Cited by 208Genetic Associations and EpidemiologyCRISPR and Genetic EngineeringGenomics and Chromatin Dynamics

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

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Morris, John A., Caragine, Christina, Daniloski, Zharko, Domingo, Júlia, Barry, Timothy, Lu, Lu, Davis, Kyrie, Ziosi, Marcello +8 more·2023·Science

Published version of a preprint

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 .

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Authors
Morris, J. A., Caragine, C., Daniloski, Z., Domingo, J., Barry, T., Lu, L., Davis, K., Ziosi, M., Glinos, D. A., Hao, S., Mimitou, E. P., Smibert, P., Roeder, K., Katsevich, E., Lappalainen, T., & Sanjana, N. E.
Affiliations
  • New York Genome Center (US)
  • Carnegie Mellon University (US)
  • University of Pennsylvania (US)
  • Science for Life Laboratory (SE)
Corresponding author
  • Lappalainen, Tuuli
  • Sanjana, Neville E.
Venue
Science
Published
2023-05-19
Volume
380
Issue
6646
Pages
eadh7699-eadh7699
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W4368347467
Cited by
208
References
133
Citations by year
2026: 54 · 2025: 61 · 2024: 66 · 2023: 20 · 2022: 3 · 2021: 3 · 2020: 1
FWCI
34.53
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Science Foundation (2113072)
  • Cancer Research Institute
  • American Heart Association (20POST35220040)
  • Sidney Kimmel Foundation
  • New York Genome Center (DP2HG010099)
  • York University
  • National Institutes of Health
  • Defense Advanced Research Projects Agency (D18AP00053)
  • Canadian Institutes of Health Research
  • National Institute of Mental Health (R01MH106842, R01MH123184)
  • National Human Genome Research Institute (UM1HG008901, K99HG012792, DP2HG010099)
  • National Cancer Institute (D18AP00053, R01CA279135, R01CA218668)
  • National Institute of General Medical Sciences (R01GM122924, R01GM138635)
  • National Institute of Allergy and Infectious Diseases (R01AI176601)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
non-coding variants, GWAS loci, blood characteristics, single-cell CRISPR screens, base editing, transcription factors, microRNA, polygenic traits, gene expression regulation, biobank-scale data
MeSH terms
RNA-Seq, Blood Cells, Disease, Humans, Genetic Predisposition to Disease, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Proteomics, Genome-Wide Association Study, Single-Cell Analysis, Clustered Regularly Interspaced Short Palindromic Repeats

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