To investigate the causal relationship between thyroid function and ischemic stroke using a two-sample Mendelian randomization (MR) approach.

Genetic instruments in the form of single-nucleotide polymorphisms (SNP) strongly associated with exposures—hyperthyroidism, hypothyroidism, thyroid-stimulating hormone (TSH), and free thyroxine (FT4)—were selected from publicly available genome-wide association study (GWAS) databases. Outcomes comprised ischemic stroke and its three etiological subtypes according to the trial of Org 10172 in acute stroke treatment (TOAST) classification: large-artery atherosclerotic stroke, cardioembolic stroke, and small-artery occlusion stroke. A two-sample MR analysis was performed to assess causal associations between thyroid function traits and ischemic stroke outcomes.

Genetically predicted hyperthyroidism was potentially causally associated with an increased risk of small-artery occlusion stroke (OR=1.09, 95%CI: 1.02 – 1.18, P=0.016). Conversely, genetically predicted hypothyroidism was linked to a reduced overall risk of ischemic stroke (OR=0.96, 95%CI: 0.93 – 0.99, P=0.007). Additionally, higher genetically determined TSH levels were associated with a lower risk of cardioembolic stroke (OR=0.87, 95%CI: 0.79 – 0.95, P=0.004). Sensitivity analyses supported the robustness of these findings.

Hyperthyroidism may represent a potential risk factor for small-artery occlusion stroke, whereas hypothyroidism and elevated TSH levels might exert protective effects against specific ischemic stroke subtypes.