Genomic Characterisation of the Relationship and Causal Links Between Vascular Calcification, Alzheimer’s Disease, and Cognitive Traits
Background/Objectives: Observational studies suggest a link between vascular calcification and dementia or cognitive decline, but the evidence is conflicting, and the underlying mechanisms are unclear. Here, we investigate the shared genetic and causal relationships of vascular calcification—coronar...
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| Format: | Journal Article |
| Language: | English |
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MDPI
2025
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| Online Access: | http://hdl.handle.net/20.500.11937/97601 |
| _version_ | 1848766295652171776 |
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| author | Adewuyi, Emmanuel |
| author_facet | Adewuyi, Emmanuel |
| author_sort | Adewuyi, Emmanuel |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Background/Objectives: Observational studies suggest a link between vascular calcification and dementia or cognitive decline, but the evidence is conflicting, and the underlying mechanisms are unclear. Here, we investigate the shared genetic and causal relationships of vascular calcification—coronary artery calcification (CAC) and abdominal aortic calcification (AAC)—with Alzheimer’s disease (AD), and five cognitive traits. Methods: We analyse large-scale genome-wide association studies (GWAS) summary statistics, using well-regarded methods, including linkage disequilibrium score regression (LDSC), Mendelian randomisation (MR), pairwise GWAS (GWAS-PW), and gene-based association analysis. Results: Our findings reveal a nominally significant positive genome-wide genetic correlation between CAC and AD, which becomes non-significant after excluding the APOE region. CAC and AAC demonstrate significant negative correlations with cognitive performance and educational attainment. MR found no causal association between CAC or AAC and AD or cognitive traits, except for a bidirectional borderline-significant association between AAC and fluid intelligence scores. Pairwise-GWAS analysis identifies no shared causal SNPs (posterior probability of association [PPA]3 < 0.5). However, we find pleiotropic loci (PPA4 > 0.9), particularly on chromosome 19, with gene association analyses revealing significant genes in shared regions, including APOE, TOMM40, NECTIN2, and APOC1. Moreover, we identify suggestively significant loci (PPA4 > 0.5) on chromosomes 1, 6, 7, 9 and 19, implicating pleiotropic genes, including NAV1, IPO9, PHACTR1, UFL1, FHL5, and FOCAD. Conclusions: Current findings reveal limited genetic correlation and no significant causal associations of CAC and AAC with AD or cognitive traits. However, significant pleiotropic loci, particularly at the APOE region, highlight the complex interplay between vascular calcification and neurodegenerative processes. Given APOE’s roles in lipid metabolism, neuroinflammation, and vascular integrity, its involvement may link vascular and neurodegenerative disorders, pointing to potential targets for further investigation. |
| first_indexed | 2025-11-14T11:48:53Z |
| format | Journal Article |
| id | curtin-20.500.11937-97601 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | eng |
| last_indexed | 2025-11-14T11:48:53Z |
| publishDate | 2025 |
| publisher | MDPI |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-976012025-04-25T13:23:15Z Genomic Characterisation of the Relationship and Causal Links Between Vascular Calcification, Alzheimer’s Disease, and Cognitive Traits Adewuyi, Emmanuel Alzheimer’s disease Mendelian randomisation abdominal aortic calcification cognitive traits coronary artery calcification vascular calcification Background/Objectives: Observational studies suggest a link between vascular calcification and dementia or cognitive decline, but the evidence is conflicting, and the underlying mechanisms are unclear. Here, we investigate the shared genetic and causal relationships of vascular calcification—coronary artery calcification (CAC) and abdominal aortic calcification (AAC)—with Alzheimer’s disease (AD), and five cognitive traits. Methods: We analyse large-scale genome-wide association studies (GWAS) summary statistics, using well-regarded methods, including linkage disequilibrium score regression (LDSC), Mendelian randomisation (MR), pairwise GWAS (GWAS-PW), and gene-based association analysis. Results: Our findings reveal a nominally significant positive genome-wide genetic correlation between CAC and AD, which becomes non-significant after excluding the APOE region. CAC and AAC demonstrate significant negative correlations with cognitive performance and educational attainment. MR found no causal association between CAC or AAC and AD or cognitive traits, except for a bidirectional borderline-significant association between AAC and fluid intelligence scores. Pairwise-GWAS analysis identifies no shared causal SNPs (posterior probability of association [PPA]3 < 0.5). However, we find pleiotropic loci (PPA4 > 0.9), particularly on chromosome 19, with gene association analyses revealing significant genes in shared regions, including APOE, TOMM40, NECTIN2, and APOC1. Moreover, we identify suggestively significant loci (PPA4 > 0.5) on chromosomes 1, 6, 7, 9 and 19, implicating pleiotropic genes, including NAV1, IPO9, PHACTR1, UFL1, FHL5, and FOCAD. Conclusions: Current findings reveal limited genetic correlation and no significant causal associations of CAC and AAC with AD or cognitive traits. However, significant pleiotropic loci, particularly at the APOE region, highlight the complex interplay between vascular calcification and neurodegenerative processes. Given APOE’s roles in lipid metabolism, neuroinflammation, and vascular integrity, its involvement may link vascular and neurodegenerative disorders, pointing to potential targets for further investigation. 2025 Journal Article http://hdl.handle.net/20.500.11937/97601 10.3390/biomedicines13030618 eng MDPI unknown |
| spellingShingle | Alzheimer’s disease Mendelian randomisation abdominal aortic calcification cognitive traits coronary artery calcification vascular calcification Adewuyi, Emmanuel Genomic Characterisation of the Relationship and Causal Links Between Vascular Calcification, Alzheimer’s Disease, and Cognitive Traits |
| title | Genomic Characterisation of the Relationship and Causal Links Between Vascular Calcification, Alzheimer’s Disease, and Cognitive Traits |
| title_full | Genomic Characterisation of the Relationship and Causal Links Between Vascular Calcification, Alzheimer’s Disease, and Cognitive Traits |
| title_fullStr | Genomic Characterisation of the Relationship and Causal Links Between Vascular Calcification, Alzheimer’s Disease, and Cognitive Traits |
| title_full_unstemmed | Genomic Characterisation of the Relationship and Causal Links Between Vascular Calcification, Alzheimer’s Disease, and Cognitive Traits |
| title_short | Genomic Characterisation of the Relationship and Causal Links Between Vascular Calcification, Alzheimer’s Disease, and Cognitive Traits |
| title_sort | genomic characterisation of the relationship and causal links between vascular calcification, alzheimer’s disease, and cognitive traits |
| topic | Alzheimer’s disease Mendelian randomisation abdominal aortic calcification cognitive traits coronary artery calcification vascular calcification |
| url | http://hdl.handle.net/20.500.11937/97601 |