Genome-wide cross-trait analysis of vascular dementia and Alzheimer’s disease highlights novel loci and lung-brain axis

Abstract Until now, most genetic risk for vascular dementia (VD) remains unknown. Here, we firstly performed the largest cross-ancestry genome-wide association study meta-analysis comprising 5,886 VD and 1,027,883 controls of European, East Asian, South Asian, African, and Admixed American ancestry. We identified 37 genome-wide significant loci including CLU and APOE tagged by common variants and 35 loci tagged by rare variants, and demonstrated enrichment of VD heritability in lung and genetic association between VD and lung function traits. We further conducted a cross-trait of VD and Alzheimer’s disease, and identified 13 genome-wide significant loci including CR1 , BIN1 , GRM7 , HLA-DRA , TREM2 , CLU , ECHDC3 , AGBL2 , MS4A4E , PICALM , SLC24A4 , ABCA7 , and APOE. A multi-omics integrative analysis identified 619 genes. 241 genes were significantly differentially expressed in VD cells and 21 exhibited strong evidence of interaction with FDA-approved drugs. Collectively, our findings provide valuable insights into the potential underlying mechanisms of VD.