Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens-Reference-Cited by-同舟云学术

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

Published:2023-05-19 Issue:6646 Volume:380 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Morris John A.¹²^ORCID,Caragine Christina¹²^ORCID,Daniloski Zharko¹²^ORCID,Domingo Júlia¹,Barry Timothy³,Lu Lu¹²^ORCID,Davis Kyrie¹²,Ziosi Marcello¹,Glinos Dafni A.¹^ORCID,Hao Stephanie⁴,Mimitou Eleni P.⁴^ORCID,Smibert Peter⁴^ORCID,Roeder Kathryn³⁵^ORCID,Katsevich Eugene⁶^ORCID,Lappalainen Tuuli¹⁷^ORCID,Sanjana Neville E.¹²^ORCID

Affiliation:

1. New York Genome Center, New York, NY 10013, USA.

2. Department of Biology, New York University, New York, NY 10003, USA.

3. Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.

4. Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA.

5. Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA.

6. Department of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, PA 19104, USA.

7. Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, 171 65 Solna, Stockholm, Sweden.

Abstract

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 .

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/science.adh7699

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