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Hamilton, Marisa C.; Fife, James D.; Akinci, Ersin; Yu, Tian; Khowpinitchai, Benyapa; Cha, Minsun; Barkal, Sammy; Thi, Thi Tun; Yeo, Grace H.T.; Ramos Barroso, Juan Pablo; Francoeur, Matthew Jake; Velimirovic, Minja; Gifford, David K.; Lettre, Guillaume; Yu, Haojie; Cassa, Christopher A.; Sherwood, Richard I.
Cell genomics, 05/2023, Letnik: 3, Številka: 5Journal Article
Genetic variation contributes greatly to LDL cholesterol (LDL-C) levels and coronary artery disease risk. By combining analysis of rare coding variants from the UK Biobank and genome-scale CRISPR-Cas9 knockout and activation screening, we substantially improve the identification of genes whose disruption alters serum LDL-C levels. We identify 21 genes in which rare coding variants significantly alter LDL-C levels at least partially through altered LDL-C uptake. We use co-essentiality-based gene module analysis to show that dysfunction of the RAB10 vesicle transport pathway leads to hypercholesterolemia in humans and mice by impairing surface LDL receptor levels. Further, we demonstrate that loss of function of OTX2 leads to robust reduction in serum LDL-C levels in mice and humans by increasing cellular LDL-C uptake. Altogether, we present an integrated approach that improves our understanding of the genetic regulators of LDL-C levels and provides a roadmap for further efforts to dissect complex human disease genetics. Display omitted •Genome-scale CRISPR screens identify 490 genes that alter liver cell LDL-C uptake•21 LDL-C uptake-altering genes enriched in rare coding variants in UK Biobank exomes•Dysfunction in the RAB10 exocytosis pathway raises LDL-C levels in mice and humans•OTX2 loss of function robustly reduces serum LDL-C in mice and humans By combining analysis of rare coding variants from the UK Biobank and genome-scale CRISPR-Cas9 knockout and activation screening, Hamilton et al. improve the identification of genes whose disruption alters serum LDL-C levels. They show that RAB10 vesicle transport pathway dysfunction leads to hypercholesterolemia and that OTX2 disruption reduces serum LDL-C levels.
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in: SICRIS
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