Assessment of the relationships between genetic determinants of thyroid functions and bipolar disorder: A mendelian randomization study

Thyroid functions (TFs) have been implicated in the initiation and propagation of psychiatric disorders. Observational studies have shown associations of TFs with psychiatric disorders. However, the relationship between TFs and psychiatric diseases were still unclear.Genetic instruments for 6 TF-realted indexes, including free thyroxine (FT4), triiodothyronine (FT3):FT4 ratio, thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb) concentration, hypothyroidism, and hyperthyroidism, were obtained from several genome-wide association studies (GWASs). Their associations with BD were evaluated using Psychiatric Genomics Consortium (PGC) datasets (41,917 cases and 371,549 controls). All GWAS summary statitics were from European ancestry. Mendelian randomization (MR) estimates from each genetic instrument were combined using inverse variance weighted (IVW) meta-analysis, with complementary methods (eg, weighted median and MR Egger). We also multiple sensitivity analyses to examine horizontal pleiotropy and heterogeneity.Genetically predicted level of FT4 was significantly associated with BD (odds ratio (OR)=0.89, 95% confidence interval (CI): 0.83-0.95; P=4.65 × 10-3), survived after the Bonferroni correction (P<0.05/6=0.008). Consistent directional effects for all sensitivity analyses were observed in the weighted median and MR Egger methods. Furthermore, our sensitive test suggested no significant horizontal pleiotropy (intercept=-0.01, P=0.12) and no notable heterogeneity (Q = 29.9; P=0.09). However, other TF indexes (FT3:FT4 ratio [OR=1.24, P=0.10], TSH [OR=1.01, P=0.61], TPOAb concentration [OR=1.20, P=0.54], hypothyroidism [OR=1.00, P=0.91], and hyperthyroidism [OR=0.99, P=0.57]) were not associated with BD.Our results provide further evidence that higher FT4 level is associated with a reduced risk of BD, and suggest the importance of FT4 level in BD risk assessment and potential therapeutic targets development.