Wang Jianxiu, Gao Qian
Department of Emergency Medicine, Shandong University, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Qingdao, China.
Turk J Gastroenterol. 2024 Dec 23;36(5):280-292. doi: 10.5152/tjg.2024.24326.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is considered the most widespread chronic liver condition globally. Genome-wide association studies (GWAS) have pinpointed several genetic loci correlated to MASLD, yet the biological significance of these loci remains poorly understood. Initially, we applied Functional Mapping and Annotation (FUMA) to conduct a functional annotation of the MASLD GWAS summary statistics, which included data from 3242 cases and 707 631 controls. Additionally, a MASLD transcriptome association study (TWAS) was conducted utilizing FUSION software in combination with the genotype-tissue expression project (GTEx-v8) expression weight set to identify susceptibility genes. Furthermore, to elucidate the observed correlations, we carried out conditional and joint analyses, probabilistic causal fine-mapping of TWAS signals, summary data-based Mendelian randomization (SMR), and phenome-wide association analyses. Following functional annotation analysis, we identified 4 genetic risk loci, annotated 6 lead single nucleotide polymorphisms (SNPs), 27 independent significant SNPs, and 511 candidate SNPs. TWAS also found four genes related to MASLD, including MAU2 sister chromatid cohesion factor (MAU2), EPH receptor A2 (EPHA2), GATA zinc finger domain containing 2A (GATAD2A), and transmembrane 6 superfamily member 2 (TM6SF2). Moreover, fine mapping of TWAS signatures identified 13 causal genes associated with MASLD that were located at 3 genetic risk loci, but SMR results could not rule out the possibility that the relationship between significant genes and MASLD was caused by a linkage disequilibrium structure. Our study found new significantly associated genes for MASLD and highlighted the ability of TWAS to identify and prioritize potentially pathogenic genes.
代谢功能障碍相关脂肪性肝病（MASLD）被认为是全球最普遍的慢性肝脏疾病。全基因组关联研究（GWAS）已确定了几个与MASLD相关的基因位点，但这些位点的生物学意义仍知之甚少。首先，我们应用功能映射和注释（FUMA）对MASLD的GWAS汇总统计数据进行功能注释，该数据包括3242例病例和707631例对照的数据。此外，利用FUSION软件结合基因型-组织表达项目（GTEx-v8）表达权重集进行了MASLD转录组关联研究（TWAS），以识别易感基因。此外，为了阐明观察到的相关性，我们进行了条件分析和联合分析、TWAS信号的概率因果精细定位、基于汇总数据的孟德尔随机化（SMR）以及全表型关联分析。经过功能注释分析，我们确定了4个遗传风险位点，注释了6个主要单核苷酸多态性（SNP）、27个独立的显著SNP和511个候选SNP。TWAS还发现了4个与MASLD相关的基因，包括MAU2姐妹染色单体黏连因子（MAU2）、EPH受体A2（EPHA2）、含GATA锌指结构域2A（GATAD2A）和跨膜6超家族成员2（TM6SF2）。此外，TWAS特征的精细定位确定了13个与MASLD相关的因果基因，这些基因位于3个遗传风险位点，但SMR结果不能排除显著基因与MASLD之间的关系是由连锁不平衡结构引起的可能性。我们的研究发现了与MASLD新的显著相关基因，并突出了TWAS识别和优先排序潜在致病基因的能力。
