Modifiable lifestyle factors influencing neurological and psychiatric disorders mediated by structural brain reserve: An observational and Mendelian randomization study

Abstract

Modifiable lifestyle factors are implicated as risk factors for neurological and psychiatric disorders, but whether these associations are causal remains uncertain. We aimed to evaluate associations and ascertain causal relationships between modifiable lifestyle factors, neurological and psychiatric disorder risk, and brain structural magnetic resonance imaging (MRI) markers. We analyzed data from over 50,000 UK Biobank participants with self-reported lifestyle factors, including alcohol consumption, smoking, physical activity, diet, sleep, electronic device use, and sexual factors. Primary outcomes were stroke, all-cause dementia, Parkinson's disease (PD), Major depression disorder (MDD), Anxiety Disorders (ANX), and Bipolar Disorder (BIP), alongside MRI markers. Summary statistics were obtained from genome-wide association studies and Mendelian randomization (MR) analyses investigated bidirectional associations between lifestyle factors, neurological/psychiatric disorders, and MRI markers, with mediation assessed using multivariable Mendelian randomization (MVMR). Cross-sectional analyses identified lifestyle factors were associated with neurological and psychiatric disorders and brain morphology. MR confirmed causal relationships, including lifetime smoking index on Stroke, PD, MDD, ANX and BIP; play computer games on BIP; leisure screen time on Stroke and MDD; automobile speeding propensity on MDD; sexual factors on MDD and BIP; sleep characteristics on BIP and MDD. Brain structure mediated several lifestyle-disorder associations, such as daytime dozing and dementia, lifetime smoking and PD and age first had sexual intercourse and PD. Our results provide support for a causal effect of multiple lifestyle measures on the risk of neurological and psychiatric disorders, with brain structural morphology serving as a potential biological mediator in their associations. • Comprehensive and Large-scale Analysis: We utilized a large dataset from the UK Biobank, encompassing a diverse range of lifestyle factors and neurological/psychiatric outcomes, which enhances the robustness and generalizability of our findings. • Causal Inference: Using bidirectional two-sample MR, we examined causal effects of lifestyle traits on brain reserve and disorders, reducing confounding bias. Extensive sensitivity analyses validated MR assumptions. • Brain Morphology as a Mediator: Exploring brain structure as a mediator revealed biological pathways linking lifestyle to brain health, offering insights into disease mechanisms.