He Wei, Shi Jiajia, Qian Yiming, Fan Tao, Cai Xuehong, Li Haochang, Huang Peng, Shi Qin
Department of Physical Medicine and Rehabilitation, The Affiliated Jiangyin People's Hospital of Southeast University Medical College, Wuxi, China.
Department of Physical Medicine and Rehabilitation, Kunshan Rehabilitation Hospital, Suzhou, China.
PLoS One. 2025 Apr 23;20(4):e0320479. doi: 10.1371/journal.pone.0320479. eCollection 2025.
Previous studies have demonstrated the genetic basis of stroke and also revealed their genetic correlation with some cardiovascular related diseases or traits at the entire genome, which, however, would not give the answer which regions may mainly account for the genetic overlap. This study aims to identify specific genetic loci that contribute to the shared genetic basis between ischemic stroke subtypes and common cardiovascular traits.
We used Local Analysis of [co]Variant Annotation (LAVA), a recent developed local genetic correlation method, to perform a system local genetic correlation analysis on GWAS summary data of two major subtypes of stroke, including any ischemic stroke (AIS) and intracerebral hemorrhage (ICH), and ten common cardiovascular related diseases or traits (CRTs). We further used colocalization analysis to explore potential shared causal genes in loci with significant local genetic correlation. In addition, we also performed Transcriptome-wide association (TWAS) analysis and fine-mapping for each phenotype to functionally annotate significant loci.
LAVA analysis identified a total of 3 significant local genetic correlations (Bonferroni-adjusted P < 0.05) across 3 chromosomes between AIS and systolic blood pressure (SBP), AIS and hypertension (HT), and ICH and body mass index (BMI), among which locus 7.24 explicated to harbor a shared causal variant for AIS and SBP. TWIST1 in locus 7.24 was defined to be nominally associated with SBP, but not for AIS. Fine-mapping analysis also only identified TWIST1 a credible causal gene for BMI.
Our study revealed the local genetic correlations between two stroke subtypes and ten common CRTs. Gene-level analyses indicated that biological explanations underlying these identified local genetic correlations may existed elsewhere beyond a common pattern of genetic-gene expression regulation.
既往研究已证实中风的遗传基础，并在全基因组层面揭示了其与一些心血管相关疾病或性状的遗传相关性，然而，这并不能明确哪些区域可能是导致遗传重叠的主要原因。本研究旨在确定导致缺血性中风亚型与常见心血管性状之间存在共同遗传基础的特定基因位点。
我们使用了最近开发的局部遗传相关性分析方法——[共]变异注释局部分析（LAVA），对两种主要中风亚型（包括任何缺血性中风（AIS）和脑出血（ICH））以及十种常见心血管相关疾病或性状（CRT）的全基因组关联研究（GWAS）汇总数据进行系统的局部遗传相关性分析。我们进一步使用共定位分析来探索具有显著局部遗传相关性的基因座中的潜在共享因果基因。此外，我们还对每个表型进行了全转录组关联（TWAS）分析和精细定位，以对显著基因座进行功能注释。
LAVA分析在3条染色体上共鉴定出3个显著的局部遗传相关性（Bonferroni校正P < 0.05），分别存在于AIS与收缩压（SBP）、AIS与高血压（HT）以及ICH与体重指数（BMI）之间，其中7.24位点被明确为AIS和SBP的共享因果变异位点。7.24位点的TWIST1基因被确定与SBP存在名义上的关联，但与AIS无关。精细定位分析也仅确定TWIST1是BMI的可信因果基因。
我们的研究揭示了两种中风亚型与十种常见CRT之间的局部遗传相关性。基因水平分析表明，这些已确定的局部遗传相关性背后的生物学解释可能存在于基因-基因表达调控的共同模式之外的其他地方。
