title: Rare Genetic Variants of the Transthyretin Gene Are Associated with Alzheimer's Disease in Han Chinese.
abstract: Alzheimer's disease (AD) is the most prevalent form of dementia in the world. The neuropathological characteristics of AD patients are the accumulation of extracellular plaques of β-amyloid (Aβ) and intracellular hyperphosphorylated tau protein. Transthyretin (TTR) may alleviate AD symptom by reducing Aβ concentration in the brain. There were reports for a decreased TTR level in both AD brain and blood. However, there is still no robust evidence to support the genetic association of the TTR gene with AD. In this study, we aimed to investigate the potential association of TTR variation with AD by directly sequencing the whole exons and the promoter region of the TTR gene in 529 AD patients and 334 healthy controls from Han Chinese population. We found no association between TTR common variants and AD but observed an enrichment of TTR rare variants in AD patients relative to controls. Further in silico prediction analysis and functional assessment at the cellular level identified four potentially pathogenic rare variants in AD patients. In particular, variant c.-239C>A could potentially downregulate the TTR promoter activity; c.200+4A>G might influence the constitutive splicing of TTR mRNA; c.148G>A (p.V50M) and c.332C>T (p.A111V) would change the structure of TTR and decrease its Aβ-binding ability. Our results provided direct genetic evidence to support the active involvement of TTR in AD.
authors: 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: Qun
authors: Q
authors: Xiang
authors: 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. birui@mail.kiz.ac.cn.
authors: Rui
authors: R
authors: Bi
authors: 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: Min
authors: M
authors: Xu
authors: 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: Deng-Feng
authors: DF
authors: Zhang
authors: The Institute of Mental Health, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors: Liwen
authors: L
authors: Tan
authors: Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
authors: Chen
authors: C
authors: Zhang
authors: Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
authors: Yiru
authors: Y
authors: Fang
authors: 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.|Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, 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: Yong-Gang
authors: YG
authors: Yao
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D044466:Asian People; D001921:Brain / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism; D011228:Prealbumin / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011228:Prealbumin
keywords: Alzheimer’s disease; Aβ-binding ability; Genetic association; Rare variant; TTR