C-reactive protein and cognitive impairment: A bidirectional Mendelian randomization study
Wenhuo Xie1, Chenghua Kong1, Wei Luo2
1Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fujian Medical University, Fuzhou, China.
Insights
Genetically proxied C-reactive protein (CRP) is linked to prospective memory decline. Reverse analysis suggests cognitive performance and fluid intelligence may influence CRP levels, indicating a complex relationship between inflammation and cognition.
Area of Science:
- Neuroscience
- Genetics
- Inflammation Research
Background:
- C-reactive protein (CRP) is a known risk factor for cognitive impairment.
- Observational studies suggest a link, but causal relationships remain unclear.
- Mendelian randomization (MR) can investigate genetic associations to infer causality.
Purpose of the Study:
- To determine the causal association between C-reactive protein (CRP) and cognitive impairment using bidirectional Mendelian randomization (MR).
- To investigate the genetic link between CRP levels and various cognitive functions.
Main Methods:
- Utilized genome-wide association studies (GWAS) summary statistics for CRP and cognitive traits (performance, fluid intelligence, prospective memory, reaction time).
- Employed bidirectional MR analysis with multiple methods (IVW, MR Egger, weighted median, etc.).
- Conducted MR sensitivity analyses to assess pleiotropy and heterogeneity.
Main Results:
- Forward MR indicated a significant association between genetically proxied CRP and prospective memory (P=0.009).
- Little evidence supported CRP's association with other cognitive tests.
- Reverse MR suggested potential associations between genetically proxied cognitive performance/fluid intelligence and CRP levels (P=0.002, P=0.019).
Conclusions:
- Genetically proxied CRP impacts prospective memory, but not other cognitive measures.
- Evidence suggests a bidirectional relationship, with cognition potentially influencing CRP levels.
- MR sensitivity analyses confirmed the robustness of the CRP-prospective memory association.
Objectives:
While C-reactive protein (CRP) has been solidly linked as a risk factor for cognitive impairment, observational research alone cannot definitively demonstrate a causal relationship. This study therefore sought to determine whether there was an association between CRP and the development of cognitive impairment.
Methods:
This study employed bidirectional Mendelian randomization (MR) to investigate the genetic association between CRP and cognitive impairment. genome-wide association studies (GWAS) summary statistics for both were sourced from IEU Open GWAS or prior reports. Cognitive GWAS's used were on tests designed to assess cognitive performance, fluid intelligence, prospective memory, and reaction time. The MR analysis applied several methods, including inverse variance-weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode approaches, then use of MR sensitivity analyses to interrogate findings.
Results:
Forward MR analysis showed that genetically proxied CRP was associated with prospective memory (P = 0.009), whereas there is little evidence to support an association between CRP and other cognitive tests. Reverse MR analysis indicated a potential association between genetic proxy cognitive performance (P = 0.002) and fluid intelligence score (P = 0.019) with CRP levels. For genetically proxied CRP on prospective memory, the level of pleiotropy (P > 0.05) and no genetic variant heterogeneity (P > 0.05) made bias unlikely, and leave-one-out tests also confirmed robust associations.
Conclusions:
The effect of genetically proxied CRP on prospective memory, with little evidence on other cognitive tests. The reverse MR shows some evidence of genetically proxied cognition (cognitive performance and fluid intelligence) on CRP levels.
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