Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic alanine aminotransferase elevation (cALT) without other liver diseases, we performed a trans-ancestry genome-wide association study in the Million Veteran Program including 90,408 cALT cases and 128,187 controls. In the Discovery stage, seventy-seven loci exceeded genome-wide significance – including 25 without prior NAFLD or ALT associations – with one additional locus identified in European-American-only and two in African-American-only analyses (P<5×10^-8). External replication in cohorts with NAFLD defined by histology (7,397 cases, 56,785 controls) or liver fat extracted from radiologic imaging (n=44,289) validated 17 SNPs (P<6.5×10^-4) of which 9 were novel (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH, and IFI30). Pleiotropy analysis showed that 61 of 77 trans-ancestry and all 17 validated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.

中文翻译：

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一项将不明原因的慢性 ALT 升高作为非酒精性脂肪肝疾病代理的跨血统全基因组关联研究，并经组织学和放射学验证

非酒精性脂肪性肝病 (NAFLD) 是导致慢性肝病的一个日益严重的原因。使用无其他肝脏疾病的慢性丙氨酸氨基转移酶升高 (cALT) 的代理 NAFLD 定义，我们在百万退伍军人计划中进行了跨血统全基因组关联研究，包括 90,408 例 cALT 病例和 128,187 例对照。在发现阶段，77 个基因座超过了全基因组的显着性——包括 25 个没有先前 NAFLD 或 ALT 关联的基因座——仅在欧洲裔美国人中发现了一个额外的基因座，在非裔美国人的分析中发现了两个（P<5×10 ^-8）。由组织学定义的 NAFLD 队列（7,397 例，56,785 名对照）或从放射成像中提取的肝脏脂肪（n = 44,289）中的外部复制验证了 17 个 SNP（P<6.5×10 ^-4) 其中 9 个是新的（TRIB1、PPARG、MTTP、SERPINA1、FTO、IL1RN、COBLL1、APOH和IFI30）。多效性分析表明，77 个跨血统中的 61 个和所有 17 个经过验证的 SNP 与代谢和/或炎症特征共同相关，揭示了遗传结构的复杂模型。我们整合 cALT、组织学和成像的方法揭示了对 NAFLD 遗传责任的新见解。