title: Mitochondrial DNA haplogroup B5 confers genetic susceptibility to Alzheimer's disease in Han Chinese.
abstract: Mitochondrial dysfunction has been widely reported in psychiatric and neurodegenerative diseases. We aimed to investigate the association between matrilineal structures of Han Chinese populations and Alzheimer's disease (AD) by a 2-stage case-control study: A total of 341 AD patients and 435 normal individuals from Southwest China were analyzed for mitochondrial DNA sequence variations and were classified into respective haplogroups. A total of 371 AD patients and 470 normal individuals from East China, as validation samples, were genotyped for the variants defining the risk haplogroup. Haplogroup B5 had a significantly higher frequency in AD patients (7.33%) than in control subjects (3.68%) from Southwest China, and we found a similar pattern of higher frequency of B5 in patients in the case-control sample from East China. In the combined population, association of haplogroup B5 with AD risk was strengthened (p = 0.02; odds ratio = 1.74; 95% confidence interval = 1.10-2.76). In lymphoblastoid cell lines belonging to haplogroup B5a, we observed significantly increased reactive oxygen species and decreased mitochondrial mass. Hela cells with stable expression of the MT-ATP6 gene with B5-defining variant m.8584G>A also showed a significantly decreased mitochondrial function. Taken together, our results indicated that haplogroup B5 conferred genetic susceptibility to AD in Han Chinese, and this effect was most likely mediated by ancient variant m.8584G>A. The predisposing effect of B5 to AD is consistent with the ancestral-susceptibility model of complex diseases.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 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 & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Yu
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: Hui-Zhen
authors.initials: HZ
authors.lastname: Wang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Qiu-Xiang
authors.initials: QX
authors.lastname: Hu
authors.affiliation: Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong, University School of Medicine, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong, University School of Medicine, Shanghai, China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Lu
authors.affiliation: First Geriatric Department, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Ni
authors.affiliation: Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong, University School of Medicine, Shanghai, China.
authors.forename: Yiru
authors.initials: Y
authors.lastname: Fang
authors.affiliation: The Mental Health Center & Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China. Electronic address: ygyaozh@gmail.com.
authors.forename: Yong-Gang
authors.initials: YG
authors.lastname: Yao
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics; D010101:Oxygen Consumption / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012306:Risk; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; C501005:MT-ATP6 protein, human; D017382:Reactive Oxygen Species; D025261:Mitochondrial Proton-Translocating ATPases
keywords: Alzheimer's disease; Chinese; Genetic susceptibility; mtDNA haplogroup