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The links between Thyroid dysfunction diseases (TDFDs) and osteoporosis (OP) has received widespread attention, but the causal relationships and mediating factors have not been systematically studied. We used two-sample Mendelian randomization (MR) analysis to elucidate the causal relationship between TDFDs and OP. Moreover, we performed mediation MR analyses to explore the role of thyroid-related hormones and OP risk factors in the association between TDFDs and OP. Two sample MR analyses showed that hyperthyroidism increased OP (OR = 1.080, 95% CI 1.026 to 1.137; P = 0.0032) risk. Hypothyroidism increases OP (OR = 1.183, 95% CI 1.125 to 1.244; P < 0.0001) risk. Furthermore, mediation analysis revealed that TSH mediated 5.314% of the relationship between hypothyroidism and OP. In contrast, FT4 mediated 9.670% of the relationship between hyperthyroidism and OP. In European populations, TDFDs may increase OP risk. TSH mediates in the causal association between hypothyroidism and OP, and similarly, FT4 mediates in the causal link between hyperthyroidism and OP. Our findings underscore the significance of improving integrative care for individuals with TDFDs to mitigate the risk of OP. It is essential to maintain stable levels of thyroid hormones and closely monitor bone health to effectively mitigate and prevent OP., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

With the development of thyroid pathology in the past decade, thyroid pathological diagnosis has entered the era of molecular pathology. As the most influential academic journal in the field of pathology in China, Chinese Journal of Pathology has published nearly one hundred articles related to thyroid diseases in the past decade. These results have made a great difference to the scientific research and clinicopathological diagnosis of thyroid diseases in China, and have also provided Chinese data for the pathological communication of thyroid diseases internationally. Pathologists should make full use of thyroid cytology and histopathology, combined with molecular testing and digital intelligence technology, to play a core guiding role in the multidisciplinary precise diagnosis and treatment of thyroid diseases.

Introduction: The interplay between emotional disorders and thyroid disorders has been subject to numerous observational studies, which have consistently reported associations but have failed to establish clear causal links due to the multifactorial etiology and influences. We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to explore the genetic causal association between emotional disorders and thyroid disorders., Methods: We employed several methods, including inverse-variance weighted (IVW), weighted median, weighted mode, and MR Egger regression. Additionally, sensitivity analyses were conducted using MR-Egger, MR Pleiotropy Residual Sum and Outlier (MR-PRESSO), Cochran's Q, and leave-one-out methods., Results: IVW results showed negative causal relationships between bidirectional emotional disorders and hypothyroidism, toxic single thyroid nodules in thyrotoxicosis, and hyperthyroidism/toxicity. Additionally, there was a positive causal relationship between anxiety disorders and hypothyroidism. IVW results of reverse MR analysis estimates revealed a positive causal relationship between hypothyroidism, autoimmune thyroiditis, and recurrent or chronic depression. Additionally, there was a negative causal relationship between hyperthyroidism/toxicity and bipolar disorder., Conclusion: This bidirectional two-sample MR study preliminarily reveals a complex, bidirectional causal relationship between emotional disorders and thyroid disorders, particularly highlighting the role of thyroid dysfunction in the development of certain emotional disorders and vice versa., (© 2025 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Thyroid diseases are increasingly prevalent, posing significant challenges to patients' quality of life and placing substantial financial burdens on families and society. Despite these impacts, the underlying pathophysiology of many thyroid conditions remains poorly understood, complicating efforts in treatment, management, and prevention. Observational studies can identify associations between exposure variables and disease; however, they often struggle to account for confounding factors and reverse causation. Understanding disease occurrence, epidemiological trends, and clinical diagnosis, prevention, and treatment relies heavily on robust etiological research. Mendelian randomization, a method grounded in genetics and epidemiology, has been widely employed in studying the etiology of thyroid diseases, offering a solution to some of these challenges. This paper categorizes thyroid diseases into thyroid dysfunction and thyroid cancer, reviewing related Mendelian randomization studies. It further provides novel perspectives and approaches for investigating the mechanisms underlying thyroid diseases and designing intervention strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Wang, Liu, Jia, Zhou and He.)

Background: Thyroid dysfunction exhibits a heightened prevalence among people with diabetes compared to those without diabetes. Furthermore, TD emerges as a notable correlated risk factor for the onset of diabetic retinopathy., Methods: Using data from the FinnGen database (R9), we investigated the causal relationship between thyroid dysfunction (TD) and four stages of diabetic retinopathy (DR). A two-sample univariable Mendelian randomization (UVMR) approach was employed to estimate the total causal effect of TD on four stages of DR, while multivariable Mendelian randomization (MVMR) was used to assess the direct causal effect. The meta-analysis was conducted to summarize the collective effect of TD on four stages of DR. The inverse variance weighted (IVW) method was the primary approach for Mendelian randomization analysis, with heterogeneity, horizontal pleiotropy, and leave-one-out sensitivity analyses performed to validate the robustness of the findings., Results: In UVMR analysis, thyrotoxicosis (TOS) was significantly associated with an increased risk of diabetic retinopathy across four stages (OR, 1.10-1.19; P<0.025). However, MVMR analysis, after adjusting for Graves' disease (GD) and/or rheumatoid arthritis (RA), revealed no significant association between TOS and the four stages of diabetic retinopathy. The Meta-analysis demonstrated the collective effect of TOS on diabetic retinopathy across all stages [OR=1.11; 95% CI (1.08-1.15); P<0.01]. In UVMR analysis, the estimates for hypothyroidism (HPT) and GD were similar to those for TOS. In the MVMR analysis, after adjusting for RA, the significant effect of HPT on DR and non-proliferative diabetic retinopathy (NPDR) remained. Additionally, MVMR analysis suggested that the estimates for GD on DR were not affected by TOS, except for GD-proliferative diabetic retinopathy (PDR). However, no significant correlation persisted after adjusting for RA, including for GD-PDR., Conclusion: Our study demonstrated a significant association between thyroid dysfunction TD and DR, with the relationship being particularly pronounced in HPT-DR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ouyang, Zhou, Wang and Yan.)

