Background: The hypothalamus-pituitary-thyroid axis coordinates brain development and postdevelopmental function. Thyroid hormone (TH) variations, even within the normal range, have been associated with the risk of developing common psychiatric disorders, although the underlying mechanisms remain poorly understood. Methods: To get new insight into the potentially shared mechanisms underlying thyroid dysfunction and psychiatric disorders, we performed a comprehensive analysis of multiple phenotypic and genotypic databases. We investigated the relationship of thyroid disorders with depression, bipolar disorder (BIP), and anxiety disorders (ANXs) in 497,726 subjects from U.K. Biobank. We subsequently investigated genetic correlations between thyroid disorders, thyrotropin (TSH), and free thyroxine (fT4) levels, with the genome-wide factors that predispose to psychiatric disorders. Finally, the observed global genetic correlations were furthermore pinpointed to specific local genomic regions. Results: Hypothyroidism was positively associated with an increased risk of major depressive disorder (MDD; OR = 1.31, p = 5.29 × 10 −89 ), BIP (OR = 1.55, p = 0.0038), and ANX (OR = 1.16, p = 6.22 × 10 −8 ). Hyperthyroidism was associated with MDD (OR = 1.11, p = 0.0034) and ANX (OR = 1.34, p = 5.99 × 10 − ⁶). Genetically, strong coheritability was observed between thyroid disease and both major depressive ( r g = 0.17, p = 2.7 × 10 − ⁴) and ANXs ( r g = 0.17, p = 6.7 × 10 − ⁶). This genetic correlation was particularly strong at the major histocompatibility complex locus on chromosome 6 ( p < 10 − ⁵), but further analysis showed that other parts of the genome also contributed to this global effect. Importantly, neither TSH nor fT4 levels were genetically correlated with mood disorders. Conclusions: Our findings highlight an underlying association between autoimmune hypothyroidism and mood disorders, which is not mediated through THs and in which autoimmunity plays a prominent role. While these findings could shed new light on the potential ineffectiveness of treating (minor) variations in thyroid function in psychiatric disorders, further research is needed to identify the exact underlying molecular mechanisms.

BackgroundThe hypothalamus-pituitary-thyroid axis coordinates brain development and post-developmental function. Thyroid hormone variations, even within the normal range, have been associated with the risk of developing common psychiatric disorders, although the underlying mechanisms remain poorly understood.Materials and methodsTo get new insight into the potentially shared mechanisms underlying thyroid dysfunction and psychiatric disorders, we performed a comprehensive analysis of multiple phenotypic and genotypic databases. We investigated the relationship of thyroid disorders with depression, bipolar disorder, and anxiety disorders in 502,480 subjects from UK Biobank. We subsequently investigated genetic correlations between thyroid disorders, thyroid stimulating hormone (TSH) and free T4 (FT4) levels, with the genome-wide factors that predispose to psychiatric disorders. Finally, the observed global genetic correlations were furthermore pinpointed to specific local genomic regions.ResultsHypothyroidism was positively associated with an increased risk of major depressive disorder (OR=1.51, p<10−16) and bipolar disorder (OR=1.99, p=2.1×10−6). Genetically, strong coheritability was observed between autoimmune hypothyroidism and both major depressive (rg=0.17, p=2.7×10−4) and anxiety disorders (rg=0.17, p=6.7×10−6). This genetic correlation was particularly strong at the Major Histocompatibility Complex (MHC) locus on chromosome six (p<10−5), but further analysis showed that other parts of the genome also contributed to this global effect. Importantly, neither TSH nor FT4 levels were genetically correlated with mood disorders.ConclusionOur findings highlight an underlying association between autoimmune hypothyroidism and mood disorders, which is not mediated via thyroid hormones, and in which autoimmunity plays a prominent role. While these findings could shed new light on the potential ineffectiveness of treating (minor) variations in thyroid function in psychiatric disorders, further research is needed to identify the exact underlying molecular mechanisms.