The brain structure, immunometabolic and genetic mechanisms underlying the association between lifestyle and depression

Acknowledgements: This study used the UK Biobank Resource under application no. 19542. We thank all participants and researchers from the UK Biobank. The study was supported by grants from the National Natural Science Foundation of China (nos. 82071997 and 82071201), Science and Technology Innovation 2030 Major Projects (2022ZD0211600), the National Key R&D Program of China (nos. 2018YFC1312900 and 2019YFA0709502), Shanghai Municipal Science and Technology Major Project (no. 2018SHZDZX01), Shanghai Rising-Star Program (21QA1408700), 111 Project (B18015) and Zhangjiang Lab, Tianqiao and Chrissy Chen Institute, the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of the Ministry of Education, Shanghai Center for Brain Science and Brain-Inspired Technology, Fudan University.Funder: National Key R&D Program of China(no.2018YFC1312900 and 2019YFA0709502);Shanghai Municipal Science and Technology Major Project(no.2018SHZDZX01);ZHANGJIANG LAB, Shanghai Center for Brain Science and Brain-Inspired Technology and the 111 Project (no.B18015)Funder: Science and Technology Innovation 2030 Major Projects (no. 2022ZD0211600); Shanghai Municipal Science and Technology Major Project (no.2018SHZDZX01); Research Start-up Fund of Huashan Hospital (no.2022QD002); Excellence 2025 Talent Cultivation Program at Fudan University (no.3030277001), and ZHANGJIANG LAB, Tianqiao and Chrissy Chen Institute, and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University.Funder: Shanghai Rising-Star Program (no.21QA1408700)AbstractLifestyle factors have been acknowledged to be modifiable targets that can be used to counter the increasing prevalence of depression. This study aims to investigate combining an extensive range of lifestyle factors, including alcohol consumption, diet, physical activity, sleep, smoking, sedentary behavior and social connection, that contribute to depression, and examine the underlying neurobiological mechanisms. Over nine years of follow-up, a multivariate Cox model was utilized on 287,282 participants from UK Biobank to demonstrate the protective roles of seven lifestyle factors and combined lifestyle score on depression. Combining genetic risk and lifestyle category in 197,344 participants, we found that a healthy lifestyle decreased the risk of depression across a population with varied genetic risk. Mendelian randomization confirmed the causal relationship between lifestyle and depression. A broad range of brain regions and peripheral biomarkers were related to lifestyle, including the pallidum, the precentral cortex, triglycerides and C-reactive protein. Structural equation modeling on 18,244 participants revealed underlying neurobiological mechanisms involving lifestyle, brain structure, immunometabolic function, genetics and depression. Together, our findings suggest that adherence to a healthy lifestyle could aid in the prevention of depression.