Liu Zhenqiu, Chen Xiaochen, Yuan Huangbo, Jin Li, Zhang Tiejun, Chen Xingdong
State Key Laboratory of Genetic Engineering and Human Phenome Institute, Fudan University, 825 Zhangheng RD, Pudong New Area, Shanghai 201203, China.
Fudan University Taizhou Institute of Health Sciences, 799 Yaocheng RD, Taizhou 225316, China.
Hum Mol Genet. 2025 Feb 8;34(4):338-346. doi: 10.1093/hmg/ddae184.
Observational studies have reported a bidirectional correlation between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), but the shared genetic basis between the two conditions remains unclear. Using genome-wide association study (GWAS) summary data from European-ancestry populations, we examined the cross-trait genetic correlation and identified genomic overlaps and shared risk loci. We employed a latent causal variable model and Mendelian randomization (MR) analysis to infer causal relationships. Colocalization analysis and conditional/conjunctional false discovery rate (condFDR/conjFDR) were used to identify genomic overlaps and shared risk loci. Two-step MR analysis was utilized to identify potential mediators. We observed a strong positive genomic correlation between NAFLD and T2D (rg = 0.652, P = 5.67 × 10-6) and identified tissue-specific transcriptomic correlations in the pancreas, liver, skeletal muscle, subcutaneous adipose, and blood. Genetic enrichment was observed in NAFLD conditional on associations with T2D and vice versa, indicating significant polygenic overlaps. We found robust evidence for the causal effect of NAFLD on T2D, particularly insulin-related T2D, rather than vice versa. Colocalization analysis identified shared genomic regions between NAFLD and T2D, including GCKR, FTO, MAU2-TM6SF2, and PNPLA3-SAMM50. High-density lipoprotein cholesterol and insulin were partly mediated the association between NAFLD and T2D. These findings unveil a close genetic link between NAFLD and T2D, shedding light on the biological mechanisms connecting NAFLD progression to T2D.
观察性研究报告了非酒精性脂肪性肝病（NAFLD）与2型糖尿病（T2D）之间的双向相关性，但这两种疾病之间共享的遗传基础仍不清楚。利用欧洲血统人群的全基因组关联研究（GWAS）汇总数据，我们检测了跨性状遗传相关性，并确定了基因组重叠区域和共享风险位点。我们采用潜在因果变量模型和孟德尔随机化（MR）分析来推断因果关系。共定位分析以及条件/联合错误发现率（condFDR/conjFDR）用于识别基因组重叠区域和共享风险位点。利用两步MR分析来识别潜在的中介因素。我们观察到NAFLD与T2D之间存在很强的正向基因组相关性（rg = 0.652，P = 5.67×10−6），并在胰腺、肝脏、骨骼肌、皮下脂肪和血液中确定了组织特异性转录组相关性。在以与T2D的关联为条件的NAFLD中观察到遗传富集，反之亦然，这表明存在显著的多基因重叠。我们发现了有力证据支持NAFLD对T2D，特别是胰岛素相关T2D的因果效应，而非相反。共定位分析确定了NAFLD与T2D之间的共享基因组区域，包括GCKR、FTO、MAU2-TM6SF2和PNPLA3-SAMM50。高密度脂蛋白胆固醇和胰岛素部分介导了NAFLD与T2D之间的关联。这些发现揭示了NAFLD与T2D之间紧密的遗传联系，为连接NAFLD进展与T2D的生物学机制提供了线索。
