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Rare Genetic Variants of the Transthyretin Gene Are Associated with Alzheimer’s Disease in Han Chinese

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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.

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Acknowledgments

We thank all participants in this study. We thank Miss Dandan Yu and Dr. Ling Xu for technical assistance. This study was supported by the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020003).

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Authors and Affiliations

  1. 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

    Qun Xiang, Rui Bi, Min Xu, Deng-Feng Zhang & Yong-Gang Yao

  2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China

    Qun Xiang, Min Xu & Yong-Gang Yao

  3. The Institute of Mental Health, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China

    Liwen Tan

  4. Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China

    Chen Zhang & Yiru Fang

  5. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China

    Yong-Gang Yao

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  1. Qun Xiang
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  2. Rui Bi
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  3. Min Xu
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Corresponding authors

Correspondence to Rui Bi or Yong-Gang Yao.

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Written informed consents following the principles of the Declaration of Helsinki were obtained from each participant or guardian. This study was approved by the institutional review board of the Kunming Institute of Zoology, Chinese Academy of Sciences.

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The authors declare that they have no conflict in interest.

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Xiang, Q., Bi, R., Xu, M. et al. Rare Genetic Variants of the Transthyretin Gene Are Associated with Alzheimer’s Disease in Han Chinese. Mol Neurobiol 54, 5192–5200 (2017). https://doi.org/10.1007/s12035-016-0065-2

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  • DOI: https://doi.org/10.1007/s12035-016-0065-2

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