Objectives: Thyroid dysfunction is commonly associated with the risk of infertility in both females and males. However, recent randomized controlled trials have demonstrated that thyroid function levels in females are not significantly related to infertility, and evidence on the association between male thyroid function and infertility is limited. We aim to investigate the association between thyroid function levels and infertility in both females and males., Method: A two-sample Mendelian randomization study was conducted using four methods, with the inverse variance weighted method (IVW) as the primary approach. Data on thyroid function as the exposure were obtained from the ThyroidOmics Consortium and UK Biobank, including over 700,000 individuals from a large meta-analysis of genome-wide association studies for thyroid function and dysfunction. The outcome data for infertility in both sex encompassed more than 70,000 individuals from the FinnGen Consortium. All participants were adults of European ancestry. The MR Egger regression intercept and Cochran's Q test were employed to evaluate directional pleiotropy and heterogeneity., Results: The results indicated no causal effect of thyroid-stimulating hormone (TSH) and free tetraiodothyronine (fT4) on female and male infertility. Furthermore, no causal association between hypo- and hyperthyroidism and infertility were identified. Notably, we observed a causal relationship between high TSH and endometriosis-related infertility (OR=0.82, 95% CI: 0.74-0.91, P = 1.49E-04)., Conclusions: This study did not find evidence for casual relationship between thyroid function levels and risk of infertility. The findings suggest that overall thyroid function levels may not be a significant predictor of infertility risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Qiu, Jiang, Long, Zhu, Chen and Wen.)

