Adewuyi Emmanuel O, Laws Simon M
School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia.
Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia.
Biomedicines. 2025 Mar 3;13(3):618. doi: 10.3390/biomedicines13030618.
Observational studies suggest a link between vascular calcification and dementia or cognitive decline, but the evidence is conflicting, and the underlying mechanisms are unclear. Here, we investigate the shared genetic and causal relationships of vascular calcification-coronary artery calcification (CAC) and abdominal aortic calcification (AAC)-with Alzheimer's disease (AD), and five cognitive traits. We analyse large-scale genome-wide association studies (GWAS) summary statistics, using well-regarded methods, including linkage disequilibrium score regression (LDSC), Mendelian randomisation (MR), pairwise GWAS (GWAS-PW), and gene-based association analysis. Our findings reveal a nominally significant positive genome-wide genetic correlation between CAC and AD, which becomes non-significant after excluding the region. CAC and AAC demonstrate significant negative correlations with cognitive performance and educational attainment. MR found no causal association between CAC or AAC and AD or cognitive traits, except for a bidirectional borderline-significant association between AAC and fluid intelligence scores. Pairwise-GWAS analysis identifies no shared causal SNPs (posterior probability of association [PPA]3 < 0.5). However, we find pleiotropic loci (PPA4 > 0.9), particularly on chromosome 19, with gene association analyses revealing significant genes in shared regions, including , , , and . Moreover, we identify suggestively significant loci (PPA4 > 0.5) on chromosomes 1, 6, 7, 9 and 19, implicating pleiotropic genes, including , , , , , and . Current findings reveal limited genetic correlation and no significant causal associations of CAC and AAC with AD or cognitive traits. However, significant pleiotropic loci, particularly at the region, highlight the complex interplay between vascular calcification and neurodegenerative processes. Given 's roles in lipid metabolism, neuroinflammation, and vascular integrity, its involvement may link vascular and neurodegenerative disorders, pointing to potential targets for further investigation.
观察性研究表明血管钙化与痴呆或认知衰退之间存在联系，但证据相互矛盾，其潜在机制尚不清楚。在此，我们研究血管钙化（冠状动脉钙化[CAC]和腹主动脉钙化[AAC]）与阿尔茨海默病（AD）以及五种认知特征之间的共同遗传和因果关系。我们使用包括连锁不平衡评分回归（LDSC）、孟德尔随机化（MR）、成对全基因组关联研究（GWAS-PW）和基于基因的关联分析等备受认可的方法，分析大规模全基因组关联研究（GWAS）汇总统计数据。我们的研究结果显示，CAC与AD之间在全基因组水平上存在名义上显著的正遗传相关性，在排除该区域后变得不显著。CAC和AAC与认知表现和受教育程度呈显著负相关。MR发现CAC或AAC与AD或认知特征之间不存在因果关联，除了AAC与流体智力得分之间存在双向临界显著关联。成对GWAS分析未发现共享的因果单核苷酸多态性（关联后验概率[PPA]3<0.5）。然而，我们发现了多效性位点（PPA4>0.9），特别是在19号染色体上，基因关联分析揭示了共享区域中的重要基因，包括、、和。此外，我们在1、6、7、9和19号染色体上发现了提示性显著位点（PPA4>0.5），涉及多效性基因，包括、、、、和。当前研究结果显示，CAC和AAC与AD或认知特征之间的遗传相关性有限，且无显著因果关联。然而，显著的多效性位点，特别是在区域，突出了血管钙化与神经退行性过程之间的复杂相互作用。鉴于在脂质代谢、神经炎症和血管完整性中的作用，其参与可能将血管和神经退行性疾病联系起来，指出了进一步研究的潜在靶点。
