Mendelian Randomization Estimates the Effects of Plasma and Cerebrospinal Fluid Proteins on Intelligence, Fluid Intelligence Score, and Cognitive Performance

Observational studies have revealed associations between levels of plasma and cerebrospinal fluid (CSF) proteins and cognition-related traits. However, these associations may be influenced by confounding factors inherent in observational research. This study aims to identify plasma and CSF proteins associated with intelligence, fluid intelligence score, and cognitive performance through the application of Mendelian randomization (MR). Proteomic quantitative trait locus (pQTL) data for plasma and CSF proteins were sourced from existing genome-wide association study (GWAS). Intelligence, fluid intelligence score, and cognitive performance GWAS summary statistics provided comprehensive data for two-sample MR analysis. Extensive sensitivity analyses, including Steiger testing, reverse MR analysis, and Bayesian co-localization, were conducted to validate associations and identify shared genetic variants. Phenotype scanning explored potential pleiotropic effects. MR analysis identified several proteins in plasma and CSF significantly associated with intelligence, fluid intelligence scores, and cognitive performance. For intelligence, negatively associated proteins in plasma include endoplasmic reticulum aminopeptidase 2 (ERAP2) and secretogranin III (SCG3), while positively associated proteins are myeloperoxidase (MPO), signal regulatory protein alpha (SIRPA), regulator of microtubule dynamics 1 (RMDN1), and endoplasmic reticulum lectin 1 (ERLEC1). In CSF, C1-esterase inhibitor and carboxypeptidase E (CBPE) both exhibited positive associations with intelligence. For fluid intelligence scores, negatively associated proteins in plasma are copine 1 (CPNE1) and SCG3, while positively associated proteins are nudix hydrolase 12 (NUDT12) and RMDN1. In CSF, Macrophage Stimulating Protein (MSP) demonstrated a significant negative impact. For cognitive performance, negatively associated proteins in plasma include ERAP2, tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1), and SCG3, while positively associated proteins are NUDT12, RMDN1, ERLEC1, and ectonucleotide pyrophosphatase/phosphodiesterase family member 5 (ENPP5). In CSF, C1-esterase inhibitor was positively associated, while MSP and soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 1(sTie-1) showed a negative association. Bayesian co-localization analysis revealed significant genetic overlaps between SIRPA, RMDN1, and ERLEC1 in plasma with intelligence; NUDT12 and SCG3 in plasma with fluid intelligence scores; and TIE1, NUDT12, RMDN1, ERLEC1, and ENPP5 in plasma with cognitive performance. Additionally, significant co-localization was identified between C1-esterase inhibitor and CBPE in CSF with intelligence, as well as between C1-esterase inhibitor and sTie-1 in CSF with cognitive performance. Reverse causality analysis confirmed the causal direction from proteins to cognitive traits. This study identifies specific plasma and CSF proteins that significantly impact intelligence, fluid intelligence scores, and cognitive performance. These proteins could serve as biomarkers and targets for future research and therapeutic interventions aimed at sustaining cognitive abilities and reducing impairment risks.