Large-scale genetic study identifies shared genetic regions between cerebrovascular and neurodegenerative diseases

Cerebrovascular diseases (CeVD) and neurodegenerative diseases (NDs) are two major neurological disorders, which are associated with increasing global morbidity and mortality. Population-based studies have indicated a complex link between CeVD and ND. However, the shared genetic etiology between these disease conditions remains less explored.

We conducted genome-wide genetic correlation analysis and investigated the shared genetic architecture through pleiotropy analysis between ND and CeVD, like stroke and its subtypes, to understand shared genetic factors and biological mechanisms. Publicly available large-scale genome-wide association studies (GWAS) summary statistics data of cross-ancestry, European, and South Asian (SAS) ancestry were analyzed using methods implemented in the tools linkage disequilibrium score regression (LDSC), PLeiotropic Analysis under COmposite null hypothesis (PLACO), and Bayesian-based method of colocalization (COLOC).

We detected 116 shared genetic loci consisting of 770 lead pleiotropic single nucleotide polymorphisms (SNPs) (ND-CeVD P-range: 4.81×10^-8 to 4.57×10^-16) and 40 shared causal genetic regions (ND-CeVD PP.H4-range: 0.70-0.9, posterior probability of H4 (PP.H4) ⩾ 0.7) between multiple CeVD and ND pairs. The genetic regions near ICA1L, HLA-DQA1, HLA-DRB1, MIR297, and PITX2 genes were identified as highly pleiotropic across multiple CeVD-ND pairs. We report ERGIC1 (5q35.1) for the first time as a shared causal genetic locus between Amyotrophic Lateral Sclerosis and small vessel stroke. The genetic risk score of stroke derived from the SAS population of the GIGASTROKE study was associated with ND (P-range = 2.23×10^-28 to 0.02), despite a small sample size compared to other ethnic groups, indicating high penetrance.

The shared genetic loci and pathway analysis in this study provide new genes and pathways shared between ND and CeVD, which may help in a better understanding of disease mechanisms in these neurological diseases.