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Causal associations between chronic heart failure and the cerebral cortex: results from Mendelian randomization study
Liqi Peng1, Huzhi Cai2, Yanping Tang3
1The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China.
Insights
Chronic heart failure (CHF) is linked to increased thickness in the pars opercularis region of the cerebral cortex. This study used Mendelian randomization to explore the causal relationship between CHF and brain structure.
Area of Science:
- Neuroscience
- Genetics
- Cardiology
Background:
- Chronic heart failure (CHF) is associated with changes in brain structure and cognitive function.
- The precise mechanisms linking CHF to cerebral cortical alterations remain unclear.
- Investigating these links is crucial for understanding neurological comorbidities of CHF.
Purpose of the Study:
- To investigate the potential causal relationship between chronic heart failure (CHF) and cerebral cortical structure using Mendelian randomization (MR).
- To identify specific regions of the cerebral cortex affected by CHF.
- To explore potential mediating genes involved in the observed associations.
Main Methods:
- Genome-wide association studies (GWAS) were employed to identify genetic variants associated with CHF and cerebral cortical structure.
- Mendelian randomization analysis, primarily using the inverse-variance weighted (IVW) method, was conducted.
- Pleiotropy and heterogeneity tests (MR-Egger, Cochran's Q) were used for validation, alongside replication analysis and bioinformatics approaches.
Main Results:
- No significant causal association was found between genetically predicted CHF and overall cerebral cortical surface area (SA).
- A significant causal association was identified, showing that CHF increases the thickness (TH) of the pars opercularis.
- Replication analysis confirmed the positive causal link between CHF and pars opercularis thickness, with specific mediator genes identified.
Conclusions:
- Genetic evidence supports a positive causal relationship between chronic heart failure and increased thickness of the pars opercularis.
- These findings highlight a specific structural brain alteration in individuals with CHF.
- Further research into the identified mediator genes may elucidate the underlying biological mechanisms.
Background:
Chronic heart failure (CHF) patients exhibit alterations in cerebral cortical structure and cognitive function. However, the mechanisms by which CHF affects cortical structure and functional regions remain unknown. This study aims to investigate potential causal relationship between CHF and cerebral cortical structure through Mendelian randomization (MR).
Methods:
The research utilized genome-wide association studies (GWAS) to explore the causal association between CHF and cerebral cortical structure. The results were primarily analyzed using the inverse-variance weighted (IVW). The reliability of the data was verified through horizontal pleiotropy and heterogeneity analysis by MR-Egger intercept test and Cochran's Q-test, respectively. Replication analysis was conducted in the Integrative Epidemiology Unit (IEU) OpenGWAS project for further validation. In addition, we collected mediator genes that mediate causality to reveal potential mechanisms. Integrated bioinformatics analysis was conducted using the Open Target Genetics platform, the STRING database, and Cytoscape software.
Results:
The IVW results did not reveal any significant causal association between genetically predicted CHF and the overall structure of the cerebral cortex or the surface area (SA) of the 34 functional regions of the cerebral cortex (P > 0.05). However, the results revealed that CHF increased the thickness (TH) of pars opercularis (IVW: β = 0.015, 95% CI: 0.005-0.025, P = 3.16E-03). Replication analysis supported the causal association between CHF and pars opercularis TH (IVW: β = 0.02, 95% CI: 0.010-0.033, P = 1.84E-04). We examined the degree centrality values of the top 10 mediator genes, namely CDKN1A, CELSR2, NME5, SURF4, PSMA5, TSC1, RPL7A, SURF6, PRDX3, and FTO.
Conclusion:
Genetic evidence indicates a positive correlation between CHF and pars opercularis TH.
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