Circulatory proteins relate cardiovascular disease to cognitive performance: a Mendelian randomisation study
Jian Huang, Dipender Gill, Verena Zuber, Paul M Matthews, Paul Elliott, Ioanna Tzoulaki, Abbas Dehghan- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. The objective of this study was to investigate the causal relationship between cardiovascular disease (CVD) related proteins and cognitive decline.
Method
We applied Mendelian randomisation (MR) and colocalization analysis to investigate the causal relationships of 90 CVD‐related proteins measured by the Olink CVD I panel with cognitive traits. Genetic instruments for circulatory protein concentrations were obtained from a genome‐wide association study (GWAS) meta‐analysis from the SCALLOP consortium (N = 17,747) based on three sets of criteria: 1) protein quantitative trait loci (pQTL); 2) cis‐pQTL (pQTL within ±500kb from the coding gene); and 3) brain‐specific cis‐expression QTL (cis‐eQTL) which accounts for coding gene expression based on GTEx8. Genetic associations of cognitive performance were obtained from GWAS for either: 1) general cognitive function constructed using Principal Component Analysis (N = 300,486); or, 2) g‐Factor constructed using genomic structural equation modelling (N = 11,263‐331,679). Findings for candidate causal proteins were replicated using a separate protein GWAS in Icelanders (N = 35,559).
Result
A higher concentration of genetically predicted circulatory myeloperoxidase (MPO) was nominally associated with better cognitive performance (P<0.05) using different selection criteria for genetic instruments. Particularly, brain‐specific cis‐eQTL predicted MPO, which accounts for protein coding gene expression in brain tissues, was associated with general cognitive function (βWald = 0.22, PWald = 2.4×10−4). The posterior probability for colocalization (PP.H4) of MPO pQTL with the g Factor was 0.58. Findings for MPO were replicated using a GWAS on cognitive score in an Icelandic population. Although we did not find evidence for colocalization, we found that higher genetically predicted concentrations of cathepsin D and CD40 were associated with better cognitive performance and higher genetically predicted concentration of CSF‐1 were associated with poorer cognitive performance.
Conclusion
The study suggests that proteins primarily identified for their role in cardiovascular diseases may be involved in shared pathways with cognitive reserve or cognitive decline, and may confer therapeutic targets for neurodegenerative diseases such as Alzheimer’s disease.