Unraveling the brain-joint axis: genetic, transcriptomic, and cohort insights from neuroticism to osteoarthritis

The causal relationships between neuroticism and osteoarthritis (OA) were inconclusive in observational studies. We conducted bidirectional two-sample Mendelian randomization (MR) and transcriptome-wide association studies to determine the associations and the underlying transcriptomic basis. The summary-level genome-wide association study data for any site OA, knee OA, erosive hand OA, and hip OA were mainly derived from UK Biobank, and neuroticism was derived from CTGlab. We then utilized weighted regression and propensity score matching (PSM) models to investigate the relationship between neuroticism and OA in 11,948 participants of European ancestry from the National Health and Nutrition Examination Survey from 2005 to 2018. Bidirectional two-sample MR studies revealed that feelings of being fed-up, a sense of miserableness, mood swings, and a higher neuroticism score were all linked to an increased risk of OA. These factors were specifically associated with OA at various sites, including the knee. Conversely, there was no evidence to suggest that OA had any influence on traits related to neuroticism. In a comprehensive analysis that accounted for variables such as age, sex, blood lipids, blood glucose, body weight, smoking, alcohol consumption, and physical activity, it was determined that mental fluctuation significantly increased the incidence of self-reported OA (OR 1.37, 95% CI 1.20-1.58, P < 0.001) based on weighted regression. Further confirmation was provided by PSM analysis, which showed that mental fluctuation was associated with a higher incidence of self-reported OA (OR 1.28, 95% CI 1.08-1.52, P = 0.004). Moreover, differentially expressed genes were enriched in several biological processes, including the cell cycle, lipid metabolism, RNA processing, and immuno-inflammatory responses. The results revealed significant genetic and population-based associations, as well as underlying mechanisms, between neuroticism and osteoarthritis, supporting the concept of a brain-joint axis.