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

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Morris, John A.New York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA (author)

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

Article/chapterEnglish2023

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American Association for the Advancement of Science (AAAS),2023
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LIBRIS-ID:oai:DiVA.org:kth-342543
https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-342543URI
https://doi.org/10.1126/science.adh7699DOI

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Language:English
Summary in:English

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QC 20240124
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 and genre

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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Caragine, ChristinaNew York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA (author)
Daniloski, ZharkoNew York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA (author)
Domingo, JúliaNew York Genome Center, New York, NY 10013, USA (author)
Barry, TimothyDepartment of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA (author)
Lu, LuNew York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA (author)
Davis, KyrieNew York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA (author)
Ziosi, MarcelloNew York Genome Center, New York, NY 10013, USA (author)
Glinos, Dafni A.New York Genome Center, New York, NY 10013, USA (author)
Hao, StephanieTechnology Innovation Lab, New York Genome Center, New York, NY 10013, USA (author)
Mimitou, Eleni P.Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA (author)
Smibert, PeterTechnology Innovation Lab, New York Genome Center, New York, NY 10013, USA (author)
Roeder, KathrynDepartment of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA (author)
Katsevich, EugeneDepartment of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, PA 19104, USA (author)
Lappalainen, TuuliKTH,Genteknologi,Science for Life Laboratory, SciLifeLab,New York Genome Center, New York, NY 10013, USA(Swepub:kth)u1o81n30 (author)
Sanjana, Neville E.New York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA (author)
New York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USANew York Genome Center, New York, NY 10013, USA (creator_code:org_t)

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In:Science: American Association for the Advancement of Science (AAAS)380:66460036-80751095-9203

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By the author/editor: Morris, John A.; Caragine, Christ ...; Daniloski, Zhark ...; Domingo, Júlia; Barry, Timothy; Lu, Lu; show more...; Davis, Kyrie; Ziosi, Marcello; Glinos, Dafni A.; Hao, Stephanie; Mimitou, Eleni P ...; Smibert, Peter; Roeder, Kathryn; Katsevich, Eugen ...; Lappalainen, Tuu ...; Sanjana, Neville ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medical Genetics

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Genetics

Articles in the publication: Science

By the university: Royal Institute of Technology

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