Zhang Xueli, Zhu Zhuoting, Huang Yu, Shang Xianwen, O'Brien Terence J, Kwan Patrick, Ha Jason, Wang Wei, Liu Shunming, Zhang Xiayin, Kiburg Katerina, Bao Yining, Wang Jing, Yu Honghua, He Mingguang, Zhang Lei
Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People's Republic of China.
BMJ Neurol Open. 2024 Apr 15;6(1):e000570. doi: 10.1136/bmjno-2023-000570. eCollection 2024.
Alzheimer's disease (AD) and age-related macular degeneration (AMD) share similar pathological features, suggesting common genetic aetiologies between the two. Investigating gene associations between AD and AMD may provide useful insights into the underlying pathogenesis and inform integrated prevention and treatment for both diseases.
A stratified quantile-quantile (QQ) plot was constructed to detect the pleiotropy among AD and AMD based on genome-wide association studies data from 17 008 patients with AD and 30 178 patients with AMD. A Bayesian conditional false discovery rate-based (cFDR) method was used to identify pleiotropic genes. UK Biobank was used to verify the pleiotropy analysis. Biological network and enrichment analysis were conducted to explain the biological reason for pleiotropy phenomena. A diagnostic test based on gene expression data was used to predict biomarkers for AD and AMD based on pleiotropic genes and their regulators.
Significant pleiotropy was found between AD and AMD (significant leftward shift on QQ plots). APOC1 and APOE were identified as pleiotropic genes for AD-AMD (cFDR <0.01). Network analysis revealed that APOC1 and APOE occupied borderline positions on the gene co-expression networks. Both APOC1 and APOE genes were enriched on the herpes simplex virus 1 infection pathway. Further, machine learning-based diagnostic tests identified that APOC1, APOE (areas under the curve (AUCs) >0.65) and their upstream regulators, especially ZNF131, ADNP2 and HINFP, could be potential biomarkers for both AD and AMD (AUCs >0.8).
In this study, we confirmed the genetic pleiotropy between AD and AMD and identified APOC1 and APOE as pleiotropic genes. Further, the integration of multiomics data identified ZNF131, ADNP2 and HINFP as novel diagnostic biomarkers for AD and AMD.
阿尔茨海默病（AD）和年龄相关性黄斑变性（AMD）具有相似的病理特征，提示两者存在共同的遗传病因。研究AD与AMD之间的基因关联可能为潜在发病机制提供有用的见解，并为两种疾病的综合防治提供依据。
基于17008例AD患者和30178例AMD患者的全基因组关联研究数据，构建分层分位数-分位数（QQ）图以检测AD和AMD之间的多效性。采用基于贝叶斯条件错误发现率（cFDR）的方法来识别多效性基因。利用英国生物银行验证多效性分析。进行生物网络和富集分析以解释多效性现象的生物学原因。基于基因表达数据的诊断测试用于根据多效性基因及其调控因子预测AD和AMD的生物标志物。
在AD和AMD之间发现了显著的多效性（QQ图上有明显的左移）。APOC1和APOE被鉴定为AD-AMD的多效性基因（cFDR<0.01）。网络分析显示，APOC1和APOE在基因共表达网络中占据临界位置。APOC1和APOE基因均富集于单纯疱疹病毒1感染途径。此外，基于机器学习的诊断测试确定，APOC1、APOE（曲线下面积（AUC）>0.65）及其上游调控因子，尤其是ZNF131、ADNP2和HINFP，可能是AD和AMD的潜在生物标志物（AUC>0.8）。
在本研究中，我们证实了AD和AMD之间的遗传多效性，并将APOC1和APOE鉴定为多效性基因。此外，多组学数据的整合确定ZNF131、ADNP2和HINFP为AD和AMD的新型诊断生物标志物。
