Re: “Exploring the Genetic Link Between Thyroid Dysfunction and Common Psychiatric Disorders: A Specific Hormonal or a General Autoimmune Comorbidity” by Soheili-Nezhad et al.

Dear Editor:

In the February 2023 issue of Thyroid, Soheili-Nezhad et al. report the results of a study exploring a genetic link between thyroid dysfunction and common psychiatric disorders. ¹ It is well known that ∼10% of patients with autoimmune hypothyroidism have persisting symptoms, impaired quality of life (QoL), and even psychiatric comorbidity despite adequate levothyroxine treatment. Several hypotheses have been postulated to explain this phenomenon, often focusing on suboptimal serum/tissue triiodothyronine levels. ² However, none of these hypotheses has been proven.

Soheili-Nezhad et al. studied phenotypic and genetic correlations in large data sets of thyroid diseases, thyroid hormone levels, and three common psychiatric disorders—major depressive disorder (MDD), bipolar disorder, and anxiety disorder (ANX). Autoimmune thyroid disease (ATD), but not serum free thyroxine or thyrotropin (TSH) concentrations, was found to be strongly genetically correlated with MDD and ANX. Further analyses revealed strong local genetic correlation between ATD, ANX, and MDD at loci 6p22.1 and 6p22.2, flanking the major histocompatibility complex region.

After a realistic summary of strengths and weaknesses, the authors conclude that, rather than thyroid hormone itself, other phenomena—such as autoimmunity—may play a key role in the genetically determined relationship between ATD, and mood and anxiety, and that further research is warranted. ¹

In the accompanying commentary, Nygaard concludes that—despite the analysis being valuable—“the explanation of the increased risk of psychiatric disease and persistent symptoms in LT4-treated hypothyroid patients is still missing.” ³ Of course, we agree; finding a correlation does not prove causality. However, we do not agree with the following statement in the paragraphs discussing the role of thyroid autoantibodies “… population-based studies do not demonstrate a correlation between thyroid peroxidase antibodies (TPO-Abs), and QoL or depression.,” referring to only three observational studies.

We recently published a systematic review on the relationship between the presence of TPO-Abs (as proxy for thyroid autoimmunity) and persisting symptoms and impaired QoL and included 30 observational studies (7 disease-based and 23 population-based studies). ⁴ The majority of these 30 studies (5 of 7 disease-based, 16 of 23 population-based studies) reported an association between the presence of TPO-Abs and persisting symptoms or impaired QoL.

This contradicts the statement in the commentary. In all included studies, serum thyroid hormone and TSH concentrations were similar between TPO-Ab positive and negative groups. Based on this literature study free of selection bias, we conclude that (thyroid) autoimmunity does seem to be associated with persisting symptoms or lower QoL and hypothesize that autoimmunity might play a causal role.

What exactly underlies this association, and the possible causal relationship remain to be elucidated. Although various cellular mechanisms have been proposed, ⁵ more research is needed. Besides basic and translational studies, a next step might be conducting an intervention study in patients with ATD and persisting symptoms, using, for example, immunomodulatory drugs in a randomized placebo-controlled trial, with symptoms and QoL as main outcomes. ⁴