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Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer's disease

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收录情况: ◇ SCIE ◇ SSCI

机构: [a]Center for Neurodegenerative Diseases, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China [b]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 [c]Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China [d]Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China [e]Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China [f]Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, 410011, China [g]Division of Nuclear Technology and Applications, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China [h]Beijing Engineering Research Center of Radiographic Techniques and Equipment, Beijing, 100049, China [i]CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China [j]KIZ – CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China [k]China National Clinical Research Center for Neurological Diseases, Beijing, 100050, China [l]Parkinson's Disease Center, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100050, China
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关键词: Alzheimer's disease Dementia Mutation Association Next-generation sequencing

摘要:
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. It shares clinical and pathological features with other types of dementia, such as vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD). We have hypothesized that there might be an overlapping molecular mechanism and genetic basis to the different types of dementia. In this study, we analyzed the mutation pattern of dementia-causal genes in 169 Han Chinese patients with familial and early-onset AD by using whole exome sequencing or targeted resequencing. We identified 9 potentially pathogenic mutations in the AD-causal genes APP, PSEN1, PSEN2, and 6 mutations in a group of non-AD dementia-causal genes including the FTD-causal gene GRN and the VaD-causal gene NOTCH3. A common splice-site variant rs514492 in the FTD-causal gene VCP showed a positive association with AD risk (P = 0.0003, OR = 1.618), whereas the rare missense variant rs33949390 (p. R 1628P) in the LBD-causal gene LRRK2 showed a protective effect on AD risk (P = 0.0004, OR = 0.170). The presence of putative pathogenic mutations and risk variants in these causal genes for different types of dementia in clinically diagnosed familial and early-onset AD patients suggests a need to screen for mutations of the dementia-causal genes in cases of AD to avoid misdiagnosis. These mutations also support the idea that there are overlapping pathomechanisms between AD and other forms of dementia.

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出版当年[2020]版:
大类 | 2 区 医学
小类 | 3 区 精神病学
最新[2023]版:
大类 | 2 区 医学
小类 | 2 区 精神病学
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出版当年[2019]版:
Q1 PSYCHIATRY Q2 PSYCHIATRY
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Q1 PSYCHIATRY

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第一作者机构: [a]Center for Neurodegenerative Diseases, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
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通讯机构: [*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 Neurodegenerative Diseases, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China. [*3]Division of Nuclear Technology and Applications, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China.
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