Table1_Linking coronary artery disease to neurodegenerative diseases through systems genetics.XLSX

Coronary artery disease (CAD) is still a leading cause of death worldwide despite the extensive research and the considerable progresses made through the years. As other cardiovascular diseases, CAD is the result of the complex interaction between genetic variants and environmental factors. Currently identified genetic loci associated to CAD revealed the contribution of multiple molecular pathways to its pathogenesis, suggesting the need for a systemic approach to understand the role of genetic determinants. In this study we wanted to investigate how GWAS variants associated to CAD interact with each other and with nearby genes in the context of the coronary artery molecular interactome. GWAS variants associated to CAD were selected from GWAS Catalog, then, a tissue-specific interactome was constructed integrating protein-protein interactions (PPI) from multiple public repositories and computationally inferred co-expression relationships. To focus on the part of the network most relevant for CAD, we selected the interactions connecting the genes carrying a variant associated to the disease. A functional enrichment analysis conducted on the subnetwork revealed that genes carrying genetic variants associated to CAD closely interact with genes related to relevant biological processes, such as extracellular matrix organization, lipoprotein clearance, arterial morphology and inflammatory response. These results confirm that the identified subnetwork reflects the molecular pathways altered in CAD and intercepted by the selected variants. Interestingly, the most connected nodes of the network included amyloid beta precursor protein (APP) and huntingtin (HTT), both implicated in neurodegenerative disorders. In recent years the interest in investigating the common processes between cardiovascular diseases and neurodegenerative disorders is increasing, with growing evidence of a link between CAD and Alzheimer’s disease. The results obtained in this work support the association between such apparently unrelated diseases and highlight the necessity of a systems biology approach to better elucidate shared pathological mechanisms.

冠状动脉粥样硬化性心脏病（Coronary Artery Disease, CAD）尽管多年来已有大量研究与长足进展，目前仍是全球范围内的主要致死病因。与其他心血管疾病类似，CAD是遗传变异与环境因素复杂交互作用的产物。目前已鉴定出的与CAD相关的遗传位点，揭示了多条分子通路在其发病机制中的贡献，这提示需采用系统生物学方法来阐明遗传决定因素的具体功能。本研究旨在探究在冠状动脉分子互作组背景下，与CAD相关的全基因组关联研究（Genome-Wide Association Study, GWAS）变异如何彼此之间以及与邻近基因发生相互作用。研究人员从全基因组关联研究目录（GWAS Catalog）中选取与CAD相关的GWAS变异，随后整合来自多个公共资源库的蛋白质-蛋白质相互作用（Protein-Protein Interaction, PPI）数据以及计算推导得到的共表达关系，构建组织特异性互作组。为聚焦于与CAD最为相关的网络部分，本研究选取了携带疾病相关变异的基因之间的相互作用。对该子网开展功能富集分析后发现，携带CAD相关遗传变异的基因，可与参与诸多关键生物学过程的基因发生紧密互作，例如细胞外基质组织、脂蛋白清除、动脉形态维持以及炎症应答。上述结果证实，本研究鉴定得到的子网能够反映CAD中发生异常改变且被所选变异靶向的分子通路。值得注意的是，该网络中连接度最高的节点包含β淀粉样前体蛋白（Amyloid Beta Precursor Protein, APP）与亨廷顿蛋白（Huntingtin, HTT），二者均与神经退行性疾病相关。近年来，学界对心血管疾病与神经退行性疾病共通通路的研究兴趣与日俱增，且越来越多的证据表明CAD与阿尔茨海默病之间存在关联。本研究所得结果证实了这类看似无关的疾病之间存在关联，并凸显了采用系统生物学方法以进一步阐明二者共通病理机制的必要性。