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Discovery of target genes and pathways of blood trait loci using pooled CRISPR screens and single cell RNA sequencing

View ORCID ProfileJohn A. Morris, View ORCID ProfileZharko Daniloski, View ORCID ProfileJúlia Domingo, Timothy Barry, Marcello Ziosi, View ORCID ProfileDafni A. Glinos, Stephanie Hao, View ORCID ProfileEleni P. Mimitou, View ORCID ProfilePeter Smibert, View ORCID ProfileKathryn Roeder, View ORCID ProfileEugene Katsevich, View ORCID ProfileTuuli Lappalainen, View ORCID ProfileNeville E. Sanjana
doi: https://doi.org/10.1101/2021.04.07.438882
John A. Morris
1New York Genome Center, New York, USA
2Department of Biology, New York University, New York, USA
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Zharko Daniloski
1New York Genome Center, New York, USA
2Department of Biology, New York University, New York, USA
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Júlia Domingo
1New York Genome Center, New York, USA
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Timothy Barry
3Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, USA
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Marcello Ziosi
1New York Genome Center, New York, USA
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Dafni A. Glinos
1New York Genome Center, New York, USA
4Department of Systems Biology, Columbia University, New York, USA
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Stephanie Hao
5Technology Innovation Lab, New York Genome Center, New York, USA
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Eleni P. Mimitou
5Technology Innovation Lab, New York Genome Center, New York, USA
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Peter Smibert
5Technology Innovation Lab, New York Genome Center, New York, USA
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Kathryn Roeder
3Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, USA
6Computational Biology Department, Carnegie Mellon University, Pittsburgh, USA
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Eugene Katsevich
7Department of Statistics, Wharton School, University of Pennsylvania, Philadelphia, USA
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Tuuli Lappalainen
1New York Genome Center, New York, USA
4Department of Systems Biology, Columbia University, New York, USA
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  • For correspondence: tlappalainen@nygenome.org nsanjana@nygenome.org
Neville E. Sanjana
1New York Genome Center, New York, USA
2Department of Biology, New York University, New York, USA
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  • ORCID record for Neville E. Sanjana
  • For correspondence: tlappalainen@nygenome.org nsanjana@nygenome.org
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Abstract

The majority of variants associated with complex traits and common diseases identified by genome-wide association studies (GWAS) map to noncoding regions of the genome with unknown regulatory effects in cis and trans. By leveraging biobank-scale GWAS data, massively parallel CRISPR screens and single cell transcriptome sequencing, we discovered target genes of noncoding variants for blood trait loci. The closest gene was often the target gene, but this was not always the case. We also identified trans-effects networks of noncoding variants when cis target genes encoded transcription factors, such as GFI1B and NFE2. We observed that GFI1B trans-target genes were enriched for GFI1B binding sites and fine-mapped GWAS variants, and expressed in human bone marrow progenitor cells, suggesting that GFI1B acts as a master regulator of blood traits. This platform will enable massively parallel assays to catalog the target genes of human noncoding variants in both cis and trans.

Competing Interest Statement

N.E.S. is an advisor to Vertex. T.L. is an advisor to Goldfinch Bio and GSK and, with equity, Variant Bio.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 08, 2021.
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Discovery of target genes and pathways of blood trait loci using pooled CRISPR screens and single cell RNA sequencing
John A. Morris, Zharko Daniloski, Júlia Domingo, Timothy Barry, Marcello Ziosi, Dafni A. Glinos, Stephanie Hao, Eleni P. Mimitou, Peter Smibert, Kathryn Roeder, Eugene Katsevich, Tuuli Lappalainen, Neville E. Sanjana
bioRxiv 2021.04.07.438882; doi: https://doi.org/10.1101/2021.04.07.438882
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Discovery of target genes and pathways of blood trait loci using pooled CRISPR screens and single cell RNA sequencing
John A. Morris, Zharko Daniloski, Júlia Domingo, Timothy Barry, Marcello Ziosi, Dafni A. Glinos, Stephanie Hao, Eleni P. Mimitou, Peter Smibert, Kathryn Roeder, Eugene Katsevich, Tuuli Lappalainen, Neville E. Sanjana
bioRxiv 2021.04.07.438882; doi: https://doi.org/10.1101/2021.04.07.438882

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