Stroke and brain white/gray matter alterations: A Mendelian randomization investigation

Disruptions or abnormalities in white and gray matter (WM/GM) microstructure are closely associated with the severity of neurological impairment and long-term prognosis and are often regarded as pathological sequelae in stroke patients. Still, their direct causal linkage remains to be elucidated. This study obtained genome-wide association study (GWAS) data of 5 stroke phenotypes from the MEGASTROKE consortium, as well as the GWAS data of 283 structural imaging-derived phenotypes (IDPs), including intracellular volume fraction (ICVF), isotropic/free water volume fraction (ISOVF), orientation dispersion index (ODI), and gray matter volume (GMV) from the UK Biobank. Two-sample Mendelian randomization (MR) analysis was conducted to examine causal interactions between stroke phenotypes and IDPs. In forward MR results, any stroke was positively associated with ISOVF in the genu of the corpus callosum, while any ischemic stroke was positively associated with ISOVF in the body of the corpus callosum and the right superior corona radiata. Small-vessel stroke (SVS) was positively associated with ODI in the right superior cerebellar peduncle. In inverse MR results, GMV in the left planum polare was negatively associated with SVS, while ISOVF in specific brain regions was positively associated with SVS. This study systematically elucidated the causal relationships between stroke and brain structure involving WM/GM from the perspective of MR, which suggested that stroke-related genetic liability may causally contribute to white matter injury; genetically determined structural abnormalities in specific brain regions may causally increase the risk of SVS; GM atrophy may be an upstream causal factor for SVS, rather than merely a consequence.