全基因组研究揭示肝脏脂肪含量的遗传风险因素

Yanni Li, Eline H van den Berg, Alexander Kurilshikov, Dasha V Zhernakova, Ranko Gacesa, Shixian Hu, Esteban A Lopera-Maya, Alexandra Zhernakova, Vincent E de Meijer, Serena Sanna, Robin P F Dullaart, Hans Blokzijl, Eleonora A M Festen, Jingyuan Fu, Rinse K Weersma
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引用次数: 0

摘要

代谢相关性脂肪肝(MAFLD)的遗传易感性复杂且特征不清。准确描述肝脏脂肪含量的遗传背景将有助于深入了解疾病的病因和风险因素的因果关系。我们对肝脏脂肪含量的两种无创定义进行了全基因组关联研究(GWAS):磁共振成像质子密度脂肪分数(MRI-PDFF)(16,050 名参与者)和脂肪肝指数(FLI)(388,701 名来自英国生物库(UKBB)的参与者)。对肝脏脂肪含量表型之间的遗传性、遗传重叠和相似性进行了分析,并在格罗宁根大学医学中心(UMCG)遗传学生命线倡议(UGLI)的 10,398 名参与者中进行了复制。对UKBB中MRI-PDFF的GWAS进行元分析,发现了5个具有统计学意义的基因位点,包括两个新的基因组位点,分别是CREB3L1(rs72910057-T,P=5.40E-09)和GCM1(rs1491489378-T,P=3.16E-09),以及3个以前报道过的基因位点:PNPLA3、TM6SF2 和 APOE。对UKBB的FLI进行的GWAS发现了196个全基因组显著位点,其中49个在UGLI中得到了复制,ZPR1(P = 3.35E-13)和FTO(P = 2.11E-09)的信号最强。MRI-PDFF(UKBB)和 FLI(UGLI)的 GWAS 结果之间存在统计学意义上的遗传相关性(rg)(rg = 0.5276,P = 1.45E-03)。新的 MRI-PDFF 遗传信号(CREB3L1 和 GCM1)在 FLI GWAS 中得到了复制。我们为 MRI-PDFF 确定了两个新基因,为 FLI 确定了 49 个可复制的基因位点。尽管 MRI-PDFF 和 FLI 在肝脏脂肪含量评估方面存在差异,但却发现了非常相似的遗传结构。FLI 被认为是在人群水平上研究肝脏脂肪含量的一种简单可靠的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genome-wide Studies Reveal Genetic Risk Factors for Hepatic Fat Content.

Genetic susceptibility to metabolic associated fatty liver disease (MAFLD) is complex and poorly characterized. Accurate characterization of the genetic background of hepatic fat content would provide insights into disease etiology and causality of risk factors. We performed genome-wide association study (GWAS) on two noninvasive definitions of hepatic fat content: magnetic resonance imaging proton density fat fraction (MRI-PDFF) in 16,050 participants and fatty liver index (FLI) in 388,701 participants from the United Kingdom (UK) Biobank (UKBB). Heritability, genetic overlap, and similarity between hepatic fat content phenotypes were analyzed, and replicated in 10,398 participants from the University Medical Center Groningen (UMCG) Genetics Lifelines Initiative (UGLI). Meta-analysis of GWASs of MRI-PDFF in UKBB revealed five statistically significant loci, including two novel genomic loci harboring CREB3L1 (rs72910057-T, P = 5.40E-09) and GCM1 (rs1491489378-T, P = 3.16E-09), respectively, as well as three previously reported loci: PNPLA3, TM6SF2, and APOE. GWAS of FLI in UKBB identified 196 genome-wide significant loci, of which 49 were replicated in UGLI, with top signals in ZPR1 (P = 3.35E-13) and FTO (P = 2.11E-09). Statistically significant genetic correlation (rg) between MRI-PDFF (UKBB) and FLI (UGLI) GWAS results was found (rg = 0.5276, P = 1.45E-03). Novel MRI-PDFF genetic signals (CREB3L1 and GCM1) were replicated in the FLI GWAS. We identified two novel genes for MRI-PDFF and 49 replicable loci for FLI. Despite a difference in hepatic fat content assessment between MRI-PDFF and FLI, a substantial similar genetic architecture was found. FLI is identified as an easy and reliable approach to study hepatic fat content at the population level.

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