Long Yu, Liu Jinfeng, Guo Jinniu, Jiang Jinzhao, Wang Xiangyu, Sun Ruohan
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, China.
Department of Neurology, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, China.
BMC Neurol. 2025 Jul 1;25(1):260. doi: 10.1186/s12883-025-04278-2.
This study aimed to evaluate the genetic relationship between Alzheimer's disease (AD) and stroke, including its subtypes.
The Linkage Disequilibrium Score Regression (LDSC) for heritability and genetic correlations, Polygenic Likelihood Ratio under a Composite Null Hypothesis (PLACO) method for pleiotropic loci and locus, and Functional maps and annotations from genome-wide association studies (FUMA) for function analysis of multi-effect loci, multi-marker analysis of genoMic annotation (MAGMA) for gene tissue specificity, Mendelian Randomization (MR) analyses for causal relationships between AD and five stroke subtypes were performed through Single Nucleotide Polymorphism (SNP) heritability enrichments and causal associations were analyzed using comprehensive GWAS data.
Manhattan plots revealed pleiotropic SNPs mainly on chromosomes 11 and 19, with additional loci on chromosomes 1, 2, and 3 for specific subgroups. Key genes like DEDD, UFC1, USP21, affecting both AD and stroke subtypes, were enriched in brain tissues, highlighting shared mechanisms. Stratified LD score regression showed overlaps in brain regions such as substantia nigra and spinal cord. MR analysis indicated AD as a risk factor for LAS and AS but protective for cerebral embolism stroke (CES), supported by consistent causal effect estimates without publication bias. This study reveals that AD shares genetic factors with multiple stroke subtypes, notably in brain tissues, impacting their etiology and potential treatments.
Overall, our study revealed that AD shares genetic factors with multiple stroke subtypes, notably in brain tissues. MR analysis indicates AD is a risk factor for LAS and AS, but protective for CES.
本研究旨在评估阿尔茨海默病（AD）与中风及其亚型之间的遗传关系。
采用连锁不平衡评分回归（LDSC）进行遗传力和遗传相关性分析，采用复合零假设下的多基因似然比（PLACO）方法进行多效位点和基因座分析，采用全基因组关联研究的功能图谱和注释（FUMA）进行多效位点功能分析，采用基因组织特异性的基因组注释多标记分析（MAGMA），通过单核苷酸多态性（SNP）遗传力富集对AD与五种中风亚型之间的因果关系进行孟德尔随机化（MR）分析，并使用综合全基因组关联研究（GWAS）数据对因果关联进行分析。
曼哈顿图显示多效性单核苷酸多态性主要位于11号和19号染色体上，特定亚组在1号、2号和3号染色体上还有其他位点。影响AD和中风亚型的关键基因，如DEDD、UFC1、USP21，在脑组织中富集，突出了共同机制。分层连锁不平衡评分回归显示黑质和脊髓等脑区存在重叠。MR分析表明，AD是大动脉粥样硬化性卒中（LAS）和动脉粥样硬化性卒中（AS）的危险因素，但对脑栓塞性卒中（CES）具有保护作用，一致的因果效应估计支持这一结论，且不存在发表偏倚。本研究表明，AD与多种中风亚型存在共同遗传因素，尤其是在脑组织中，这影响了它们的病因和潜在治疗方法。
总体而言，我们的研究表明，AD与多种中风亚型存在共同遗传因素，尤其是在脑组织中。MR分析表明，AD是LAS和AS的危险因素，但对CES具有保护作用。
