机构：[1]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China[2]Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China[3]Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China[4]Center for Neurodegenerative Diseases, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China神经病学中心首都医科大学附属天坛医院[5]Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China[6]National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China[7]CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China[8]Department of Psychiatry, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China内科科室精神科昆明医科大学附属第一医院[9]Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha 410011, China[10]Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China[11]Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China[12]State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China[13]KIZ–CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
Alzheimer's disease is the most common neurodegenerative disease, and has a high level of genetic heritability and population heterogeneity. In this study, we performed the whole-exome sequencing of Han Chinese patients with familial and/or early-onset Alzheimer's disease, followed by independent validation, imaging analysis and function characterization. We identified an exome-wide significant rare missense variant rs3792646 (p.K420Q) in the C7 gene in the discovery stage (P = 1.09 x 10(-6), odds ratio = 7.853) and confirmed the association in different cohorts and a combined sample (1615 cases and 2832 controls, P-combined = 2.99 x 10(-7), odds ratio = 1.930). The risk allele was associated with decreased hippocampal volume and poorer working memory performance in early adulthood, thus resulting in an earlier age of disease onset. Overexpression of the mutant p.K420Q disturbed cell viability, immune activation and beta-amyloid processing. Electrophysiological analyses showed that the mutant p.K420Q impairs the inhibitory effect of wild type C7 on the excitatory synaptic transmission in pyramidal neurons. These findings suggested that C7 is a novel risk gene for Alzheimer's disease in Han Chinese.
基金：
This work was supported by the National Natural Science Foundation
of China (31730037), the Strategic Priority Research Program
of the Chinese Academy of Sciences (XDB32020200) and
the Bureau of Frontier Sciences and Education, CAS (QYZDJSSW-
SMC005). Data collection and sharing of the Alzheimer’s
Disease Neuroimaging Initiative (ADNI) project was funded by
the ADNI (National Institutes of Health grant U01 AG024904)
and the Department of Defense (award number W81XWH-12-
2-0012).
第一作者机构：[1]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China[2]Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Deng-Feng Zhang,Yu Fan,Min Xu,et al.Complement C7 is a novel risk gene for Alzheimer's disease in Han Chinese[J].NATIONAL SCIENCE REVIEW.2019,6(2):257-274.doi:10.1093/nsr/nwy127.
APA：
Deng-Feng Zhang,Yu Fan,Min Xu,Guihong Wang,Dong Wang...&Yong-Gang Yao.(2019).Complement C7 is a novel risk gene for Alzheimer's disease in Han Chinese.NATIONAL SCIENCE REVIEW,6,(2)
MLA：
Deng-Feng Zhang,et al."Complement C7 is a novel risk gene for Alzheimer's disease in Han Chinese".NATIONAL SCIENCE REVIEW 6..2(2019):257-274
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