Background: Observational studies have suggested a correlation between alopecia areata (AA) and thyroid dysfunction (TD). However, the causal relationship between AA and TD remains uncertain. The purpose of this study is to investigate the causal relationship between these two conditions. Understanding the potential causal relationship between AA and TD is valuable for elucidating the pathogenesis of AA and for designing innovative methods to prevent and treat AA and its related complications., Methods: All data for this two-sample Mendelian randomization (MR) study were sourced from public databases. This study selected hypothyroidism, Hashimoto's thyroiditis, hyperthyroidism, subacute thyroiditis, and Graves' disease as exposure factors, with AA as the outcome variable. Data for hypothyroidism, Hashimoto's thyroiditis, hyperthyroidism, subacute thyroiditis, Graves' disease, and AA were obtained from related genome-wide association studies (GWAS). Various MR analysis methods such as inverse variance weighted (IVW), MR-Egger, and weighted median were utilized. Additionally, Cochrane's Q test was used to detect heterogeneity in MR results, and the MR-Egger intercept test and MR pleiotropy residual sum and outlier (MR-PRESSO) test were used to detect horizontal pleiotropy. A leave-one-out analysis was conducted to investigate the sensitivity of this association., Results: We found statistically significant genetic predictions of AA with hypothyroidism, Hashimoto's thyroiditis, and subacute thyroiditis (IVW OR = 1.4009815, 95% confidence interval [CI]: 1.1210399-1.750829; p = 0.003030698, OR = 1.396101, 95% CI: 1.030134-1.89208; p = 0.03144273, OR = 0.732702, 95% CI: 0.604812-0.887634; p = 0.001483368). Furthermore, tests for pleiotropy showed no evidence of pleiotropy, enhancing the credibility of the study results. Finally, the leave-one-out test demonstrated the stability and robustness of this association., Conclusion: This study provides new evidence of a potential genetic link between thyroid issues and AA. By employing the two-sample MR method to eliminate confounding factors and reverse causation, unbiased results were obtained, confirming a causal relationship between hypothyroidism, Hashimoto's thyroiditis, subacute thyroiditis, and AA. This lays the foundation for further mechanistic studies and potential clinical applications. Future research should further explore the specific biological mechanisms between TD and the onset of AA., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: Metabolic diseases are associated with thyroid disorders. Insulin resistance is the common pathological basis of metabolic diseases. We explored the relationship between the triglyceride-glucose (TyG) index, a simple insulin-resistance marker, and thyroid disorders., Methods: Eligible TIDE (Thyroid Diseases, Iodine Status and Diabetes Epidemiology) subjects (n = 47,710) were screened with inclusion/exclusion criteria. Thyroid disorder prevalence among different TyG index groups was stratified by sex. Logistic regression evaluated the correlation between the TyG index and thyroid disorders. Multiple linear regression evaluated the association between the TyG index and TSH. Additionally, two-sample Mendelian randomization (MR) using published genome-wide association study data evaluated causality in the association between the TyG index and TSH., Results: Men and women with greater TyG indices had a significantly greater prevalence of thyroid disorders than individuals with the lowest quartile (Q1) of TyG index (p < 0.05). Following adjustment for confounding factors, we observed that a greater TyG index significantly increased the risk of subclinical hypothyroidism in men and women (men: Q2: odds ratio (OR) [95% confidence interval (CI)] = 1.22 [1.07-1.38], p = 0.002; Q3: OR [95% CI] = 1.28 [1.12-1.45], p < 0.001; Q4: OR [95% CI] = 1.29 [1.12-1.50], p = 0.001; women: Q2: OR [95% CI] = 1.25 [1.12-1.39], p < 0.001; Q3: OR [95% CI] = 1.47 [1.31-1.64], p < 0.001; Q4: OR [95% CI] = 1.61 [1.43-1.82], p < 0.001). Only among women was the highest TyG index quartile associated with hypothyroidism (OR [95% CI] = 1.70 [1.15-2.50], p = 0.007). Additionally, in men, the association exists only in the more than adequate iodine intake population. In women, the relationship between the TyG index and thyroid disorders disappears after menopause. Furthermore, the TyG index exhibited a linear positive correlation with TSH levels. The MR analysis results revealed a causal relationship between a genetically determined greater TyG index and increased TSH (inverse-variance weighting (IVW): OR [95% CI] = 1.14 [1.02-1.28], p = 0.020); however, this causal relationship disappeared after adjusting for BMI in multivariable MR (MVMR) analysis (MVMR-IVW: OR 1.03, 95% CI 0.87-1.22, p = 0.739)., Conclusions: A greater TyG index is associated with hypothyroidism and subclinical hypothyroidism and varies by sex and menopausal status. MR analysis demonstrated that the causal relationship between a genetically determined greater TyG index and elevated TSH levels is confounded or mediated by BMI., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Previous studies have indicated an association between vitamin D and thyroid- and parathyroid-related diseases. However, it remains unclear whether it is a cause of the disease, a side effect of treatment or a consequence of the disease. The Mendelian randomisation (MR) study strengthens the causal inference by controlling for non-heritable environmental confounders and reverse causation. In this study, a two-sample bidirectional MR analysis was conducted to investigate the causal relationship between serum vitamin D levels and thyroid- and parathyroid-related diseases. Inverse variance weighted, weighted median and MR-Egger methods were performed, the Cochran Q test was used to evaluate the heterogeneity and the MR-PRESSO and MR-Egger intercepts were utilised to assess the possibility of pleiotropy. The Bonferroni-corrected significance threshold was 0·0038. At the Bonferroni-corrected significance level, we found that vitamin D levels suggestively decreased the risk of benign parathyroid adenoma (OR = 0·244; 95 % CI 0·074, 0·802; P = 0·0202) in the MR analyses. In the reverse MR study, a genetically predicted risk of thyroid cancer suggestively increased the risk of elevated vitamin D (OR = 1·007; 95 % CI 1·010, 1·013; P = 0·0284), chronic thyroiditis significantly increased the risk of elevated vitamin D (OR = 1·007; 95 % CI 1·002, 1·011; P = 0·0030) and thyroid nodules was significantly decreased the vitamin D levels (OR = 0·991; 95 % CI 0·985, 0·997; P = 0·0034). The findings might be less susceptible to horizontal pleiotropy and heterogeneity ( P > 0·05). This study from a gene perspective indicated that chronic thyroiditis and thyroid nodules may impact vitamin D levels, but the underlying mechanisms require further investigation.

Maintaining normal thyroid function is crucial in pregnancy, yet thyroid dysfunction and the presence of thyroid peroxidase antibodies (TPOAb) affect 0.5% to 18% of pregnant women. Here, we conducted a genome-wide association study (GWAS) of eight thyroid traits, including two thyroid-related hormones, four thyroid dysfunctions, and two thyroid autoimmunity measurements among 85,421 Chinese pregnant women to investigate the genetic basis of thyroid function during pregnancy. Our study identified 176 genetic loci, including 125 previously unknown genome-wide associations. Joint epidemiological and Mendelian randomization analyses revealed significant associations between the gestational thyroid phenotypes and gestational complications, birth outcomes, and later-age health outcomes. Specifically, genetically elevated thyroid-stimulating hormone (TSH) levels during pregnancy correlated with lower glycemic levels, reduced blood pressure, and longer gestational duration. Additionally, TPOAb and thyroid functions during pregnancy share genetic correlations with later-age thyroid and cardiac disorders. These findings provide insights into the genetic determinants of thyroid traits during pregnancy, which may lead to new therapeutics, early pre-diagnosis and preventive strategies starting from early adulthood., (© 2024. The Author(s).)

