Pleiotropic effects of PLEC and C1Q on Alzheimer’s disease and cardiovascular traits

Abstract

Abstract Several cardiovascular (CV) traits and diseases co-occur with Alzheimer’s disease (AD). We mapped their shared genetic architecture using multi-trait genome-wide association studies. Subsequent fine-mapping and colocalisation highlighted 19 genetic loci associated with both AD and CV diseases. We prioritised rs11786896, which colocalised with AD, atrial fibrillation (AF) and expression of PLEC in the heart left ventricle, and rs7529220, which colocalised with AD, AF 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 (HF) and in brain astrocytes with AD. Similar common mechanisms are implicated for C1Q in heart macrophages with HF and in brain microglia with AD. These findings highlight inflammatory and pleomorphic risk determinants for the co-occurrence of AD and CV diseases and suggest PLEC, C1Q and their interacting proteins as novel therapeutic targets.