaul J R Barton, Daniel G MacArthur, View ORCID ProfileJames S Ware
doi: https://doi.org/10.1101/543504
Nicola Whiffin
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
2NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • ORCID record for Nicola Whiffin
  • For correspondence: n.whiffin@imperial.ac.uk
Konrad J Karczewski
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
4Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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  • ORCID record for Konrad J Karczewski
Xiaolei Zhang
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
2NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
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Sonia Chothani
5Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore
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Miriam J Smith
6NW Genomic Laboratory Hub, Centre for Genomic Medicine, Division of Evolution and Genomic Science, University of Manchester, St Mary’s Hospital, Manchester, UK
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  • ORCID record for Miriam J Smith
D Gareth Evans
6NW Genomic Laboratory Hub, Centre for Genomic Medicine, Division of Evolution and Genomic Science, University of Manchester, St Mary’s Hospital, Manchester, UK
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  • ORCID record for D Gareth Evans
Angharad M Roberts
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
2NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
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Nicholas M Quaife
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
2NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
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Sebastian Schafer
5Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore
7National Heart Centre Singapore, Singapore
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Owen Rackham
5Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore
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  • ORCID record for Owen Rackham
Jessica Alföldi
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
4Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Anne H O’Donnell-Luria
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
4Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Laurent C Francioli
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
4Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Stuart A Cook
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
5Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore
7National Heart Centre Singapore, Singapore
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Paul J R Barton
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
2NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
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Daniel G MacArthur
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
4Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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James S Ware
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
2NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Abstract

Upstream open reading frames (uORFs) are important tissue-specific cis-regulators of protein translation. Although isolated case reports have shown that variants that create or disrupt uORFs can cause disease, genetic sequencing approaches typically focus on protein-coding regions and ignore these variants. Here, we describe a systematic genome-wide study of variants that create and disrupt human uORFs, and explore their role in human disease using 15,708 whole genome sequences collected by the Genome Aggregation Database (gnomAD) project. We show that 14,897 variants that create new start codons upstream of the canonical coding sequence (CDS), and 2,406 variants disrupting the stop site of existing uORFs, are under strong negative selection. Furthermore, variants creating uORFs that overlap the CDS show signals of selection equivalent to coding missense variants, and uORF-perturbing variants are under strong selection when arising upstream of known disease genes and genes intolerant to loss-of-function variants. Finally, we identify specific genes where perturbation of uORFs is likely to represent an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in families with neurofibromatosis. Our results highlight uORF-perturbing variants as an important and under-recognised functional class that can contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data to study the deleteriousness of specific classes of non-coding variants.

Footnotes

  • Figures 1c and 2b updated to correct an oversight in the MAPS calculation for pLoF variants.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 06, 2019.
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Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Nicola Whiffin, Konrad J Karczewski, Xiaolei Zhang, Sonia Chothani, Miriam J Smith, D Gareth Evans, Angharad M Roberts, Nicholas M Quaife, Sebastian Schafer, Owen Rackham, Jessica Alföldi, Anne H O’Donnell-Luria, Laurent C Francioli, Genome Aggregation Database (gnomAD) Production Team, Genome Aggregation Database (gnomAD) Consortium, Stuart A Cook, Paul J R Barton, Daniel G MacArthur, James S Ware
bioRxiv 543504; doi: https://doi.org/10.1101/543504
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Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Nicola Whiffin, Konrad J Karczewski, Xiaolei Zhang, Sonia Chothani, Miriam J Smith, D Gareth Evans, Angharad M Roberts, Nicholas M Quaife, Sebastian Schafer, Owen Rackham, Jessica Alföldi, Anne H O’Donnell-Luria, Laurent C Francioli, Genome Aggregation Database (gnomAD) Production Team, Genome Aggregation Database (gnomAD) Consortium, Stuart A Cook, Paul J R Barton, Daniel G MacArthur, James S Ware
bioRxiv 543504; doi: https://doi.org/10.1101/543504

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