Cerebrospinal Fluid C1-Esterase Inhibitor and Tie-1 Levels Affect Cognitive Performance: Evidence from Proteome-Wide...

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• The relationship between cerebrospinal fluid (CSF) protein concentrations and cognitive function is not well understood in the general population.
• Investigating potential causal links can offer new insights into cognitive performance mechanisms.

Purpose of the Study:

• To explore the association between CSF protein levels and cognitive performance using Mendelian randomization (MR).
• To identify specific CSF proteins that may causally influence cognitive abilities.

Main Methods:

• Mendelian randomization (MR) analyses were employed to assess the causal effect of genetically predicted CSF protein levels on cognitive performance.
• Genetic data from genome-wide association studies (GWAS) for CSF proteins (up to 835 individuals) and cognitive performance (257,841 individuals) were utilized.
• Colocalization analyses and examination of cognition-related phenotypes were performed for validation.

Main Results:

• Genetically predicted levels of C1-esterase inhibitor in CSF were associated with improved cognitive performance (effect size: 0.23, p=7.91 × 10^-5).
• Soluble tyrosine-protein kinase receptor Tie-1 (sTie-1) levels in CSF were linked to worse cognitive performance (effect size: -0.43, p=2.08 × 10^-5).
• These associations were corroborated by colocalization analyses and consistent effects on related cognitive and brain measures.

Conclusions:

• Human genetic evidence suggests that C1-esterase inhibitor and sTie-1 play a role in cognitive performance.
• These findings highlight specific CSF proteins as potential targets for understanding and influencing cognitive function.