肾脏和输尿管结石、心血管疾病和代谢综合征的遗传结构和机制：一项全面的GWAS分析

IF 2.2 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports Pub Date : 2025-06-28 DOI:10.1016/j.bbrep.2025.102116

Yibo Hua , Zhengkai Huang , Yu Yin , Rijin Song , Xianghu Meng

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引用次数: 0

摘要

本研究旨在探讨肾脏和输尿管结石（KUS）与心血管疾病（cvd）和代谢综合征（MetS）之间的共同遗传结构，并探讨其共同的风险位点、潜在的关键组织和相关的遗传机制。方法基于大规模全基因组关联研究（GWAS）的汇总数据集，我们观察了KUS和cvd以及MetS之间的遗传相关性，并进行了跨疾病多效性分析，以确定共享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。我们进行遗传力富集分析以确定潜在的关键组织。最后，采用双向孟德尔随机化（MR）研究了KUS与其他性状之间的因果关系。结果3例cvd、2例MetS和KUS具有共同的遗传结构。我们在全基因组显著性水平上鉴定出937个多效位点(p <；5 × 10−8)，其中35个标记为基因组风险位点。其中4个具有较强的共地证据(PP.H4 >；0.7)。此外，在基因水平上共识别出163个独特的多性基因（pFDR <0.05），包括FTO、NEK4、GNL3、GLT8D1、SMIM4、PBRM1和TFAP2B。途径分析表明，代谢过程、转录调节过程、药物跨膜转运和心脏结构发育等重要生物学过程参与了这些疾病的发生。单核苷酸多态性水平和基因水平的组织富集分析表明，多效性机制可能涉及前列腺、胰腺、脂肪、皮下和肌肉骨骼。HyPrColoc方法和代谢物富集分析显示，色氨酸代谢可能是两种不同疾病的重要共享代谢途径。最后，双向MR分析显示KUS与cvd和MetS之间没有强有力的因果关系。结论sour研究确定了KUS和cvd以及MetS之间的共同遗传结构，并揭示了潜在的遗传机制。

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Genetic architecture and mechanisms shared between kidney and ureteral stones, cardiovascular diseases, and metabolic syndrome: A comprehensive GWAS analysis

Background

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.

Methods

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).

Results

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 × 10⁻⁸), 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.

Conclusions

Our study determined shared genetic architecture between KUS and CVDs, as well as MetS, and unraveled underlying genetic mechanisms.

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来源期刊

Biochemistry and Biophysics Reports Biochemistry, Genetics and Molecular Biology-Biophysics

CiteScore

4.60

自引率

0.00%

发文量

191

审稿时长

59 days

期刊介绍： Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.