Exploring The Causal Relationship Between Genetic Determinants Of Thyroid Functions And Psychiatric Disorders Based On Mendelian Randomization

Objective: Thyroid function is closely related to the pathogenesis of psychiatric disorders,but the causal relationship between them is unclear due to the influence of confounding factors and reverse causality.This study was based on Mendelian randomization（MR）analysis to explore the causal relationship between genetic determinants of thyroid function and three psychiatric disorders,schizophrenia,major depressive disorder,and bipolar disorder.Methods: In this study,6 thyroid function-related indicators were selected as exposure factors,including the reference levels of free thyroxine（FT4）,free triiodothyronine（FT3）: FT4 ratio,thyrotropin（TSH）levels,thyroid peroxidase concentration of thyroid peroxidase antibodies（TPOAb）,hypothyroidism,and hyperthyroidism.Using a large-scale genome-wide association study（GWAS）,the single nucleotide polymorphisms（SNPs）significantly associated with 6 thyroid function indicators were selected as instrumental variables.Based on the psychiatric disorders GWAS data of the Psychiatric Genomics Consortium（PGC）,extracting the degree of association of genetic instrumental variables with three psychiatric disorders,including schizophrenia（35,476 patients and 46,839 healthy controls）,bipolar disorder（41,917 patients and 371,549 healthy controls）,and major depressive disorder（59,851 patients and 113,154 healthy controls）.Subsequently,the two-sample MR analysis was used to evaluate the causal relationship between the 6 thyroid function indicators and the risk of three psychiatric disorders,including inverse variance weighted（IVW）analysis,weighted median method,MR-Egger regression,MR-Pleiotropy Residual Sum and Outlier（MR-PRESSO）.Multiple sensitivity analysis was used to test instrumental variables’ heterogeneity and horizontal pleiotropy.Results: The level of FT4 predicted by genetic instrumental variables was significantly associated with the risk of bipolar disorder（OR=0.89,P=0.005）,adjusted for multiple testing（P<0.05/6=0.008）.To further verify the results of the study,a supplementary analysis was performed using the MR-Egger regression and weighted median methods,and the results found consistent effect size directions.The sensitivity test showed that there was no significant horizontal pleiotropy（P>0.05）,and the results of heterogeneity analysis showed that there was no significant heterogeneity（P>0.05）.There was no significant causal relationship between genetically determined thyroid function indicators and major depressive disorder or schizophrenia（P>0.05）.Conclusion: This study found that higher FT4 levels can significantly reduce the risk of bipolar disorder,suggesting the importance of detecting thyroid function indicators in preventing and diagnosis of bipolar disorder,and supporting that adding levothyroxine（L-T4）is an effective measure to prevent bipolar disorder.