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Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens

Morris, John A. (author)
New York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA
Caragine, Christina (author)
New York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA
Daniloski, Zharko (author)
New York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA
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Domingo, Júlia (author)
New York Genome Center, New York, NY 10013, USA
Barry, Timothy (author)
Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
Lu, Lu (author)
New York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA
Davis, Kyrie (author)
New York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA
Ziosi, Marcello (author)
New York Genome Center, New York, NY 10013, USA
Glinos, Dafni A. (author)
New York Genome Center, New York, NY 10013, USA
Hao, Stephanie (author)
Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA
Mimitou, Eleni P. (author)
Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA
Smibert, Peter (author)
Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA
Roeder, Kathryn (author)
Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA
Katsevich, Eugene (author)
Department of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, PA 19104, USA
Lappalainen, Tuuli (author)
KTH,Genteknologi,Science for Life Laboratory, SciLifeLab,New York Genome Center, New York, NY 10013, USA
Sanjana, Neville E. (author)
New York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA
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 (creator_code:org_t)
American Association for the Advancement of Science (AAAS), 2023
2023
English.
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6646
Related links:
https://urn.kb.se/re...
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https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Most variants associated with complex traits and diseases identified by genome-wide association studies (GWAS) map to noncoding regions of the genome with unknown effects. Using ancestrally diverse, biobank-scale GWAS data, massively parallel CRISPR screens, and single-cell transcriptomic and proteomic sequencing, we discovered 124 cis-target genes of 91 noncoding blood trait GWAS loci. Using precise variant insertion through base editing, we connected specific variants with gene expression changes. We also identified trans-effect networks of noncoding loci when cis target genes encoded transcription factors or microRNAs. Networks were themselves enriched for GWAS variants and demonstrated polygenic contributions to complex traits. This platform enables massively parallel characterization of the target genes and mechanisms of human noncoding variants in both cis and trans.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)
NATURVETENSKAP  -- Biologi -- Genetik (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Genetics (hsv//eng)

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