Objective: Observational studies have shown positive associations between thyroid dysfunction and risk of sarcopenia. However, the causality of this association remains unknown. This study aimed to evaluate the potential causal relationship between thyroid dysfunction and sarcopenia using Mendelian randomization (MR)., Methods: This study collected pooled data from genome-wide association studies focusing on thyroid dysfunction and three sarcopenia-related features: low hand grip strength, appendicular lean mass (ALM), and walking pace, all in individuals of European ancestry. The primary analytical method used was inverse-variance weighted, with weighted median and MR-Egger serving as complementary methods to assess causal effects. Heterogeneity and pleiotropy tests were also performed, and the stability of the results was evaluated using the Leave-one-out., Results: The MR analysis indicated that hyperthyroidism could lead to a significant decrease in ALM in the extremities (OR = 1.03; 95% CI = 1.02 to 1.05; P < 0.001). The analysis also found that hypothyroidism could cause a notable reduction in grip strength (OR = 2.03; 95% CI = 1.37 to 3.01; P < 0.001) and walking pace (OR = 0.83; 95% CI = 0.77 to 0.90; P < 0.001). There was a significant association between subclinical hyperthyroidism and a reduced walking pace (OR = 1.00; 95% CI = 0.99 to 1.00; P = 0.041)., Conclusion: This study provides evidence that hyperthyroidism, hypothyroidism, and subclinical hyperthyroidism can all increase the risk of sarcopenia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wei, Hou, Hei and Wang.)

Background: To clarify the controversy between inflammatory or autoimmune skin diseases and thyroid diseases, we performed two-sample Mendelian randomization (MR) analyses., Participants: Genetic data on factors associated with atopic dermatitis (AD, n=40,835), seborrheic dermatitis (SD, n=339,277), acne (n=363,927), rosacea (n=299,421), urticaria (n=374,758), psoriasis (n=373,338), psoriasis vulgaris (n=369,830), systemic lupus erythematosus (SLE, n=14,267), vitiligo (n=353,348), alopecia areata (AA, n=361,822), pemphigus (n=375,929), bullous pemphigoid (BP, n=376,274), systemic sclerosis (SSc, n=376,864), localized scleroderma (LS, n=353,449), hypothyroidism (n=314,995 or n=337,159), and hyperthyroidism (n=281,683 or n=337,159) were derived from genome-wide association summary statistics of European ancestry., Main Measures: The inverse variance weighted method was employed to obtain the causal estimates of inflammatory or autoimmune skin diseases on the risk of thyroid diseases, complemented by MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO)., Key Results: AD, SLE, SD, and psoriasis vulgaris were associated with an increased risk of hypothyroidism, whereas BP was associated with a lower risk of hypothyroidism (all with p < 0.05). The multivariable MR analyses showed that AD (OR = 1.053; 95%CI: 1.015-1.092; p = 0.006), SLE (OR = 1.093; 95%CI: 1.059-1.127; p < 0.001), and SD (OR = 1.006; 95%CI: 1.002-1.010; p = 0.006) independently and predominately contributed to the genetic causal effect on hypothyroidism after adjusting for smoking. The results showed no causal effects of inflammatory or autoimmune skin diseases on hyperthyroidism., Conclusion: The findings showed a causal effect of AD, SLE, SD on hypothyroidism, but further investigations should be conducted to explore the pathogenic mechanisms underlying these relationships., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 You, Duan, Zhou, Yu, Zou, Wei, Chai, Zeng, Xiao, Yuan and Xiao.)

