Investigating Genetic Overlap between Alzheimer’s Disease, Lipids, and Coronary Artery Disease: A Large-Scale Genome-Wide Cross Trait Analysis
There is evidence to support a link between abnormal lipid metabolism and Alzheimer’s disease (AD) risk. Similarly, observational studies suggest a comorbid relationship between AD and coronary artery disease (CAD). However, the intricate biological mechanisms of AD are poorly understood, and its re...
| Main Authors: | , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Online Access: | http://hdl.handle.net/20.500.11937/97665 |
| _version_ | 1848766299950284800 |
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| author | Kirby, A. Porter, T. Adewuyi, Emmanuel Laws, S.M. |
| author_facet | Kirby, A. Porter, T. Adewuyi, Emmanuel Laws, S.M. |
| author_sort | Kirby, A. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | There is evidence to support a link between abnormal lipid metabolism and Alzheimer’s disease (AD) risk. Similarly, observational studies suggest a comorbid relationship between AD and coronary artery disease (CAD). However, the intricate biological mechanisms of AD are poorly understood, and its relationship with lipids and CAD traits remains unresolved. Conflicting evidence further underscores the ongoing investigation into this research area. Here, we systematically assess the cross-trait genetic overlap of AD with 13 representative lipids (from eight classes) and seven CAD traits, leveraging robust analytical methods, well-powered large-scale genetic data, and rigorous replication testing. Our main analysis demonstrates a significant positive global genetic correlation of AD with triglycerides and all seven CAD traits assessed—angina pectoris, cardiac dysrhythmias, coronary arteriosclerosis, ischemic heart disease, myocardial infarction, non-specific chest pain, and coronary artery disease. Gene-level analyses largely reinforce these findings and highlight the genetic overlap between AD and three additional lipids: high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), and total cholesterol. Moreover, we identify genome-wide significant genes (Fisher’s combined p value [FCPgene] < 2.60 × 10−6) shared across AD, several lipids, and CAD traits, including WDR12, BAG6, HLA-DRA, PHB, ZNF652, APOE, APOC4, PVRL2, and TOMM40. Mendelian randomisation analysis found no evidence of a significant causal relationship between AD, lipids, and CAD traits. However, local genetic correlation analysis identifies several local pleiotropic hotspots contributing to the relationship of AD with lipids and CAD traits across chromosomes 6, 8, 17, and 19. Completing a three-way analysis, we confirm a strong genetic correlation between lipids and CAD traits—HDL and sphingomyelin demonstrate negative correlations, while LDL, triglycerides, and total cholesterol show positive correlations. These findings support genetic overlap between AD, specific lipids, and CAD traits, implicating shared but non-causal genetic susceptibility. The identified shared genes and pleiotropic hotspots are valuable targets for further investigation into AD and, potentially, its comorbidity with CAD traits. |
| first_indexed | 2025-11-14T11:48:57Z |
| format | Journal Article |
| id | curtin-20.500.11937-97665 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | eng |
| last_indexed | 2025-11-14T11:48:57Z |
| publishDate | 2024 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-976652025-05-03T08:11:58Z Investigating Genetic Overlap between Alzheimer’s Disease, Lipids, and Coronary Artery Disease: A Large-Scale Genome-Wide Cross Trait Analysis Kirby, A. Porter, T. Adewuyi, Emmanuel Laws, S.M. Alzheimer’s disease Mendelian randomisation coronary artery disease gene-based analysis global genetic correlation linkage disequilibrium score regression lipids local analysis of [co]variant associations local genetic correlation Humans Alzheimer Disease Coronary Artery Disease Genome-Wide Association Study Genetic Predisposition to Disease Lipids Lipid Metabolism Quantitative Trait Loci Polymorphism, Single Nucleotide Triglycerides Humans Alzheimer Disease Genetic Predisposition to Disease Lipids Triglycerides Polymorphism, Single Nucleotide Quantitative Trait Loci Lipid Metabolism Coronary Artery Disease Genome-Wide Association Study There is evidence to support a link between abnormal lipid metabolism and Alzheimer’s disease (AD) risk. Similarly, observational studies suggest a comorbid relationship between AD and coronary artery disease (CAD). However, the intricate biological mechanisms of AD are poorly understood, and its