Genomic Structural Equation Modeling Reveals Cardiovascular-Kidney-Metabolic Syndrome Genetic Architecture

IF 5.9 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes Pub Date : 2026-04-13 DOI:10.1111/1753-0407.70225

Chuanlong Lu, Lizheng Li, Jinshan Chen, Runze Chang, Honglin Dong

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Abstract

Background

The genetic basis of cardiovascular-kidney-metabolic syndrome (CKMs) involves complex pleiotropy, necessitating analytical approaches capable of dissecting shared genetic architectures across multiple cardiometabolic traits.

Methods

We employed genomic structural equation modeling (genomic SEM) to integrate summary statistics from six cardiometabolic traits. The model was assessed using standard fit indices. Genome-wide association analyses were performed on 1,862,425 SNPs under stringent quality control measures, with LD Score regression applied to evaluate polygenic heritability and confounding bias. Novel loci were identified using GWAS-by-Subtraction. Functional characterization included transcriptome-wide association analysis (TWAS), fine-mapping, pathway enrichment analysis, and cell-type specificity analysis.

Results

The genomic SEM model demonstrated excellent fit (CFI = 0.99, SRMR = 0.14). Quality control metrics confirmed that genomic inflation (Lambda GC = 1.591) was primarily attributable to polygenic heritability (h² = 0.3286 ± 0.0135) rather than population stratification (Intercept = 1.0176 ± 0.0169). This framework identified 2,212 significantly associated variants, encompassing 32 novel loci discovered via GWAS-by-Subtraction. Functional annotation indicated that the majority of these loci were located in intronic (57.92%) or intergenic (30.6%) regions. TWAS and fine-mapping nominated 188 high-confidence genes; SENP2 (TWAS Z = 12.5), KIF11 (Z = 11.5), and JAZF1 (Z = 11.38) exhibited the strongest positive associations with CKMs risk, whereas TCF7L2 (Z = −13.4) demonstrated the strongest inverse association. Pathway enrichment implicated lipid balance and ubiquitin-mediated proteolysis, and cell-type specificity analysis prominently localized genetic signals to pancreatic islet cells. Fine-mapping prioritized 18 causal variants with posterior probability ⟩ 0.95, including key signals within GCKR (rs1260333, rs780093) and INADL (rs2481665). Chromosomal regions 7 and 12 exhibited significant contributions.

Conclusions

Our study unravels the shared genetic architecture of CKMs, revealing novel risk loci and pathogenic mechanisms. The results establish a direct cellular link between the pleiotropic genetic basis of CKMs and endocrine metabolic regulation within pancreatic islets.

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基因组结构方程模型揭示了心血管-肾脏-代谢综合征的遗传结构

心血管-肾脏代谢综合征（CKMs）的遗传基础涉及复杂的多效性，需要能够在多个心脏代谢特征中解剖共享遗传结构的分析方法。方法采用基因组结构方程模型（genomic structure equation modeling， SEM）对6个心脏代谢性状进行汇总统计。采用标准拟合指标对模型进行评价。在严格的质量控制措施下，对1,862,425个snp进行全基因组关联分析，并应用LD评分回归评估多基因遗传性和混杂偏倚。利用gwas -by- subtract法鉴定新的基因座。功能表征包括转录组全关联分析（TWAS）、精细定位、途径富集分析和细胞类型特异性分析。结果基因组SEM模型拟合良好（CFI = 0.99, SRMR = 0.14）。质量控制指标证实，基因组膨胀（Lambda GC = 1.591）主要归因于多基因遗传力（h2 = 0.3286±0.0135），而非群体分层（截距= 1.0176±0.0169）。该框架确定了2212个显著相关的变异，包括通过gwas -by- traction发现的32个新位点。功能注释表明，这些基因座大部分位于内含子区（57.92%）或基因间区（30.6%）。TWAS和精细定位提名188个高置信度基因；SENP2 （TWAS Z = 12.5）、KIF11 （Z = 11.5）和JAZF1 （Z = 11.38）与CKMs风险表现出最强的正相关，而TCF7L2 （Z = - 13.4）表现出最强的负相关。途径富集涉及脂质平衡和泛素介导的蛋白水解，细胞类型特异性分析突出地将遗传信号定位到胰岛细胞。精细映射优先考虑18个因果变异，后验概率⟩0.95，包括GCKR （rs1260333, rs780093）和INADL （rs2481665）中的关键信号。染色体7区和12区有显著贡献。我们的研究揭示了ckm的共同遗传结构，揭示了新的风险位点和致病机制。这些结果在CKMs的多效性遗传基础和胰岛内内分泌代谢调节之间建立了直接的细胞联系。

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来源期刊

Journal of Diabetes ENDOCRINOLOGY & METABOLISM-

CiteScore

6.50

自引率

2.20%

发文量

审稿时长

>12 weeks

期刊介绍： Journal of Diabetes (JDB) devotes itself to diabetes research, therapeutics, and education. It aims to involve researchers and practitioners in a dialogue between East and West via all aspects of epidemiology, etiology, pathogenesis, management, complications and prevention of diabetes, including the molecular, biochemical, and physiological aspects of diabetes. The Editorial team is international with a unique mix of Asian and Western participation. The Editors welcome submissions in form of original research articles, images, novel case reports and correspondence, and will solicit reviews, point-counterpoint, commentaries, editorials, news highlights, and educational content.