Objective: Some correlations between thyroid disorders and insomnia have been found in previous studies; however, the causal relationship between them is unclear. The aim of this study was to investigate the causal relationship between insomnia and five thyroid disorders (hyperthyroidism, hypothyroidism, thyroiditis, thyroid nodules, and thyroid cancer)., Methods: We assessed the causal relationship between insomnia and thyroid disorders using inverse variance weighted, weighted median, and Mendelian randomization (MR)-Egger analyses in MR analyses and then used inverse MR analyses to assess the causal relationship between thyroid disorders and insomnia., Results: MR analysis showed that insomnia did not increase the risk of hyperthyroidism, hypothyroidism, thyroiditis, thyroid nodules, and thyroid cancer. However, reverse MR analysis showed that thyroid cancer increased the risk of insomnia (OR = 1.01, 95%CI: 1.00-1.02, p = .01), and the other four thyroid disorders had no direct causal relationship with insomnia. Sensitivity analyses indicated that the results were robust and no pleiotropy or heterogeneity was detected., Conclusion: This study did not find evidence of a bidirectional causal relationship between genetically predicted insomnia and hyperthyroidism, hypothyroidism, thyroiditis, and thyroid nodules. However, we found that although insomnia does not increase the risk of thyroid cancer, thyroid cancer does increase the risk of insomnia., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Background: Variation in thyroid function parameters within the normal range has been observationally associated with adverse health outcomes. Whether those associations reflect causal effects is largely unknown., Methods: We systematically tested associations between genetic differences in thyrotropin (TSH) and free thyroxine (FT4) within the normal range and more than 1100 diseases and more than 6000 molecular traits (metabolites and proteins) in three large population-based cohorts. This was performed by combining individual and summary level genetic data and using polygenic scores and Mendelian randomization (MR) methods. We performed a phenome-wide MR study in the OpenGWAS database covering thousands of complex phenotypes and diseases., Findings: Genetically predicted TSH or FT4 levels within the normal range were predominately associated with thyroid-related outcomes, like goitre. The few extra-thyroidal outcomes that were found to be associated with genetic liability towards high but normal TSH levels included atrial fibrillation (odds ratio = 0.92, p-value = 2.13 × 10 -3 ), thyroid cancer (odds ratio = 0.57, p-value = 2.97 × 10 -4 ), and specific biomarkers, such as sex hormone binding globulin (β = -0.046, p-value = 1.33 × 10 -6 ) and total cholesterol (β = 0.027, p-value = 5.80 × 10 -3 )., Interpretation: In contrast to previous studies that have described the association with thyroid hormone levels and disease outcomes, our genetic approach finds little evidence of an association between genetic differences in thyroid function within the normal range and non-thyroidal phenotypes. The association described in previous studies may be explained by reverse causation and confounding., Funding: This research was funded by the Swiss National Science Foundation (P1BEP3&#95;200041). The Fenland study (DOI 10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC&#95;UU&#95;12015/1, MC&#95;PC&#95;13046 and MC&#95;UU&#95;00006/1). The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC-UU&#95;12015/1, MC&#95;PC&#95;13048 and MC&#95;UU&#95;00006/1)., Competing Interests: Declaration of interests All authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Studies have been conducted on the relationship between depression and thyroid diseases and function, its causal relationship remains unclear., Methods: Using summary statistics of genome-wide association studies of European and East Asian ancestry, we conducted 2-sample bidirectional Mendelian randomization to estimate the association between MDD and thyroid function (European: normal range TSH, T4, T3, fT4, TPOAb levels and TPOAb-positives; East Asian: T4) and thyroid diseases (hypothyroidism, hyperthyroidism, and Hashimoto's thyroiditis), and used Mediation analysis to evaluate potential mediators (alcohol intake, antidepressant) of the association and calculate the mediated proportions., Results: It was observed a significant causal association between MDD on hypothyroidism (P = 8.94 × 10 -5 ), hyperthyroidism (P = 8.68 × 10 -3 ), and hashimoto's thyroiditis (P = 3.97 × 10 -5 ) among European ancestry, which was mediated by Alcohol intake (alcohol intake versus 10 years previously for hypothyroidism (P = 0.026), hashimoto's thyroiditis (P = 0.042), and alcohol intake frequency for hypothyroidism (P = 0.015)) and antidepressant (for hypothyroidism (P = 0.008), hashimoto's thyroiditis (P = 0.010)), but not among East Asian ancestry (P MDD-hypothyroidism  = 0.016, but β direction was different; P MDD-hyperthyroidism  = 0.438; P MDD-hashimoto ' s thyroiditis  = 0.496). There was no evidence for bidirectional causal association between thyroid function mentioned above and MDD among both ancestry (all P > 0.05)., Conclusion: We importantly observed a significant causal association between MDD on risk of hypothyroidism, hyperthyroidism, and hashimoto's thyroiditis among European ancestry, and Alcohol intake and antidepressant as mediators for prevention of hypothyroidism, hashimoto's thyroiditis attributable to MDD., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Although descriptive studies have found an association between thyroid dysfunction (TD) and alopecia areata (AA), however, the causal relationship between TD and AA remains unclear. The purpose of this study is to investigate the causal relationship between the two and the specific directions., Methods: We performed large-scale, two-sample Mendelian randomization (MR) analyses to examine whether there was an association between TD (such as Graves' disease (GD), Hashimoto's thyroiditis (HT), thyroid cancer (TC), thyroid stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), etc.) and AA. Genome-wide association study (GWAS) summary statistics for TD and AA were from the IEU OpenGwas project. The inverse variance-weighted (IVW) method was used as the primary analysis method to evaluate the causality between TD and AA, supplemented by the weighted median, MR-Egger, simple mode and weighted mode. In addition, sensitivity analyses were performed to assess the reliability of the study results., Results: Our study found that single nucleotide polymorphisms (SNPs) in HT (IVW OR = 1.396, 95% CI 1.030-1.892, P =0.031) and hypothyroidism (IVW OR = 1.431, 95% CI 1.138-1.799, P =0.002) significantly increased the risk of AA. Reverse MR analysis indicated that genetic susceptibility to AA (β=-0.029, 95%CI=-0.051 to -0.007, P =0.009) may be a risk for TRH. Positive MR analysis observed no statistically significant causal relationship between other TD and AA (IVW P >0.05). Reverse MR analysis also showed no statistically significant association between AA and other TD (IVW P >0.05) other than TRH. Furthermore, additional sensitivity analyses were performed, including a leave-one-out test, a heterogeneity test, and a pleiotropy test to assess the robustness of the results., Conclusions: This study provides a very comprehensive analysis of the causal relationship between TD and AA, providing convincing genetic evidence to support the causal relationship between TD and alopecia areata. It reveals some causes of AA patients, which is of great significance for the management and treatment of AA patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gao, Li, Song, Gao and Chen.)

