Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen 9713 GZ, The Netherlands.
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713 GZ, The Netherlands.
Genomics Proteomics Bioinformatics. 2024 Jul 3;22(2). doi: 10.1093/gpbjnl/qzae031.
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.
遗传易感性与代谢相关脂肪性肝病（MAFLD）之间的关系复杂且尚未明确。准确描述肝内脂肪含量的遗传背景，将有助于深入了解疾病的病因学和风险因素的因果关系。我们对两种非侵入性肝内脂肪含量定义进行了全基因组关联研究（GWAS）：英国生物银行（UKBB）中 16050 名参与者的磁共振成像质子密度脂肪分数（MRI-PDFF）和 388701 名参与者的脂肪肝指数（FLI）。分析了肝内脂肪含量表型的遗传率、遗传重叠和相似性，并在格罗宁根大学医学中心遗传学生命线倡议（UGLI）的 10398 名参与者中进行了复制。UKBB 中 MRI-PDFF 的 GWAS 元分析显示，有五个统计学上显著的基因座，包括两个包含 CREB3L1（rs72910057-T，P = 5.40E-09）和 GCM1（rs1491489378-T，P = 3.16E-09）的新型基因组基因座，以及三个先前报道的基因座：PNPLA3、TM6SF2 和 APOE。UKBB 中 FLI 的 GWAS 确定了 196 个全基因组显著基因座，其中 49 个在 UGLI 中得到复制，ZPR1（P = 3.35E-13）和 FTO（P = 2.11E-09）的信号最强。发现 UKBB 的 MRI-PDFF（GWAS）和 UGLI 的 FLI（GWAS）结果之间存在统计学上显著的遗传相关性（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。我们确定了两个新的 MRI-PDFF 基因座和 49 个可复制的 FLI 基因座。尽管 MRI-PDFF 和 FLI 之间肝内脂肪含量的评估存在差异，但发现了大量相似的遗传结构。FLI 被确定为一种简单而可靠的方法，可用于在人群水平上研究肝内脂肪含量。
