Genetic insights into modifiable risk factors of stroke and their joint effects: A genome-wide pleiotropic analysis

Epidemiologic and genetic associations of modifiable risk factors with stroke have been widely reported. However, the degree to which the shared genetic determinants are involved in these associations is unclear. Our study aimed to investigate the shared genetic etiology between stroke and its leading risk factors and to identify shared genomic loci, genes, and pathways that are widely distributed across the genome.

We performed with various statistical genetic methods to sequentially investigate global genetic correlations, local genetic association, shared genome-wide single nucleotide polymorphisms (SNPs), shared genes, and biological pathways, to disentangle the underlying shared genetic etiology between stroke and its 10 leading risk factor.

Extensive genetic correlations were found among 12 of 30 trait pairs. The vertical pleiotropy of 8 of 12 pairwise traits. We found a significant pleiotropic effect in these 12 trait pairs, with 9, 592 significant potential pleiotropic SNPs, and 280 pleiotropic risk loci. Among these loci, 380 and 25 unique candidate pleiotropic genes were identified using multi-marker analysis of genomic annotation (MAGMA) and transcriptome-wide association study (TWAS), respectively. Of them, 10 important pleiotropic genes were significant in both sets of analyses. Many important pleiotropic genes could regulate multiple trait pairs simultaneously, such as ATXN2, SH2B3, ALDH2, ACAD10, and NT5C2.

These findings suggest that modifiable risk factors and stroke exhibit significant genetic co-regulation. In addition, these findings providing the potential for the concurrent control of two or even more diseases through the intervention of single or multiple genes.