relationship with lipids and CAD traits remains unresolved. Conflicting evidence further underscores the ongoing investigation into this research area. Here, we systematically assess the cross-trait genetic overlap of AD with 13 representative lipids (from eight classes) and seven CAD traits, leveraging robust analytical methods, well-powered large-scale genetic data, and rigorous replication testing. Our main analysis demonstrates a significant positive global genetic correlation of AD with triglycerides and all seven CAD traits assessed—angina pectoris, cardiac dysrhythmias, coronary arteriosclerosis, ischemic heart disease, myocardial infarction, non-specific chest pain, and coronary artery disease. Gene-level analyses largely reinforce these findings and highlight the genetic overlap between AD and three additional lipids: high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), and total cholesterol. Moreover, we identify genome-wide significant genes (Fisher’s combined p value [FCPgene] < 2.60 × 10−6) shared across AD, several lipids, and CAD traits, including WDR12, BAG6, HLA-DRA, PHB, ZNF652, APOE, APOC4, PVRL2, and TOMM40. Mendelian randomisation analysis found no evidence of a significant causal relationship between AD, lipids, and CAD traits. However, local genetic correlation analysis identifies several local pleiotropic hotspots contributing to the relationship of AD with lipids and CAD traits across chromosomes 6, 8, 17, and 19. Completing a three-way analysis, we confirm a strong genetic correlation between lipids and CAD traits—HDL and sphingomyelin demonstrate negative correlations, while LDL, triglycerides, and total cholesterol show positive correlations. These findings support genetic overlap between AD, specific lipids, and CAD traits, implicating shared but non-causal genetic susceptibility. The identified shared genes and pleiotropic hotspots are valuable targets for further investigation into AD and, potentially, its comorbidity with CAD traits. 2024 Journal Article http://hdl.handle.net/20.500.11937/97665 10.3390/ijms25168814 eng unknown |
| spellingShingle | Alzheimer’s disease Mendelian randomisation coronary artery disease gene-based analysis global genetic correlation linkage disequilibrium score regression lipids local analysis of [co]variant associations local genetic correlation Humans Alzheimer Disease Coronary Artery Disease Genome-Wide Association Study Genetic Predisposition to Disease Lipids Lipid Metabolism Quantitative Trait Loci Polymorphism, Single Nucleotide Triglycerides Humans Alzheimer Disease Genetic Predisposition to Disease Lipids Triglycerides Polymorphism, Single Nucleotide Quantitative Trait Loci Lipid Metabolism Coronary Artery Disease Genome-Wide Association Study Kirby, A. Porter, T. Adewuyi, Emmanuel Laws, S.M. Investigating Genetic Overlap between Alzheimer’s Disease, Lipids, and Coronary Artery Disease: A Large-Scale Genome-Wide Cross Trait Analysis |
| title | Investigating Genetic Overlap between Alzheimer’s Disease, Lipids, and Coronary Artery Disease: A Large-Scale Genome-Wide Cross Trait Analysis |
| title_full | Investigating Genetic Overlap between Alzheimer’s Disease, Lipids, and Coronary Artery Disease: A Large-Scale Genome-Wide Cross Trait Analysis |
| title_fullStr | Investigating Genetic Overlap between Alzheimer’s Disease, Lipids, and Coronary Artery Disease: A Large-Scale Genome-Wide Cross Trait Analysis |
| title_full_unstemmed | Investigating Genetic Overlap between Alzheimer’s Disease, Lipids, and Coronary Artery Disease: A Large-Scale Genome-Wide Cross Trait Analysis |
| title_short | Investigating Genetic Overlap between Alzheimer’s Disease, Lipids, and Coronary Artery Disease: A Large-Scale Genome-Wide Cross Trait Analysis |
| title_sort | investigating genetic overlap between alzheimer’s disease, lipids, and coronary artery disease: a large-scale genome-wide cross trait analysis |
| topic | Alzheimer’s disease Mendelian randomisation coronary artery disease gene-based analysis global genetic correlation linkage disequilibrium score regression lipids local analysis of [co]variant associations local genetic correlation Humans Alzheimer Disease Coronary Artery Disease Genome-Wide Association Study Genetic Predisposition to Disease Lipids Lipid Metabolism Quantitative Trait Loci Polymorphism, Single Nucleotide Triglycerides Humans Alzheimer Disease Genetic Predisposition to Disease Lipids Triglycerides Polymorphism, Single Nucleotide Quantitative Trait Loci Lipid Metabolism Coronary Artery Disease Genome-Wide Association Study |
| url | http://hdl.handle.net/20.500.11937/97665 |