title: The Arc Gene Confers Genetic Susceptibility to Alzheimer's Disease in Han Chinese.
abstract: Alzheimer's disease (AD) is the most common form of dementia. The deposition of β-amyloid (Aβ) plaques in the brain was considered one of the main neuropathological hallmarks of AD. As the loss of synapses always occurs during AD progression, AD has been gradually regarded as a "synaptopathy." The activity-regulated cytoskeleton-associated protein (Arc) was recently identified as a key factor for AD due to its active roles in synaptic plasticity, learning, memory, and Aβ generation. However, there is little evidence to support the association of the Arc gene with AD. In this study, a two-stage case-control study of 1471 Han Chinese was conducted to investigate the genetic association between the Arc gene and AD. Variant rs10097505 in the 3'UTR region was significantly associated with AD. The whole exons of the Arc gene were also screened in 99 AD patients with a high heritability (familial and/or onset age <55 years old). One missense variant (c.20G>A, p.T7I) was identified in two AD patients but was absent in the controls from the general populations. Both rs10097505 and c.20G>A were predicted to be potentially pathogenic. Further luciferase assay, data mining, and integrative analyses revealed that the AD-risk genotype AA of rs10097505 was associated with an increased Arc mRNA expression and an elevated Aβ level. Our results indicated that the Arc gene would confer susceptibility to AD in Han Chinese, probably through changing the protein structure or affecting the Arc expression in brain tissues, which would finally contribute to the pathogenesis and development of AD.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Bi
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.|Institute of Health Sciences, Anhui University, Hefei, Anhui, 230601, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Kong
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.|Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.|Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China.
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Li
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.
authors.forename: Deng-Feng
authors.initials: DF
authors.lastname: Zhang
authors.affiliation: The Mental Health Center and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610064, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
authors.forename: Yiru
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Health Sciences, Anhui University, Hefei, Anhui, 230601, China.
authors.forename: Buchang
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China. yaoyg@mail.kiz.ac.cn.|CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China. yaoyg@mail.kiz.ac.cn.
authors.forename: Yong-Gang
authors.initials: YG
authors.lastname: Yao
mesh_terms: D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002681:China; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein
keywords: Alzheimer’s disease; Arc gene; Genetic susceptibility; Han Chinese