Background: Depression tends to develop in correlation with hypothyroidism, however it's unclear how testosterone traits contribute to this association. We examined the causal association between depression, testosterone traits, and hypothyroidism using Mendelian randomization (MR).
Method: We conducted univariable and multivariable MR studies using summary-level statistics from genome-wide association studies (GWAS) of Hypothyroidism (n = 213,990), broad depression (n = 322,580), probable major depressive disorder (probable MDD) (n = 174,519), and International Classification of Diseases (ICD)-9 or ICD-10-coded MDD (n = 217,584) from European ancestry. The inverse variance weighted (IVW) method was used as the main MR analysis.
Results: In univariate MR analysis, there is a positive causal relationship between hypothyroidism and broad depression (P = 0.0074; OR = 1.0066; 95%CI: 1.0018-1.0114) and probable MDD (P = 0.0242; OR = 1.0056; 95%CI: 1.0007-1.0105). In females, there is a causal relationship between hypothyroidism and decreased total testosterone (P < 0.001; OR = 0.9747; 95%CI: 0.9612-0.9885) and sex hormone binding globulin (SHBG) levels (P = 0.0418; OR = 0.9858; 95%CI: 0.9723-0.9995). In females, there is an inverse causal relationship between total testosterone and broad depression (P = 0.0349; OR = 0.9898; 95%CI: 0.9804-0.9993). Furthermore, in multivariate MR analysis, after adjusting for total testosterone in females, hypothyroidism only has a positive causal relationship with probable MDD, and the relationship with broad depression is no longer significant. Most notably, after adjusting for hypothyroidism, the inverse causal effect of female total testosterone levels on broad depression becomes more significant (P = 0.0154; OR = 0.9878; 95%CI: 0.9780-0.9977).
Conclusion: Hypothyroidism increases the risk of broad depression and probable MDD development. Total Testosterone appears to play an important role in the relationship between hypothyroidism and broad depression in female.
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