Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are biomarkers for liver health. Here we report the largest genome-wide association analysis to date of serum ALT and AST levels in over 388k people of European ancestry from UK biobank and DiscovEHR. Eleven million imputed markers with a minor allele frequency (MAF) ≥ 0.5% were analyzed. Overall, 300 ALT and 336 AST independent genome-wide significant associations were identified. Among them, 81 ALT and 61 AST associations are reported for the first time. Genome-wide interaction study identified 9 ALT and 12 AST independent associations significantly modified by body mass index (BMI), including several previously reported potential liver disease therapeutic targets, for example, PNPLA3, HSD17B13, and MARC1. While further work is necessary to understand the effect of ALT and AST-associated variants on liver disease, the weighted burden of significant BMI-modified signals is significantly associated with liver disease outcomes. In summary, this study identifies genetic associations which offer an important step forward in understanding the genetic architecture of serum ALT and AST levels. Significant interactions between BMI and genetic loci not only highlight the important role of adiposity in liver damage but also shed light on the genetic etiology of liver disease in obese individuals.

中文翻译：

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38.8 万名欧洲个体的血清丙氨酸和天冬氨酸转氨酶的全基因组关联分析以及 BMI 的改变作用

血清丙氨酸转氨酶 (ALT) 和天冬氨酸转氨酶 (AST) 是肝脏健康的生物标志物。在这里，我们报告了英国生物银行和 DiscovEHR 迄今为止最大的全基因组关联分析，对超过 388,000 名欧洲血统的人的血清 ALT 和 AST 水平进行了分析。分析了 1100 万个次要等位基因频率 (MAF) ≥ 0.5% 的估算标记。总体而言，确定了 300 个 ALT 和 336 个 AST 独立的全基因组显着关联。其中，81个ALT和61个AST关联为首次报道。全基因组相互作用研究确定了 9 个 ALT 和 12 个 AST 独立关联，这些关联受体重指数 (BMI) 的显着改变，包括几个先前报道的潜在肝病治疗靶点，例如 PNPLA3、HSD17B13和MARC1。虽然需要进一步的工作来了解 ALT 和 AST 相关变异对肝病的影响，但显着 BMI 改变信号的加权负担与肝病结果显着相关。总之，这项研究确定了遗传关联，为理解血清 ALT 和 AST 水平的遗传结构迈出了重要的一步。BMI 和基因位点之间的显着相互作用不仅凸显了肥胖在肝损伤中的重要作用，而且还揭示了肥胖个体肝病的遗传病因学。