Multi-trait association analysis reveals shared genetic loci between Alzheimer’s disease and cardiovascular traits
Several cardiovascular traits and diseases co-occur with Alzheimer's disease. We mapped their shared genetic architecture using multi-trait genome-wide association studies. Subsequent fine-mapping and colocalisation highlighted 16 genetic loci associated with both Alzheimer's and cardiovascular diseases. We prioritised rs11786896, which colocalised with Alzheimer's disease, atrial fibrillation and expression of PLEC in the heart left ventricle, and rs7529220, which colocalised with Alzheimer's disease, atrial fibrillation and expression of C1Q family genes. Single-cell RNA-sequencing data, co-expression network and protein-protein interaction analyses provided evidence for different mechanisms of PLEC, which is upregulated in left ventricular endothelium and cardiomyocytes with heart failure and in brain astrocytes with Alzheimer's disease. Similar common mechanisms are implicated for C1Q in heart macrophages with heart failure and in brain microglia with Alzheimer's disease. These findings highlight inflammatory and pleomorphic risk determinants for the co-occurrence of Alzheimer's and cardiovascular diseases and suggest PLEC, C1Q and their interacting proteins as potential therapeutic targets.
Authors
- Nurun Fancy (ORCID: https://orcid.org/0000-0002-6481-6266)
- Ioanna Tzoulaki (ORCID: https://orcid.org/0000-0002-4275-9328)
- Paul Elliott (ORCID: https://orcid.org/0000-0002-7511-5684)
- Fotios Koskeridis (ORCID: https://orcid.org/0000-0002-1253-7556)
- Dennis Wang (ORCID: https://orcid.org/0000-0003-0068-1005)
- Εvangelos Εvangelou (ORCID: https://orcid.org/0000-0002-5488-2999)
- Devendra Meena
- Paul M. Matthews (ORCID: https://orcid.org/0000-0002-1619-8328)
- Pei Fang Tan (ORCID: https://orcid.org/0000-0003-1475-8886)
- Abbas Dehghan (ORCID: https://orcid.org/0000-0001-6403-016X)
Institutions
- Agency for Science, Technology and Research (SG)
- University of Ioannina (GR)
- Academy of Athens (GR)
- Biomedical Research Foundation of the Academy of Athens (GR)
- UK Dementia Research Institute (GB)
- Bioinformatics Institute (SG)
- Imperial College London (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1038/s41467-024-53452-6
- Citations
- 24
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 5.94
Funders
- UK Research and Innovation
- Alzheimer's Society
- National Institute for Health and Care Research
- British Heart Foundation
- Imperial College London
- Imperial College Healthcare NHS Trust
- UK Dementia Research Institute
- National Institutes of Health
- Medical Research Council
- NIHR Imperial Biomedical Research Centre
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Human Genome Research Institute
- NIH Office of the Director
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- Common Fund