Centre for Precision Health, Edith Cowan University, Joondalup, WA 6027, Australia.
Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia.
Int J Mol Sci. 2024 Aug 13;25(16):8814. doi: 10.3390/ijms25168814.
There is evidence to support a link between abnormal lipid metabolism and Alzheimer's disease (AD) risk. Similarly, observational studies suggest a comorbid relationship between AD and coronary artery disease (CAD). However, the intricate biological mechanisms of AD are poorly understood, and its relationship with lipids and CAD traits remains unresolved. Conflicting evidence further underscores the ongoing investigation into this research area. Here, we systematically assess the cross-trait genetic overlap of AD with 13 representative lipids (from eight classes) and seven CAD traits, leveraging robust analytical methods, well-powered large-scale genetic data, and rigorous replication testing. Our main analysis demonstrates a significant positive global genetic correlation of AD with triglycerides and all seven CAD traits assessed-angina pectoris, cardiac dysrhythmias, coronary arteriosclerosis, ischemic heart disease, myocardial infarction, non-specific chest pain, and coronary artery disease. Gene-level analyses largely reinforce these findings and highlight the genetic overlap between AD and three additional lipids: high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), and total cholesterol. Moreover, we identify genome-wide significant genes (Fisher's combined value [] < 2.60 × 10) shared across AD, several lipids, and CAD traits, including , , , , , , , , and . Mendelian randomisation analysis found no evidence of a significant causal relationship between AD, lipids, and CAD traits. However, local genetic correlation analysis identifies several local pleiotropic hotspots contributing to the relationship of AD with lipids and CAD traits across chromosomes 6, 8, 17, and 19. Completing a three-way analysis, we confirm a strong genetic correlation between lipids and CAD traits-HDL and sphingomyelin demonstrate negative correlations, while LDL, triglycerides, and total cholesterol show positive correlations. These findings support genetic overlap between AD, specific lipids, and CAD traits, implicating shared but non-causal genetic susceptibility. The identified shared genes and pleiotropic hotspots are valuable targets for further investigation into AD and, potentially, its comorbidity with CAD traits.
有证据表明，异常的脂质代谢与阿尔茨海默病（AD）风险之间存在关联。同样，观察性研究表明 AD 与冠状动脉疾病（CAD）之间存在合并症关系。然而，AD 的复杂生物学机制尚未得到很好的理解，其与脂质和 CAD 特征的关系仍未得到解决。相互矛盾的证据进一步强调了对这一研究领域的持续调查。在这里，我们使用稳健的分析方法、功能强大的大规模遗传数据和严格的复制测试，系统地评估了 AD 与 13 种代表性脂质（来自 8 个类别）和 7 种 CAD 特征之间的交叉特征遗传重叠。我们的主要分析表明，AD 与甘油三酯和评估的七个 CAD 特征之间存在显著的正全局遗传相关性——心绞痛、心律失常、冠状动脉粥样硬化、缺血性心脏病、心肌梗死、非特异性胸痛和冠状动脉疾病。基因水平分析在很大程度上加强了这些发现，并强调了 AD 与另外三种脂质之间的遗传重叠：高密度脂蛋白（HDL）、低密度脂蛋白（LDL）和总胆固醇。此外，我们确定了跨越 AD、几种脂质和 CAD 特征的全基因组显著基因（Fisher 合并值 [] < 2.60 × 10），包括、、、、、、、和。孟德尔随机化分析未发现 AD、脂质和 CAD 特征之间存在显著因果关系的证据。然而，局部遗传相关性分析确定了几个局部多效性热点，这些热点导致 AD 与脂质和 CAD 特征之间的关系，涉及染色体 6、8、17 和 19。完成三向分析后，我们确认脂质和 CAD 特征之间存在很强的遗传相关性——高密度脂蛋白和鞘磷脂呈负相关，而 LDL、甘油三酯和总胆固醇呈正相关。这些发现支持 AD、特定脂质和 CAD 特征之间的遗传重叠，表明存在共同但非因果的遗传易感性。确定的共享基因和多效性热点是进一步研究 AD 及其与 CAD 特征的合并症的有价值的目标。
