| Title: | Systematic elucidation of genetic mechanisms underlying cholesterol uptake |
| Journal: | Cell Genomics |
| Published: | 21 Apr 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37228746/ |
| DOI: | https://doi.org/10.1016/j.xgen.2023.100304 |
Publication 11366
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Abstract
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.</p>
17 Authors
- Marisa C. Hamilton
- James D. Fife
- Ersin Akinci
- Tian Yu
- Benyapa Khowpinitchai
- Minsun Cha
- Sammy Barkal
- Thi Tun Thi
- Grace H.T. Yeo
- Juan Pablo Ramos Barroso
- Matthew Jake Francoeur
- Minja Velimirovic
- David K. Gifford
- Guillaume Lettre
- Haojie Yu
- Christopher A. Cassa
- Richard I. Sherwood
1 Application
| Application ID | Title |
|---|---|
| 41250 | Prioritizing Mendelian variants using GWAS and exome sequencing data |
Enabling scientific discoveries that improve human health