I Hyun Ruisch, Joanna Widomska, Ward De Witte, Nina R Mota, Giuseppe Fanelli, Veerle Van Gils, Willemijn J Jansen, Stephanie J B Vos, Abel Fóthi, Csaba Barta, Simone Berkel, Kazi A Alam, Aurora Martinez, Jan Haavik, Aet O'Leary, David Slattery, Mairéad Sullivan, Jeffrey Glennon, Jan K Buitelaar, Janita Bralten, Barbara Franke, Geert Poelmans
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In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. 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引用次数: 0
摘要
阿尔茨海默病(AD)是一种多因素疾病,其病因既有遗传因素,也有环境因素。以往的证据表明,胰岛素信号传递紊乱是一种关键机制,在 AD 等神经退行性疾病和 2 型糖尿病(DM2)等合并躯体疾病中都起着作用。在本研究中,我们分析了现有的有关 AD 和体质性胰岛素相关疾病(SID)(即 DM2、代谢综合征和肥胖症)的全基因组关联研究(GWAS),以确定与 AD 和 SID 相关的基因,从而提高我们对其分子基础的认识。然后,我们对这些基因进行了功能富集分析。随后,我们利用(额外的)GWAS 数据,对 AD 和 SID 与血液和脑脊液(CSF)代谢物水平进行了共同遗传病因分析。此外,结合所有这些分析结果和精心的文献检索,我们建立了一个关于 AD 和 SID 重叠的分子图谱。从分子图谱中,我们发现了多个功能主题,包括胰岛素信号传导、雌激素信号传导、突触传递、脂质代谢和 tau 信号传导。我们还发现了AD/SID与血液/脑脊液中多种代谢物水平之间的共同遗传病因,这表明 "能量代谢 "是AD和SID都会受到影响的关键代谢途径。最后,该研究还提供了AD潜在新药靶点的线索(包括MARK4、TMEM219、FKBP5、NDUFS3和IL34),这些靶点可进一步开发成新的AD治疗方法。
Molecular landscape of the overlap between Alzheimer's disease and somatic insulin-related diseases.
Alzheimer's disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards "energy metabolism" as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments.
期刊介绍:
Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.