A Phenome-wide Association and Mendelian Randomization Study for Alzheimer?s Disease: A Prospective Cohort Study of 502,493 Participants From the UK Biobank

被引:7
作者
Chen, Shi-Dong [1 ]
Zhang, Wei [2 ,3 ]
Li, Yu-Zhu [2 ,3 ]
Yang, Liu [1 ]
Huang, Yu-Yuan [1 ]
Deng, Yue-Ting [1 ]
Wu, Bang-Sheng [1 ]
Suckling, John [4 ]
Rolls, Edmund T. [2 ,5 ,6 ]
Feng, Jian-Feng [2 ,3 ,7 ,8 ,9 ]
Cheng, Wei [1 ,2 ,3 ,7 ]
Dong, Qiang [1 ]
Yu, Jin-Tai [1 ,2 ]
机构
[1] Fudan Univ, Huashan Hosp, Inst Neurol, Shanghai Med Coll, Shanghai, Peoples R China
[2] Fudan Univ, Inst Sci & Technol Brain Inspired Intelligence, Shanghai, Peoples R China
[3] Fudan Univ, Key Lab Computa t Neurosci & Brain Inspired Intell, Minist Educ, Shanghai, Peoples R China
[4] Univ Cambridge, Depart ment Psychiat, Cambridge, England
[5] Oxford Ctr Computat Neurosci, Oxford, England
[6] Univ Warwick, Dept Comp Sci, Coventry, England
[7] Zhejiang Normal Univ, Fudan ISTBI ZJNU Algorithm Ctr Brain Inspired Inte, Jinhua, Peoples R China
[8] Fudan Univ, MOE Frontiers Ctr Brain Sci, Shanghai, Peoples R China
[9] Zhangjiang Fudan Int Innovat Ctr, Shanghai, Peoples R China
基金
英国医学研究理事会; 英国惠康基金; 美国国家卫生研究院; 中国国家自然科学基金;
关键词
HIPPOCAMPAL VOLUMES; ENTORHINAL CORTEX; RISK; METAANALYSIS; INFERIOR; ATROPHY; SCANS; SCORE; LOCI; MASS;
D O I
10.1016/j.biopsych.2022.08.002
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
BACKGROUND: Considerable uncertainty remains regarding associations of multiple risk factors with Alzheimer's disease (AD). We aimed to systematically screen and validate a wide range of potential risk factors for AD.METHODS: Among 502,493 participants from the UK Biobank, baseline data were extracted for 4171 factors spanning 10 different categories. Phenome-wide association analyses and time-to-event analyses were conducted to identify factors associated with both polygenic risk scores for AD and AD diagnosis at follow-up. We performed two -sample Mendelian randomization analysis to further assess their potential causal relationships with AD and imaging association analysis to discover underlying mechanisms.RESULTS: We identified 39 factors significantly associated with both AD polygenic risk scores and risk of incident AD, where higher levels of education, body size, basal metabolic rate, fat-free mass, computer use, and cognitive functions were associated with a decreased risk of developing AD, and selective food intake and more outdoor exposures were associated with an increased risk of developing AD. The identified factors were also associated with AD-related brain structures, including the hippocampus, entorhinal cortex, and inferior/middle temporal cortex, and 21 of these factors were further supported by Mendelian randomization evidence.CONCLUSIONS: To our knowledge, this is the first study to comprehensively and rigorously assess the effects of wide-ranging risk factors on AD. Strong evidence was found for fat-free body mass, basal metabolic rate, computer use, selective food intake, and outdoor exposures as new risk factors for AD. Integration of genetic, clinical, and neuroimaging information may help prioritize risk factors and prevention targets for AD.
引用
收藏
页码:790 / 801
页数:12
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