Systematic elucidation of genetic mechanisms underlying cholesterol uptake

  • bioRxiv. 2023 Jan 10:2023.01.09.500804. doi: 10.1101/2023.01.09.500804.
Marisa C Hamilton  1 ,  James D Fife  1 ,  Ersin Akinci  1 ,  Tian Yu  1 ,  Benyapa Khowpinitchai  1 ,  Minsun Cha  1 ,  Sammy Barkal  1 ,  Thi Tun Thi  2  3  4 ,  Grace H T Yeo  5 ,  Juan Pablo Ramos Barroso  1 ,  Matthew Jake Francoeur  1 ,  Minja Velimirovic  1 ,  David K Gifford  5  6 ,  Guillaume Lettre  7  8 ,  Haojie Yu  2  3  4 ,  Christopher A Cassa  1 ,  Richard I Sherwood  1
Affiliations
  • 1. Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 2. Precision Medicine Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 3. Cardiovascular Disease Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 4. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 5. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 6. Department of Biological Engineering, Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 7. Montreal Heart Institute, Montréal, Québec, H1T 1C8, Canada.
  • 8. Faculté de Médecine, Université de Montréal, Montréal, Québec, H3T 1J4, Canada.
PMID: 36711952 DOI: 10.1101/2023.01.09.500804
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 have substantially improved 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 genetic regulators of LDL-C levels and provides a roadmap for further efforts to dissect complex human disease genetics.

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