Observational Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatry. Mar 19, 2024; 14(3): 421-433
Published online Mar 19, 2024. doi: 10.5498/wjp.v14.i3.421
Causal relationship between feelings and cognitive decline: An univariable and multivariable Mendelian randomization study
Juan Liu, Lin Liu, Yi-Xin Hu, Jian-Hua Li, Xiao Zou, Hao-Yun Zhang, Li Fan
Juan Liu, Jian-Hua Li, Xiao Zou, Li Fan, Department of Cardiology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China
Lin Liu, Department of Pulmonary and Critical Care Medicine, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China
Yi-Xin Hu, The Fourth Department of Geriatric Health Care, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China
Hao-Yun Zhang, Department of Anesthesiology, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
Author contributions: Fan L ensured the overall integrity of the study, defined the intellectual content, participated in the literature search, and reviewed the manuscript; Liu J conducted the research, analyzed the data and drafted the initial manuscript; Liu L, Hu YX, and Zou X provided input and support for the research design; Li JH and Zhang HY offered assistance with statistical analysis; all authors read and approved the final manuscript.
Institutional review board statement: The study used public GWAS statistics and did not collect new human data. Hence, ethical approval was not required by the ethics committee of Chinese PLA General Hospital.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that there are no conflicts of interest associated with this research.
Data sharing statement: The data used in this study were obtained from publicly available genome-wide association studies (GWAS) databases. The summary-level data on intelligence were derived from a GWAS meta-analysis involving 14 independent epidemiological cohorts of European ancestry. The data related to feelings were obtained from separate GWAS datasets. Comprehensive GWAS information can be accessed through the public GWAS website (https://gwas.mrcieu.ac.uk/), with the provided identifiers. These datasets are publicly accessible and can be obtained directly from the GWAS website for research purposes. No additional data were used in this study.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Li Fan, MD, PhD, Dean, Department of Cardiology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China. fl6698@163.com
Received: November 30, 2023
Peer-review started: November 30, 2023
First decision: December 18, 2023
Revised: December 25, 2023
Accepted: February 4, 2024
Article in press: February 4, 2024
Published online: March 19, 2024
Processing time: 110 Days and 1.9 Hours
Abstract
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, PMVMR = 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, PUVMR = 0.037), this effect disappeared after adjusting for other feelings (ORMVMR = 1.42, 95%CI: 0.43-4.74, PMVMR = 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.

Keywords: Mendelian randomization analysis; Feelings; Cognition; Intelligence

Core Tip: Our two-sample Mendelian randomization analysis investigated the relationship between various emotions and cognitive function in the European population. We found compelling genetic evidence suggesting that sensitivity/hurt feelings may have a negative causal effect on cognition, even after adjusting for other emotional factors. In contrast, the causal link between worrier/anxious feelings and cognition remains inconclusive due to pleiotropy. Additionally, we did not find significant associations between happiness, guilty feelings, nervous feelings, miserableness, loneliness/isolation, and cognitive decline. This study sheds light on the complex interplay between emotions and cognition, highlighting the importance of sensitivity/hurt feelings in cognitive health.