Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study
Background and objectives: Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive im...
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2023.1124431/full |
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| author | Jian Huang Jian Huang Dipender Gill Verena Zuber Paul M. Matthews Paul M. Matthews Paul Elliott Paul Elliott Paul Elliott Ioanna Tzoulaki Ioanna Tzoulaki Abbas Dehghan Abbas Dehghan Abbas Dehghan |
| author_facet | Jian Huang Jian Huang Dipender Gill Verena Zuber Paul M. Matthews Paul M. Matthews Paul Elliott Paul Elliott Paul Elliott Ioanna Tzoulaki Ioanna Tzoulaki Abbas Dehghan Abbas Dehghan Abbas Dehghan |
| author_sort | Jian Huang |
| collection | DOAJ |
| description | Background and objectives: Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive impairment.Methods: 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 using a meta-analysis of genome-wide association studies (GWAS) from the SCALLOP consortium (N = 17,747) based on three sets of criteria: 1) protein quantitative trait loci (pQTL); 2) cis-pQTL (pQTL within ±500 kb 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).Results: 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 0.577. Findings for MPO were replicated using the Icelandic GWAS. 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 a higher genetically predicted concentration of CSF-1 was associated with poorer cognitive performance.Conclusion: We conclude that these proteins are involved in shared pathways between CVD and those for cognitive reserve or affecting cognitive decline, suggesting therapeutic targets able to reduce genetic risks conferred by cardiovascular disease. |
| first_indexed | 2024-04-10T09:48:18Z |
| format | Article |
| id | doaj.art-f8755f9574bd47158bff69e714d09495 |
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| language | English |
| last_indexed | 2024-04-10T09:48:18Z |
| publishDate | 2023-02-01 |
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| series | Frontiers in Genetics |
| spelling | doaj.art-f8755f9574bd47158bff69e714d094952023-02-17T04:53:29ZengFrontiers Media S.A.Frontiers in Genetics1664-80212023-02-011410.3389/fgene.2023.11244311124431Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation studyJian Huang0Jian Huang1Dipender Gill2Verena Zuber3Paul M. Matthews4Paul M. Matthews5Paul Elliott6Paul Elliott7Paul Elliott8Ioanna Tzoulaki9Ioanna Tzoulaki10Abbas Dehghan11Abbas Dehghan12Abbas Dehghan13Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, SingaporeDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomDepartment of Brain Sciences, Faculty of Medicine, Imperial College London, London, United KingdomUK Dementia Research Institute at Imperial College London, London, United KingdomDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomUK Dementia Research Institute at Imperial College London, London, United KingdomMRC Centre for Environment and Health, School of Public Health, Imperial College London, London, United KingdomDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomDepartment of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, GreeceDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomUK Dementia Research Institute at Imperial College London, London, United KingdomMRC Centre for Environment and Health, School of Public Health, Imperial College London, London, United KingdomBackground and objectives: Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive impairment.Methods: 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 using a meta-analysis of genome-wide association studies (GWAS) from the SCALLOP consortium (N = 17,747) based on three sets of criteria: 1) protein quantitative trait loci (pQTL); 2) cis-pQTL (pQTL within ±500 kb 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).Results: 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 0.577. Findings for MPO were replicated using the Icelandic GWAS. 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 a higher genetically predicted concentration of CSF-1 was associated with poorer cognitive performance.Conclusion: We conclude that these proteins are involved in shared pathways between CVD and those for cognitive reserve or affecting cognitive decline, suggesting therapeutic targets able to reduce genetic risks conferred by cardiovascular disease.https://www.frontiersin.org/articles/10.3389/fgene.2023.1124431/fullproteinscardiovascular diseasecognitionmendelian randomisationmyeloperoxidase (MPO) |
| spellingShingle | Jian Huang Jian Huang Dipender Gill Verena Zuber Paul M. Matthews Paul M. Matthews Paul Elliott Paul Elliott Paul Elliott Ioanna Tzoulaki Ioanna Tzoulaki Abbas Dehghan Abbas Dehghan Abbas Dehghan Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study Frontiers in Genetics proteins cardiovascular disease cognition mendelian randomisation myeloperoxidase (MPO) |
| title | Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study |
| title_full | Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study |
| title_fullStr | Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study |
| title_full_unstemmed | Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study |
| title_short | Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study |
| title_sort | circulatory proteins relate cardiovascular disease to cognitive performance a mendelian randomisation study |
| topic | proteins cardiovascular disease cognition mendelian randomisation myeloperoxidase (MPO) |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2023.1124431/full |
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