Objective: The aim of the study is to map the shared genetic component and relationships between thyroid and reproductive health traits to improve the understanding of the interplay between those domains., Design: A large-scale genetic analysis of thyroid traits (hyper- and hypothyroidism, and thyroid-stimulating hormone levels) was conducted in up to 743 088 individuals of European ancestry from various cohorts., Methods: We evaluated genetic associations using genome-wide association study (GWAS) meta-analysis, GWAS Catalog lookup, gene prioritization, mouse phenotype lookup, and genetic correlation analysis., Results: GWAS meta-analysis results for thyroid phenotypes showed that 50 lead variants out of 253 (including 5/52 of the novel hits) were linked to reproductive health in previous literature. Genetic correlation analyses revealed significant correlations between hypothyroidism and reproductive phenotypes. The results showed that 31.9% of thyroid-associated genes also had an impact on reproductive phenotypes, with the most affected functions being related to genitourinary tract issues., Conclusions: The study discovers novel genetic loci linked to thyroid phenotypes and highlights the shared genetic determinants between thyroid function and reproductive health, providing evidence for the genetic pleiotropy and shared biological mechanisms between these traits in both sexes., Competing Interests: Conflict of interest: the authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism, and resistance to hormone action. Mediated by heritable single-gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with the identification of pathogenic variants in causal genes, and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarizing key clinical features and useful investigations, criteria for molecular genetic diagnosis, and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.

Objective: Observational studies have suggested associations of birth weight, childhood BMI, and adulthood BMI with thyroid function or diseases. However, the causal relationships remain unclear due to residual confounding inherent in conventional epidemiological studies., Methods: We performed a two-sample Mendelian randomization (MR) study to investigate causal relationships of genetically predicted birth weight, childhood BMI, and adulthood BMI with a range of clinically relevant thyroid outcomes. Additionally, we conducted a reverse MR analysis on adulthood BMI. Data on exposures and outcomes were obtained from large-scale genome-wide association study meta-analyses predominantly composed of individuals of European ancestry., Results: The MR analysis revealed no evidence of causal associations of birth weight or BMI at different life stages with thyrotropin (TSH) levels, hypothyroidism, hyperthyroidism, autoimmune thyroid disorders, or thyroid cancer. Contrarily, thyroid cancer demonstrated a significant causal relationship with increased adulthood BMI (β = 0.010, 95% CI: 0.006-0.015; p = 5.21 × 10 -6 )., Conclusions: Our comprehensive MR did not find causal links of birth weight, childhood BMI, or adulthood BMI with thyroid diseases but provided evidence that thyroid cancer may play a role in weight gain. Our research findings offer valuable insights into the intricate relationship between body weight and thyroid health throughout an individual's life., (© 2024 The Obesity Society.)

Background: Serum thyroid-stimulating hormone (TSH) measurement is the diagnostic cornerstone for primary thyroid dysfunction. There is high inter-individual but limited intra-individual variation in TSH concentrations, largely due to genetic factors. The currently used wide population-based reference intervals may lead to inappropriate management decisions. Methods: A polygenic score (PGS) including 59 genetic variants was used to calculate genetically determined TSH reference ranges in a thyroid disease-free cohort ( n = 6,834). Its effect on reclassification of diagnoses was investigated when compared to using population-based reference ranges. Next, results were validated in a second independent population-based thyroid disease-free cohort ( n = 3,800). Potential clinical implications were assessed in a third independent population-based cohort including individuals without thyroid disease ( n = 26,321) as well as individuals on levothyroxine (LT4) treatment ( n = 1,132). Results: PGS was a much stronger predictor of individual TSH concentrations than FT4 (total variance in TSH concentrations explained 9.2-11.1% vs. 2.4-2.7%, respectively) or any other nongenetic factor (total variance in TSH concentrations explained 0.2-1.8%). Genetically determined TSH reference ranges differed significantly between PGS quartiles in all cohorts, while the differences in FT4 concentrations were absent or only minor. Up to 24.7-30.1% of individuals, previously classified as having subclinical hypo- and hyperthyroidism when using population-based TSH reference ranges, were reclassified as euthyroid when genetically determined TSH reference ranges were applied. Individuals in the higher PGS quartiles had a higher probability of being prescribed LT4 treatment compared to individuals from the lower PGS quartiles (3.3% in Q1 vs. 5.2% in Q4, P for trend =1.7 × 10 -8 ). Conclusions: Individual genetic profiles have the potential to personalize TSH reference ranges, with large effects on reclassification of diagnosis and LT4 prescriptions. As the currently used PGS can only predict approximately 10% of inter-individual variation in TSH concentrations, it should be further improved when more genetic variants determining TSH concentrations are identified in future studies.

