To investigate mechanisms of hepatocellular damage, we performed genome-wide association studies (GWAS) on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities across 411,048 subjects from four ancestry groups in the UK Biobank, and found 100 loci associating with both enzymes. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with a larger elevation in ALT and AST than any other variant tested and this association also replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These associations suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

中文翻译：

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血清ALT和AST的GWAS显示SLC30A10 Thr95Ile与高锰血症症状相关

为了研究肝细胞损伤的机制，我们对英国生物库中四个血统的411,048名受试者的丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）血清活性进行了全基因组关联研究（GWAS），发现了100个与这两个关联的位点酶。稀有的错义变体SLC30A10 Thr95Ile（rs188273166）与ALT和AST升高的关联性高于所测试的任何其他变异体，这种关联在DiscovEHR研究中也得到了证实。SLC30A10将锰从肝脏排泄到胆管，罕见的纯合子功能丧失导致伴有肌张力障碍1的高锰血症综合征（HMNDYT1），涉及肝硬化。与高锰血症的血液学症状一致，SLC30A10Thr95Ile携带者的血细胞比容和铁缺乏性贫血的风险增加。携带者也有增加肝外胆管癌的风险。这些关联表明，与诊断为HMNDYT1的患者相比，SLC30A10的遗传变异对更多个体的不利影响。