Study found important genetic risk factors for Alzheimer's disease in China
January 04, 2019 Source: Kunming Institute of Zoology
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/API/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];Alzheimer's disease (AD), commonly known as Alzheimer's disease, is a common neurodegenerative encephalopathy that occurs in pre- and post-elderly conditions and is characterized by a gradual loss of cognitive and memory functions. Its incidence increases significantly with age. As the aging process intensifies, the number of AD patients worldwide is growing rapidly, resulting in a heavy social and economic burden.
Genetic factors are one of the most important risk factors for AD, and epidemiological data show that the heritability of AD is as high as 79%. Previous studies by traditional linkage analysis found that APP, PSEN1 and PSEN2 are the causative genes of early-onset family AD; however, less than 5% of patients are caused by mutations in these disease-causing genes, especially for most patients, especially For cases of late onset sporadic cases, there are a large number of genetic susceptibility risk genes to be discovered. Recent large-scale genome-wide association analysis found a large number of common genetic variation sites associated with late-onset sporadic AD genetic risk in European populations, providing many new ideas for the analysis of AD genetic mechanisms. However, there are still two key issues that have not been resolved: (1) The common genetic variation sites associated with identified genetic risk of AD are mostly located in non-coding regions with unknown functions, from statistical correlation to functional gene identification and mechanism analysis. There is a long way to go; (2) The identified genetic factors are mainly based on the study of European populations. Due to the complexity of the disease and the heterogeneity of the genetic background of the population, the AD genetic factors of people outside Europe have not been systematically studied. . The genetic analysis of the system of AD population in China is extremely disproportionate to the huge population of AD in China. To this end, the Yao Yonggang team of the Kunming Institute of Zoology of the Chinese Academy of Sciences cooperated with the Shanghai Mental Health Center, Zhongshan Hospital affiliated to Fudan University, Xiangya Second Hospital affiliated to Central South University, Beijing Tiantan Hospital affiliated to Capital Medical University, and the First Affiliated Hospital of Kunming Medical University. The AD group in China has carried out systematic genetic analysis.
The team first performed a full exome sequencing on AD cases with extremely early onset or family history, and found that a rare missense mutation rs3792646 of the complement factor C7 gene can significantly increase the risk of AD; the genetic risk is derived from China. Effective verification of independent samples from eastern and southwestern regions. Through collaboration with the Jiang Tianzi team of the Institute of Automation of the Chinese Academy of Sciences, the genetic imaging related data analysis based on the healthy college students found that the rs3792646 risk variant carriers showed a decrease in hippocampal volume and working memory in the younger period than the non-risk variant carriers. The ability is weakened. Survival curve analysis of AD patient populations found that the age of onset of risk allele carriers was about 5 years earlier. These results suggest that individuals with genetic risk of AD have begun to have mild brain functional changes decades before onset, and early prevention and intervention are particularly necessary for individuals with high genetic risk. The research team also collaborated with Kunming Animal Research Institute Sheng Nengyin to further explore the potential pathogenic effects of this variant site. Functional experiments have found that overexpression of this variant can affect the processing of amyloid Aβ, interfere with the immune response process, and destroy the synaptic transmission function of neurons, thereby promoting the occurrence and development of AD. The data of the whole exomes generated in this study have been published in the Alzheimer's disease database AlzData (; Xu et al. 2018. Alzheimer & Dementia), which was established by the team. Examples of data sharing and utilization in research areas. The research work was recently published in the National Science Review. Zhang Dengfeng, associate researcher of Kunming Institute of Zoology, Dr. Fan Yu and Ph.D. student Xu Min are the co-first authors of the article. Yao Yonggang, a researcher at the Kunming Institute of Zoology, is the author of the communication.
In addition to screening new genes based on high-throughput methods, the team also conducted targeted analysis of important pathways. In view of a large number of studies, it is found that mitochondrial respiratory chain complex IV, cytochrome c oxidase (COX) may be involved in the pathogenesis of AD. The team analyzed 11 subunits of COX and 41 genetic loci in 6 assembly factor genes in Chinese Han cases and normal control samples, and found COX subunit genes COX6B1 and NDUFA4, and COX assembly factors. Genetic variation in the genes SURF1 and COX10 is significantly associated with the risk of AD. Further analysis revealed that the genetic loci associated with AD in these genes were also significantly associated with the corresponding gene expression levels. Moreover, these COX genes associated with the risk of AD were significantly down-regulated in the cortex of AD mice. Among them, the expression levels of Cox10 and Ndufa4 in the mouse cortex were also significantly negatively correlated with the level of Aβ deposition in the mouse brain. The results suggest that the genetic variation in COX-related genes may affect the pathological changes of AD by regulating the expression level of the corresponding genes, which is related to the risk of AD. Related work was published on Neuropsychopharmacology. Bi Rui, an associate researcher at the Kunming Institute of Zoology, is the first author of the article. Bi Rui and Yao Yonggang are co-authors of the article.
The above research was funded by the National Natural Science Foundation of China, the Chinese Academy of Sciences Brain Function Linkage Pilot Project and the Frontier Key Research Project of the Chinese Academy of Sciences.
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