Causal Relationship Between Circulating Omega‐3 Fatty Acid and Cerebral Small Vessel Disease: A Mendelian Randomization Study

Cerebral small vessel disease (CSVD) plays an important role in the onset of stroke and cognitive dysfunction. Its primary imaging manifestations encompass lacunar stroke (LS), white matter hyperintensity (WMH), white matter perivascular space (WMPVS), and cerebral microbleed (CMB). While omega-3 fatty acid (FA) has shown potential protective effects against vascular diseases, their causal role in CSVD remains unclear. This study aims to investigate the causal relationship between circulating Omega-3 FA levels and various CSVD phenotypes using Mendelian randomization (MR). Data on circulating omega-3 FA levels were derived from a large genome-wide association study (GWAS) summary dataset comprising 115,060 individuals. Data on CSVD phenotypes were obtained from several large GWAS datasets, including those on LS (6030 cases, 248,929 controls), WMH (<i>N</i> = 42,310), CMB (3556 cases, 22,306 controls), and WMPVS (9223 cases, 29,648 controls). Suitable genetic variants were extracted from GWAS summary data to serve as instrumental variables (IVs) for a two-sample MR analysis. The primary method used was inverse variance weighted (IVW), supplemented by the weighted median (WM) and MR-Egger method to assess causality. Multiple sensitivity analyses were used to assess the robustness of the results. Elevated circulating Omega-3 FA levels were found to significantly reduce the risk of CMB (IVW OR = 0.82, 95% CI: 0.69-0.96). However, no significant associations were observed with WMH, WMPVS, or LS. Sensitivity analyses confirmed the stability of these results, with no indications of horizontal pleiotropy or reverse causality. This study suggests that higher circulating omega-3 FA levels may be causally associated with a modest reduction in the risk of cerebral microbleeds. These findings highlight the potential of omega-3 FA as a modifiable factor for preventing CMB and encourage further research in diverse populations.