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Abstract：
Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10-8 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10-11 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
摘要：
全基因组关联研究（GWAS）已经确定了非酒精性脂肪性肝病（NAFLD）的几个风险位点。以前的研究在很大程度上依赖于小样本量，并评估了数量性状。我们在英国生物银行进行了病例对照GWAS，根据最近的共识指南中推荐的诊断代码，使用记录的NAFLD诊断。我们对4,761例NAFLD和373,227例没有NAFLD证据的健康对照进行了GWAS。敏感性分析排除其他共存的肝脏病理，调整体重指数（BMI）和调整酒精摄入量。通过调整年龄的逻辑回归评估了总共9,723,654种变体，性别,遗传主成分，和基因分型批次。我们使用可用的汇总关联统计数据进行了GWAS荟萃分析。确定了六个风险位点(P<5*10-8)(载脂蛋白E[APOE]，含patatatin样磷脂酶结构域3[PNPLA3，跨膜6超家族成员2[TM6SF2]，葡萄糖激酶调节因子[GCKR]，线粒体成胺肟还原成分1[MARC1]，和摩擦假激酶1[TRIB1])。在敏感性分析中，所有基因座均保留了显著性，而没有共存的肝脏病理学以及在调整BMI后。PNPLA3和TM6SF2在调整酒精后仍然很重要（只有158,388个人知道酒精摄入量），其他人表现出一致的方向和效果。在荟萃分析中，所有六个基因座均具有统计学意义。Rs429358（P=2.17*10-11）是APOE基因内的错义变异体，决定了ε4与ε2/ε3等位基因。APOE的ε4等位基因提供针对NAFLD的保护（杂合子的比值比0.84[95％置信区间0.78-0.90]和纯合子0.64[0.50-0.79]）。结论：该GWAS复制了六个已知的NAFLD易感性基因座，并证实APOE的ε4等位基因与针对NAFLD的保护相关。结果与发表的GWAS使用NAFLD的组织学和放射学测量结果一致，确认通过共识指南中的诊断代码识别的NAFLD是更具侵入性和成本更高的方法的有效替代方法。
