Causal association and mediating effect of blood biochemical metabolic traits and brain image-derived endophenotypes on Alzheimer's disease
Kang-Fu Yin,
Xiao-Jing Gu,
Wei-Ming Su,
Ting Chen,
Jiang Long,
Li Gong,
Zhi-Ye Ying,
Meng Dou,
Zheng Jiang,
Qing-Qing Duan,
Bei Cao,
Xia Gao,
Li-Yi Chi,
Yong-Ping Chen
Affiliations
Kang-Fu Yin
Department of Neurology, Institute of Brain Science and Brain-inspired Technology, Centre for Rare Diseases, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
Xiao-Jing Gu
Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
Wei-Ming Su
Department of Neurology, Institute of Brain Science and Brain-inspired Technology, Centre for Rare Diseases, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
Ting Chen
Department of Neurology, Institute of Brain Science and Brain-inspired Technology, Centre for Rare Diseases, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
Jiang Long
Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
Li Gong
Rare Diseases Center, Outpatient Department, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
Zhi-Ye Ying
West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
Meng Dou
Chengdu institute of computer application, Chinese Academy of Sciences, Chengdu, 610041, Sichuan, China
Zheng Jiang
Department of Neurology, Institute of Brain Science and Brain-inspired Technology, Centre for Rare Diseases, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
Qing-Qing Duan
Department of Neurology, Institute of Brain Science and Brain-inspired Technology, Centre for Rare Diseases, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
Bei Cao
Department of Neurology, Institute of Brain Science and Brain-inspired Technology, Centre for Rare Diseases, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
Xia Gao
Department of Geriatrics, Dazhou central hospital, Dazhou, 635000, Sichuan, China
Li-Yi Chi
Department of Neurology, First Affiliated Hospital of Air Force Military Medical University, Xi'an, 710072, Shanxi, China
Yong-Ping Chen
Department of Neurology, Institute of Brain Science and Brain-inspired Technology, Centre for Rare Diseases, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Corresponding author.
Background: Recent genetic evidence supports that circulating biochemical and metabolic traits (BMTs) play a causal role in Alzheimer's disease (AD), which might be mediated by changes in brain structure. Here, we leveraged publicly available genome-wide association study data to investigate the intrinsic causal relationship between blood BMTs, brain image-derived phenotypes (IDPs) and AD. Methods: Utilizing the genetic variants associated with 760 blood BMTs and 172 brain IDPs as the exposure and the latest AD summary statistics as the outcome, we analyzed the causal relationship between blood BMTs and brain IDPs and AD by using a two-sample Mendelian randomization (MR) method. Additionally, we used two-step/mediation MR to study the mediating effect of brain IDPs between blood BMTs and AD. Results: Twenty-five traits for genetic evidence supporting a causal association with AD were identified, including 12 blood BMTs and 13 brain IDPs. For BMTs, glutamine consistently reduced the risk of AD in 3 datasets. For IDPs, specific alterations of cortical thickness (atrophy in frontal pole and insular lobe, and incrassation in superior parietal lobe) and subcortical volume (atrophy in hippocampus and its subgroups, left accumbens and left choroid plexus, and expansion in cerebral white matter) are vulnerable to AD. In the two-step/mediation MR analysis, superior parietal lobe, right hippocampal fissure and left accumbens were identified to play a potential mediating role among three blood BMTs and AD. Conclusions: The results obtained in our study suggest that 12 circulating BMTs and 13 brain IDPs play a causal role in AD. Importantly, a subset of BMTs exhibit shared genetic architecture and potentially causal relationships with brain structure, which may contribute to the alteration of brain IDPs in AD.
