Hua Yibo, Huang Zhengkai, Yin Yu, Song Rijin, Meng Xianghu
Department of Urology, The First Afffliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, 210029, PR China.
Department of Urology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, PR China.
Biochem Biophys Rep. 2025 Jun 28;43:102116. doi: 10.1016/j.bbrep.2025.102116. eCollection 2025 Sep.
Our study aims to investigate the shared genetic architecture between kidney and ureteral stones (KUS) and cardiovascular diseases (CVDs), as well as metabolic syndrome (MetS), and explore the shared risk loci, potentially critical tissues and relevant genetic mechanisms.
Dependent on large-scale genome-wide association study (GWAS) summary-level data sets, we observed genetic correlations between KUS and CVDs, as well as MetS, and cross-diseases pleiotropic analysis was conducted to identify shared pleiotropic loci and genes. Furthermore, we performed functional annotation and tissue-specific analysis to detect potential relationships between complex traits. We performed heritability enrichment analysis to determine potentially critical tissues. At last, we investigate the causal effects between KUS and other traits using bidirectional Mendelian randomization (MR).
Our findings underlined shared genetic architecture between three CVDs, two MetS and KUS. We identified 937 pleiotropic loci at the genome-wide significance level (p < 5 × 10), 35 of which were annotated as genomic risk loci. Among them, 4 had strong evidence of colocalization (PP.H4 > 0.7). In addition, a total of 163 unique pleiotropic genes (pFDR <0.05) were recognized at the gene level, including FTO, NEK4, GNL3, GLT8D1, SMIM4, PBRM1 and TFAP2B. Pathway analysis illustrated the essential biological process including metabolic processes, transcriptional regulation processes, transmembrane transport of drugs, and cardiac structure development were involved in these diseases. Analysis of tissue enrichment at single nucleotide polymorphism (SNP) level and gene level indicated pleiotropic mechanisms may engage in prostate, pancreas, adipose subcutaneous, and muscle skeletal. HyPrColoc method and metabolite enrichment analysis revealed tryptophan metabolism might be a crucial shared metabolic pathway in two different diseases. At last, bidirectional MR analysis demonstrated no strong evidence of causal associations between KUS and CVDs, as well as MetS.
Our study determined shared genetic architecture between KUS and CVDs, as well as MetS, and unraveled underlying genetic mechanisms.
我们的研究旨在调查肾结石和输尿管结石（KUS）与心血管疾病（CVD）以及代谢综合征（MetS）之间的共同遗传结构，探索共同的风险位点、潜在的关键组织和相关的遗传机制。
基于大规模全基因组关联研究（GWAS）汇总水平数据集，我们观察了KUS与CVD以及MetS之间的遗传相关性，并进行跨疾病多效性分析以确定共同的多效性位点和基因。此外，我们进行了功能注释和组织特异性分析，以检测复杂性状之间的潜在关系。我们进行了遗传力富集分析，以确定潜在的关键组织。最后，我们使用双向孟德尔随机化（MR）研究KUS与其他性状之间的因果关系。
我们的研究结果强调了三种CVD、两种MetS和KUS之间的共同遗传结构。我们在全基因组显著性水平（p < 5×10）上确定了937个多效性位点，其中35个被注释为基因组风险位点。其中，4个有强烈的共定位证据（PP.H4 > 0.7）。此外，在基因水平上共识别出163个独特的多效性基因（pFDR < 0.05），包括FTO、NEK4、GNL3、GLT8D1、SMIM4、PBRM1和TFAP2B。通路分析表明，这些疾病涉及的基本生物学过程包括代谢过程、转录调控过程、药物跨膜转运和心脏结构发育。在单核苷酸多态性（SNP）水平和基因水平上的组织富集分析表明，多效性机制可能涉及前列腺、胰腺、皮下脂肪和骨骼肌。HyPrColoc方法和代谢物富集分析表明，色氨酸代谢可能是两种不同疾病中一个关键的共同代谢途径。最后，双向MR分析表明，没有强有力的证据表明KUS与CVD以及MetS之间存在因果关联。
我们的研究确定了KUS与CVD以及MetS之间的共同遗传结构，并揭示了潜在的遗传机制。
