Bai Wenya, Zhou Guilin, Jiang Huan, Li Xuelian, Shao Jianlin
Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan Province, China.
Hum Genomics. 2025 Jul 3;19(1):75. doi: 10.1186/s40246-025-00789-8.
Blood lipid levels are linked to stroke risk, but the genetic correlation between blood lipids and stroke is not well understood. We investigated the shared genetic architecture between blood lipids and stroke, including its subtypes, identifying common risk loci, genes, and underlying genetic mechanisms.
Utilizing large-scale genome-wide association study (GWAS) summary data, we identified genetic overlap between blood lipid levels and stroke. Cross-trait pleiotropic analysis was conducted to detect shared pleiotropic loci and genes. The statistical methods employed encompassed linkage disequilibrium score regression (LDSC), stratified-LDSC (s-LDSC), heritability estimation from summary statistics (rho-HESS), pleiotropic analysis under composite null hypothesis (PLACO), cross-trait meta-analyses, colocalization analysis, multi-marker analysis of genomic annotation (MAGMA), tissue-specific enrichment analysis (TSEA), and transcriptome-wide association studies (TWASs). Bidirectional Mendelian randomization (MR) analysis was employed to explore causal associations.
Our research highlights the shared genetic mechanisms between stroke and blood lipid levels. We identified 147 pleiotropic loci at a genome-wide significance level ( < 5 × 10). Further gene-level analysis identified 10 unique pleiotropic genes shared by stroke and lipid traits, including CUX2, SH2B3, and ICA1L. Cross-trait meta-analysis identified 28 loci, with colocalization analysis revealing two unique pleiotropic genes, PPTPN11 and SH2B3, significantly enriched in adipose, musculoskeletal, and brain tissues. Two-sample MR analysis indicated that higher HDL-C levels were associated with reduced risks of stroke and IS, while elevated TG levels increased IS risk. In a transcriptome-wide association study, we identified one previously unreported pleiotropic gene (ALDH2).
Our research revealed a common genetic architecture between stroke and blood lipid levels, highlighting potential genetic pathways involved in both conditions.
The online version contains supplementary material available at 10.1186/s40246-025-00789-8.
血脂水平与中风风险相关，但血脂与中风之间的遗传相关性尚不清楚。我们研究了血脂与中风之间共享的遗传结构，包括其亚型，确定常见风险位点、基因及潜在遗传机制。
利用大规模全基因组关联研究（GWAS）汇总数据，我们确定了血脂水平与中风之间的遗传重叠。进行跨性状多效性分析以检测共享的多效性位点和基因。所采用的统计方法包括连锁不平衡评分回归（LDSC）、分层LDSC（s-LDSC）、基于汇总统计量的遗传力估计（rho-HESS）、复合零假设下的多效性分析（PLACO）、跨性状荟萃分析、共定位分析、基因组注释多标记分析（MAGMA）、组织特异性富集分析（TSEA）以及全转录组关联研究（TWAS）。采用双向孟德尔随机化（MR）分析来探索因果关联。
我们的研究突出了中风与血脂水平之间共享的遗传机制。我们在全基因组显著水平（<5×10）上确定了147个多效性位点。进一步的基因水平分析确定了中风和血脂性状共有的10个独特多效性基因，包括CUX2、SH2B3和ICA1L。跨性状荟萃分析确定了28个位点，共定位分析揭示了两个独特的多效性基因PPTPN11和SH2B3，在脂肪组织、肌肉骨骼组织和脑组织中显著富集。两样本MR分析表明，较高的高密度脂蛋白胆固醇（HDL-C）水平与中风和缺血性中风（IS）风险降低相关，而甘油三酯（TG）水平升高会增加IS风险。在全转录组关联研究中，我们确定了一个先前未报道的多效性基因（ALDH2）。
我们的研究揭示了中风与血脂水平之间共同的遗传结构，突出了两种情况中涉及的潜在遗传途径。
在线版本包含可在10.1186/s40246-025-00789-8获取的补充材料。
