Causal relationship between feelings and cognitive decline: An univariable and multivariable Mendelian randomization study

BACKGROUND While the impact of depression on cognition is well-documented, the relationship between feelings and cognition has received limited attention. AIM To explore the potential association between feelings and cognition with a two-sample Mendelian randomization (MR) analysis. METHODS Our analysis utilized genome-wide association data on various feelings (fed-up feelings, n = 453071; worrier/anxious feelings, n = 450765; guilty feelings, n = 450704; nervous feelings, n = 450700; sensitivity/hurt feelings, n = 449419; miserableness, n = 454982; loneliness/isolation, n = 455364; happiness, n = 152348) in the European population and their impact on cognitive functions (intelligence, n = 269867). Conducting a univariable MR (UVMR) analysis to assess the relationship between feelings and cognition. In this analysis, we applied the inverse variance weighting (IVW), weighted median, and MR Egger methods. Additionally, we performed sensitivity analysis (leave-one-out analysis), assessed heterogeneity (using MR-PRESSO and Cochran's Q test), and conducted multiple validity test (employing MR-Egger regression). Subsequently, a multivariable MR (MVMR) analysis was employed to examine the impact of feelings on cognition. IVW served as the primary method in the multivariable analysis, complemented by median-based and MR-Egger methods. RESULTS In this study, UVMR indicated that sensitivity/hurt feelings may have a negative causal effect on cognition (OR = 0.63, 95%CI: 0.43-0.92, P = 0.017). After adjustment of other feelings using MVMR, a direct adverse causal effect on cognition was observed (ORMVMR = 0.39, 95%CI: 0.17-0.90, P-MVMR = 0.027). While a potential increased risk of cognitive decline was observed for fed-up feelings in the UVMR analysis (ORUVMR = 0.64, 95%CI: 0.42-0.97, P-UVMR = 0.037), this effect disappeared after adjusting for other feelings (ORMVMR = 1.42, 95%CI: 0.43-4.74, P-MVMR = 0.569). These findings were generally consistent across MV-IVW, median-based, and MR-Egger analyses. MR-Egger regression revealed pleiotropy in the impact of worrier/anxious feelings on cognition, presenting a challenge in identifying the effect. Notably, this study did not demonstrate any significant impact of guilty feelings, nervous feelings, miserableness, or loneliness/isolation on cognition. Due to a limited number of instrumental variables for happiness, this study was unable to analyze the relationship between happiness and cognition. CONCLUSION This MR study finds that sensitivity/hurt feelings are associated with cognitive decline, while the link between worrier/anxious feelings and cognition remains inconclusive. Insufficient evidence supports direct associations between happiness, guilty feelings, nervous feelings, miserableness, loneliness/isolation, and cognition.