Causality between thyroid dysfunction and lacunar stroke： a bidirectional，two-sample Mendelian randomization study

Abstract:

Objective To explore the causality between thyroid dysfunction and lacunar stroke using two-sample Mendelian randomization（MR） analysis.Methods The study extracted summary data from published genome-wide association studies（GWAS） for hypothyroidism，hyperthyroidism，and lacunar stroke，comprising 494 577，172 938，and 254 459 samples，respectively. In the forward MR analysis，hypothyroidism and hyperthyroidism were used as the exposure，with 103 and 5 single nucleotide polymorphisms（SNPs） selected as instrumental variables（IVs），respectively，and lacunar stroke as the outcome. In the reverse MR analysis，lacunar stroke was used as the exposure，with 3 SNPs selected as IVs，and hypothyroidism and hyperthyroidism as the outcomes. Bidirectional MR analyses were performed using the inverse variance weighted（IVW） method as the primary analysis method，and weighted median（WM） and MR-Egger methods were used as supplementary analysis methods to evaluate causal effects. Additionally，heterogeneity and pleiotropy tests were conducted，and the leave-one-out analysis was employed to assess the stability of the results.Results Genetic predisposition to hypothyroidism was significantly associated with an increased risk of lacunar stroke（IVW：odds ratio［OR］=1.118，95%CI=1.030-1.214）. No causal association was found between hyperthyroidism and lacunar stroke（IVW：OR=1.011，95%CI=0.958-1.067），lacunar stroke and hypothyroidism（IVW：OR=1.093，95%CI=0.996-1.200），and lacunar stroke and hyperthyroidism（IVW：OR=0.857，95%CI=0.556-1.320）.Conclusion Hypothyroidism is causally related to an increased risk of lacunar stroke. However，no causal associations were found for hyperthyroidism and lacunar stroke or in the reverse study. These results require further verification through laboratory investigation and evidence from future studies with larger sample sizes.