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, Jake Francoeur Matthew, Velimirovic Minja, Gifford David K, Lettre Guillaume, Yu Haojie, Cassa Christopher A, Sherwood Richard I
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Precision Medicine Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
bioRxiv. 2023 Jan 10:2023.01.09.500804. doi: 10.1101/2023.01.09.500804.
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 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.
基因变异对低密度脂蛋白胆固醇（LDL-C）水平和冠状动脉疾病风险有很大影响。通过结合对英国生物银行中罕见编码变异的分析以及全基因组规模的CRISPR-Cas9基因敲除和激活筛选，我们显著改进了对那些其破坏会改变血清LDL-C水平的基因的识别。我们鉴定出21个基因，其中罕见编码变异至少部分通过改变LDL-C摄取而显著改变LDL-C水平。我们使用基于共必需性的基因模块分析来表明，RAB10囊泡运输途径的功能障碍通过损害表面LDL受体水平导致人类和小鼠的高胆固醇血症。此外，我们证明，[此处原文缺失基因名称]的功能丧失通过增加细胞LDL-C摄取导致小鼠和人类血清LDL-C水平大幅降低。总之，我们提出了一种综合方法，增进了我们对LDL-C水平遗传调节因子的理解，并为进一步剖析复杂人类疾病遗传学的努力提供了路线图。