Autoimmune thyroid diseases (AITDs), including Graves' disease and Hashimoto's thyroiditis, are organ-specific autoimmune disorders characterized by conditions including goiter, autoimmune thyroiditis, hyperthyroidism, and hypothyroidism, which represent the most severe clinical manifestations of AITDs. The prevalence of autoimmune thyroid disorders is on the rise, influenced by increased environmental factors and changes in modern lifestyles. Understanding the pathophysiology of AITDs is crucial for identifying key factors that affect the disease's onset, progression, and recurrence, thereby laying a solid foundation for precise diagnosis and treatment. The development of AITDs involves a complex interplay of environmental influences, immune dysfunctions, and genetic predispositions. Genetic predispositions, in particular, are significant, with numerous genes identified as being linked to AITDs. This article focuses on examining the genes vulnerable to AITDs to deepen our understanding of the relevant genetic contributors, ultimately facilitating the development of effective prevention and treatment methods., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To explore the causal relationship between thyroid dysfunction and sepsis based on the bidirectional two-sample Mendelian randomization (MR) method., Methods: The genome-wide association study (GWAS) dataset were selected to screen single nucleotide polymorphisms (SNP) associated with thyroid dysfunction as instrumental variable (IV) for genetic variation, using hypothyroidism and hyperthyroidism as exposure factor and sepsis as outcome factor. Potential causal relationship between thyroid dysfunction and sepsis was analyzed using a bidirectional two-sample MR method primary analysis method of inverse-variance weighted (IVW). Potential pleiotropic analysis of SNP was performed using the MR Egger regression intercept test. Sensitivity analysis was performed using the "leave one out" test. Reverse MR method was used to prove the causal relationship., Results: The GWAS data were screened based on the three main assumptions of MR, resulting in 101 SNP strongly associated with hypothyroidism and 10 SNP strongly associated with hyperthyroidism entering the MR analysis. The results of the MR using the IVW method showed that the risk of sepsis in individuals with hypothyroidism was 2.293 times higher than those without hypothyroidism [odds ratio (OR) = 2.293, 95% confidence interval (95%CI) was 1.199-4.382, P = 0.012]. There was no significant difference in the risk of sepsis between hyperthyroid and non-hyperthyroid populations (OR = 1.049, 95%CI was 0.999-1.100, P = 0.560). MR Egger regression intercept test showed that the included SNP did not have pleiotropy, and the MR-PRESSO test did not find outliers. Sensitivity analysis suggested that the results of MR were stable. The results of the reverse MR analysis showed that the reverse causal relationship between hyperthyroidism and sepsis was not proved (OR = 0.996, 95%CI was 0.988-1.004, P = 0.338), which further confirmed the robust MR analysis result., Conclusions: The results of the bidirectional two-sample MR analysis show that hypothyroidism can increase the risk of sepsis onset, while there is no causal relationship between hyperthyroidism and sepsis.

Background: Previous studies have shown an association between acute respiratory distress syndrome (ARDS) and thyroid function. However, their causal relationship remains unspecified. Therefore, this study aims to explore the causal relationship between ARDS and thyroid function-related diseases with Mendelian Randomization (MR) analysis., Methods: ARDS dataset finn-b-J10&#95;ARDS, finn-b-E4&#95;THYROID dataset of disorders of the thyroid gland (DTG) and finn-b-E4&#95;HYTHYNAS of hypothyroidism were acquired from public database. In univariate MR (UVMR), causal effects between DTG, hypothyroidism and ARDS were investigated using 5 types of algorithms, and reliability was validated by sensitivity analysis. Moreover, multivariate MR (MVMR), enrichment and interaction network analyses of genes corresponding to SNPs of DTG and hypothyroidism were carried out. Significant level was chosen as p<0.05., Results: UVMR identified DTG and hypothyroidism ( P < 0.05, OR > 1) as risk factors, and were causally related to ARDS. Reliability of UVMR results was confirmed through sensitivity analysis, and results were stable and reliable. However, DTG and hypothyroidism had no effect on ARDS in MVMR, possibly because these factors had independent effects on ARDS. Ultimately, 96 and 113 genes corresponding to SNPs of DTG and hypothyroidism were found closely related to immune-related pathways., Conclusions: UVMR and MVMR analysis revealed a causal connection between DTG and hypothyroidism as risk factors with ARDS, providing robust evidence for investigation into relationship of hypothyroidism on ARDS and between DTG and ARDS.

The link between celiac disease (CeD) and thyroid dysfunction has been investigated. However, it is uncertain if CeD is causally linked to thyroid dysfunction. A 2-sample Mendelian randomization study was conducted to ascertain the causal connection between CeD and thyroid dysfunction. Using data from the FinnGen Consortium, a 2-sample Mendelian randomization study was conducted to look at the connection between thyroid dysfunction and CeD. Another replication of the data from the UK Biobank was subsequently performed to confirm our findings. Furthermore, a sequence of sensitivity analyses was performed. The inverse variance weighting technique demonstrates that genetically determined CeD is substantially linked with hypothyroidism, thyrotoxicosis, Graves' disease, and free thyroxine. However, no significant associations were found between CeD and thyroid-stimulating hormone or thyroiditis. Moreover, we achieve the same results in duplicate datasets, which increases the reliability of our findings. This study suggests that CeD and thyroid dysfunction are linked, and it gives theoretical support and new ways of thinking about how to diagnose and treat both conditions., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Some previous observational studies have linked deep venous thrombosis (DVT) to thyroid diseases; however, the findings were contradictory. This study aimed to investigate whether some common thyroid diseases can cause DVT using a two-sample Mendelian randomization (MR) approach., Methods: This two-sample MR study used single nucleotide polymorphisms (SNPs) identified by the FinnGen genome-wide association studies (GWAS) to be highly associated with some common thyroid diseases, including autoimmune hyperthyroidism (962 cases and 172,976 controls), subacute thyroiditis (418 cases and 187,684 controls), hypothyroidism (26,342 cases and 59,827 controls), and malignant neoplasm of the thyroid gland (989 cases and 217,803 controls. These SNPs were used as instruments. Outcome datasets for the GWAS on DVT (6,767 cases and 330,392 controls) were selected from the UK Biobank data, which was obtained from the Integrative Epidemiology Unit (IEU) open GWAS project. The inverse variance weighted (IVW), MR-Egger and weighted median methods were used to estimate the causal association between DVT and thyroid diseases. The Cochran's Q test was used to quantify the heterogeneity of the instrumental variables (IVs). MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO) was used to detect horizontal pleiotropy. When the causal relationship was significant, bidirectional MR analysis was performed to determine any reverse causal relationships between exposures and outcomes., Results: This MR study illustrated that autoimmune hyperthyroidism slightly increased the risk of DVT according to the IVW [odds ratio (OR) = 1.0009; p = 0.024] and weighted median methods [OR = 1.001; p = 0.028]. According to Cochran's Q test, there was no evidence of heterogeneity in IVs. Additionally, MR-PRESSO did not detect horizontal pleiotropy (p = 0.972). However, no association was observed between other thyroid diseases and DVT using the IVW, weighted median, and MR-Egger regression methods., Conclusions: This study revealed that autoimmune hyperthyroidism may cause DVT; however, more evidence and larger sample sizes are required to draw more precise conclusions., (© 2024. The Author(s).)

