Thyroid Function and Mood Disorders: A Mendelian Randomization Study

Abstract

Background: Observational studies suggest that even minor variations in thyroid function are associated with the risk of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). However, it is unknown whether these associations are causal or not. We used a Mendelian randomization (MR) approach to investigate causal effects of minor variations in thyrotropin (TSH) and free thyroxine (fT4) levels on MDD and BD risk. Materials and Methods: We performed two-sample MR analyses using data from the largest publicly available genome-wide association studies on normal-range TSH (n = 54,288) and fT4 (n = 49,269) levels, MDD (170,756 cases, 329,443 controls) and BD (20,352 cases, 31,358 controls). Secondary MR analyses investigated the effects of TSH and fT4 levels on specific MDD and BD subtypes. Reverse MR was also performed to assess the effects of MDD and BD on TSH and fT4 levels. Results: There were no associations between genetically predicted TSH and fT4 levels and MDD risk, nor MDD subtypes and minor depressive symptoms. A one standard deviation increase in fT4 levels was nominally associated with an 11% decrease in the overall BD risk (odds ratio [OR] = 0.89, 95% confidence interval [CI] = 0.80-0.98, p = 0.022) and a 13% decrease in the BD type 1 risk (OR = 0.87, CI = 0.75-1.00, p = 0.047). In the reverse direction, genetic predisposition to MDD and BD was not associated with TSH nor fT4 levels. Conclusions: Variations in normal-range TSH and fT4 levels have no effects on the risk of MDD and its subtypes, and neither on minor depressive symptoms. This indicates that depressive symptoms should not be attributed to minor variations in thyroid function. Borderline associations with BD and BD type 1 risks suggest that further clinical studies should investigate the effect of thyroid hormone treatment in BD.

Keywords: Mendelian randomization study; bipolar disorder; depression; mood disorders; normal-range thyroid function; thyroid.

Figure 1. Schematic diagram illustrating the study design.

Two-sample Mendelian Randomization (MR) approach based on the summary-level data from large-scale meta-analyses of the genome-wide association studies (GWAS) was used to investigate the causal effects of thyroid function on mood disorders. Genetic variants associated with normal-range TSH and FT4 levels (genetic instruments, represented by the solid line) and their corresponding effect estimates were established in the GWAS by the ThyroidOmics Consortium (35). Effect estimates on major depressive disorder (MDD) and bipolar disorder (BD) for these genetic variants were derived from the GWAS in the UK Biobank (UKBB) and/or the Psychiatric Genomics Consortium (PGC) (–38). All datasets used in this study are publicly available at the ThyroidOmics Consortium and the PGC websites.

Figure 2. Causal effects of variation in normal-ranged thyrotropin (TSH) and free thyroxine (FT4) levels on major depressive disorder (A) and bipolar disorder (B) overall and specific subtypes risk.

Presented odds ratios (OR) and confidence intervals (CI) correspond to the effects of a one standard deviation change in TSH and FT4 levels. The results of Mendelian Randomization (MR) analyses using various analysis methods (inverse variance weighted [IVW], MR-Egger, weighted median [WM], MR Pleiotropy RESidual Sum and Outlier [MR-PRESSO]) are presented for comparison. The number of Single Nucleotide Polymorphisms (SNPs) indicates the number of genetic variants used as instruments for MR analysis. rMDD - recurrent major depressive disorder; sMDD - single-episode major depressive disorder; subMDD - sub-threshold depression (i.e. individuals reporting depressive symptoms but not meeting formal major depressive disorder criteria); BD1 - bipolar disorder type 1; BD2 - bipolar disorder type 2; SABD - schizoaffective bipolar disorder.

Figure 3. Causal effects of major depressive disorder and bipolar disorder on thyrotropin (TSH) and free thyroxine (FT4) levels.

The results of Mendelian Randomization (MR) analyses using various analysis methods (inverse variance weighted [IVW], MR-Egger, weighted median [WM], MR Pleiotropy RESidual Sum and Outlier [MR-PRESSO]) are presented for comparison. The number of Single Nucleotide Polymorphisms (SNPs) indicates the number of genetic variants used as instruments for MR analysis.