Drug-induced liver injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market; this is partially due to the inability to identify patients who are at risk¹. In this study, we developed a polygenic risk score (PRS) for DILI by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies². The PRS predicted the susceptibility to DILI in patients treated with fasiglifam, amoxicillin–clavulanate or flucloxacillin and in primary hepatocytes and stem cell-derived organoids from multiple donors treated with over ten different drugs. Pathway analysis highlighted processes previously implicated in DILI, including unfolded protein responses and oxidative stress. In silico screening identified compounds that elicit transcriptomic signatures present in hepatocytes from individuals with elevated PRS, supporting mechanistic links and suggesting a novel screen for safety of new drug candidates. This genetic-, cellular-, organoid- and human-scale evidence underscored the polygenic architecture underlying DILI vulnerability at the level of hepatocytes, thus facilitating future mechanistic studies. Moreover, the proposed ‘polygenicity-in-a-dish’ strategy might potentially inform designs of safer, more efficient and robust clinical trials.

药物性肝损伤 (DILI) 是导致药物开发计划终止和药物退出市场的主要原因；这部分是由于无法识别有风险的患者¹。在这项研究中，我们通过汇总先前大规模全基因组关联研究中确定的众多全基因组位点的影响，开发了 DILI 的多基因风险评分 (PRS) ². PRS 预测了接受法西格列、阿莫西林-克拉维酸或氟氯西林治疗的患者，以及用十多种不同药物治疗的多个供体的原代肝细胞和干细胞衍生的类器官对 DILI 的易感性。通路分析强调了先前涉及 DILI 的过程，包括未折叠蛋白反应和氧化应激。计算机筛选确定了可在 PRS 升高的个体的肝细胞中引发转录组学特征的化合物，支持机制联系并建议对新候选药物的安全性进行新筛选。这种遗传、细胞、类器官和人类尺度的证据强调了肝细胞水平上 DILI 脆弱性的多基因结构，从而促进了未来的机制研究。而且，