Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver diseases in high-income countries and the burden of NAFLD is increasing at an alarming rate. The risk of developing NAFLD and related complications is highly variable among individuals and is determined by environmental and genetic factors. Genome-wide association studies have uncovered robust and reproducible associations between variations in genes such as PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13 and the natural history of NAFLD. These findings have provided compelling new insight into the biology of NAFLD and highlighted potential attractive pharmaceutical targets. More recently the development of polygenic risk scores, which have shown promising results in clinical risk prediction in other complex traits such as cardiovascular disease and breast cancer, has provided new impetus for the clinical validation of genetic variants in NAFLD risk stratification. Here we review the current knowledge on the genetic architecture of NAFLD, including gene-environment interactions, and discuss the implications and limitations of the current knowledge on NAFLD risk variants on disease pathobiology, drug discovery and risk prediction. We particularly focus on the potential clinical translation of recent genetic, discussing methodological hurdles that will have to be tackled before these discoveries are implemented in everyday practice.

中文翻译：

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NAFLD 遗传学更新：从新变异到临床

非酒精性脂肪性肝病 (NAFLD) 是高收入国家肝脏疾病的主要原因，并且 NAFLD 的负担正以惊人的速度增加。发生 NAFLD 和相关并发症的风险因人而异，并由环境和遗传因素决定。全基因组关联研究发现，PNPLA3、TM6SF2、MBOAT7、GCKR、HSD17B13 等基因变异与 NAFLD 的自然史之间存在强大且可重复的关联。这些发现为 NAFLD 的生物学提供了令人信服的新见解，并突出了潜在的有吸引力的药物靶点。最近，多基因风险评分的发展，在心血管疾病和乳腺癌等其他复杂特征的临床风险预测中显示出有希望的结果，为 NAFLD 风险分层中遗传变异的临床验证提供了新的动力。在这里，我们回顾了关于 NAFLD 遗传结构的当前知识，包括基因-环境相互作用，并讨论了当前关于 NAFLD 风险变异的知识对疾病病理学、药物发现和风险预测的影响和局限性。我们特别关注最近遗传学的潜在临床转化，讨论在这些发现在日常实践中实施之前必须解决的方法学障碍。并讨论当前关于 NAFLD 风险变异的知识对疾病病理学、药物发现和风险预测的影响和局限性。我们特别关注最近遗传学的潜在临床转化，讨论在这些发现在日常实践中实施之前必须解决的方法学障碍。并讨论当前关于 NAFLD 风险变异的知识对疾病病理学、药物发现和风险预测的影响和局限性。我们特别关注最近遗传学的潜在临床转化，讨论在这些发现在日常实践中实施之前必须解决的方法学障碍。