The genetic correlation among imaging markers of cerebral small vessel disease: A Mendelian randomization analysis

Previous studies have indicated associations between imaging markers of cerebral small vessel disease (CSVD), but their genetic correlations remain largely unknown. We analyzed large-scale GWAS summary data for lacunar stroke (6030 cases; 248,929 controls), cerebral microbleeds (N = 25,862), white matter hyperintensities (WMH; 18,381 population-based subjects and 2850 stroke patients), perivascular spaces (PVS; N = 40,095), and brain volume (N = 33,224). Linkage disequilibrium score regression (LDSR) was used to estimate heritability and genetic correlations. Bidirectional Mendelian randomization (MR) and mediation MR were performed to assess causal relationships. Except for cerebral microbleeds, all other CSVD imaging markers showed significant heritability, with decreased brain volume being the most prominent. MR analyses provided evidence supporting potential unidirectional causal relationships where lacunar stroke increased the risk of WMH, PVS, and decreased brain volume. MR identified a potential bidirectional causal relationship between WMH and decreased brain volume. Mediation analysis revealed that lacunar stroke mediated the effects of hypertension on various imaging markers. Cerebral microbleeds appear genetically distinct from other CSVD markers. Lacunar stroke acts as a key upstream factor linking multiple imaging features, while WMH and brain atrophy exhibit a potential bidirectional causal relationship. These findings provide insight into the heterogeneous mechanisms underlying CSVD imaging markers.