Multi-trait association analysis reveals shared genetic loci between Alzheimer's disease and cardiovascular traits

Abstract

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.

Fig. 1. Study design schematic overview.

AD Alzheimer’s disease, AF atrial fibrillation, CAD coronary artery disease, cIMT carotid intima media thickness, BP blood pressure, CV cardiovascular, HF heart failure. Created in BioRender. Wang, D. (2023) BioRender.com/q29l509.

Fig. 2. Circular figure visualising regional plots on the colocalised loci between Alzheimer’s disease (AD) and cardiovascular traits (CV).

The figure presents the distribution of P-values (–log₁₀P) from MTAG with inner orientation (P-values are derived from two-sided statistical tests). The annotations show the mapped genes of the AD/CV top lead SNPs on the colocalised loci.

Fig. 3. Regional plot on the colocalised locus of candidate causal variant rs11786896 (mapped in PLEC) for Alzheimer’s disease (bottom), atrial fibrillation (middle) and the expression quantitative trait loci (top) for the associated tissues.

The x-axis presents the chromosomal positions of single-nucleotide polymorphisms, while the y-axis shows the negative logarithm to base 10 of P-values (–log₁₀P) from two-sided statistical tests.

Fig. 4. Single-nuclei transcriptomes of cardiac tissue for genes increasing the risk of cardiomyopathy.

A The transcriptomes form discrete cell-specific clusters using Uniform Manifold Approximation and Projection (UMAP). B Expression of PLEC and C1Q genes across cell-specific clusters from UMAP. Red indicates higher expression. C Enriched pathways of the PLEC-containing module in cardiovascular endothelial cells between dilated cardiomyopathy cases and healthy controls (P-values are derived from two-sided statistical tests). D Enrichment of pathway genes in the protein interactomes of candidate genes in cardiovascular endothelial cells. The PLEC-interacting module is the brown and the C1q-interacting module is the pink.

Fig. 5. Single-nuclei transcriptomes of human post-mortem brains for genes increasing the risk of Alzheimer’s disease.

A The transcriptomes form discrete cell-specific clusters using Uniform Manifold Approximation and Projection (UMAP). B Expression of candidate genes across cell types in human brain. C Enriched pathways of the PLEC-containing module in astrocytes between Alzheimer’s disease cases and healthy controls (P-values are derived from two-sided statistical tests). D Enrichment of pathway genes in the protein interactomes of candidate genes in astrocytes. The PLEC-interacting module is the cyan and the NDUFS3-interacting module is the dark red. Astro Astrocytes, Exc Excitatory Neuron, Inh Inhibitory Neuron, Micro Microglia, Oligo Oligodendrocytes, OPC Oligodendrocytes Progenitor Cells, Vasc Vascular cells.