Background: Previous observational studies have shown conflicting results of vitamins supplementation for thyroid diseases. The causal relationships between vitamins and thyroid diseases are unclear. Therefore, we conducted a two-sample bidirectional Mendelian randomization (MR) study to explore association of circulating vitamin levels with thyroid diseases., Methods: We performed a bidirectional MR analysis using genome-wide association study (GWAS) data. Genetic tool variables for circulating vitamin levels include vitamins A, B 9 , B 12 , C, D, and E, Genetic tool variables of thyroid diseases include autoimmune hyperthyroidism, autoimmune hypothyroidism, thyroid nodules (TNs), and Thyroid cancer (TC). Inverse-variance weighted multiplicative random effects (IVW-RE) was mainly used for MR Analysis, weighted median (WM) and MR Egger were used as supplementary methods to evaluate the relationships between circulating vitamin levels and thyroid diseases. Sensitivity and pluripotency were evaluated by Cochran's Q test, MR-PRESSO, Radial MR, MR-Egger regression and leave-one-out analysis., Results: Positive MR evidence suggested that circulating vitamin C level is a protective factor in autoimmune hypothyroidism (OR IVW-RE =0.69, 95%CI: 0.58-0.83, p = 1.05E-04). Reverse MR Evidence showed that genetic susceptibility to autoimmune hyperthyroidism is associated with reduced level of circulating vitamin A(OR IVW-RE = 0.97, 95% CI: 0.95-1.00, p = 4.38E-02), genetic susceptibility of TNs was associated with an increased level of circulating vitamin D (OR IVW-RE = 1.02, 95% CI: 1.00-1.03, p = 6.86E-03). No causal and reverse causal relationship was detected between other circulating vitamin levels and thyroid diseases., Conclusion: Our findings provide genetic evidence supporting a bi-directional causal relationship between circulating vitamin levels and thyroid diseases. These findings provide information for the clinical application of vitamins prevention and treatment of thyroid diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Liu and Que.)

The prevalence of thyroid dysfunction diseases (TDFDs) and osteoporosis (OP) is high. Previous studies have indicated a potential association between TDFDs and OP, yet the causal direction remains unclear. This study aimed to investigate the potential causal relationship between TDFDs and the risk of developing OP and related fractures. We obtained pooled data from genome-wide association studies (GWASs) conducted on TDFDs and OP in European populations and identified single-nucleotide polymorphisms (SNPs) with genome-wide significance levels associated with exposure to TDFDs as instrumental variables. Inverse variance weighted (IVW) was employed as the primary method for Mendelian randomization (MR) analysis, supplemented by MR‒Egger, weighted median, simple mode and weighted mode methods. Sensitivity analyses were conducted to evaluate the robustness of the findings. The IVW method demonstrated an increased risk of OP in patients with TDFDs, including hyperthyroidism and hypothyroidism (TDFDs: OR = 1.11; 95% CI 1.09, 1.13; hypothyroidism: OR = 1.14; 95% CI 1.10, 1.17; hyperthyroidism: OR = 1.09; 95% CI 1.06, 1.12). These findings were supported by supplementary analysis, which revealed a positive correlation between TDFDs and the risk of OP. Multiple sensitivity analyses confirmed the absence of horizontal pleiotropy in the study, thus indicating the robustness of our results. The causal relationship between TDFDs and increased risk of OP implies the need for early bone mineral density (BMD) screening and proactive prevention and treatment strategies for individuals with TDFDs., (© 2024. The Author(s).)

Introduction: The established association between thyroid disorders (TD) and its two main subtypes-hyperthyroidism and hypothyroidism-and the incidence of oral and oropharyngeal cancer (OCPC) has been substantiated. However, the direct causal relationship and potential intermediary mechanisms linking these conditions have not been clearly defined in prior studies., Material & Methods: This study employed univariate Mendelian randomization (MR) analysis to explore those relationship. Instrumental variables from genome-wide association study (GWAS) datasets for TD (n = 218,792), hyperthyroidism (n = 460,499), hypothyroidism (n = 213,990), and OCPC (n = 12,619), along with 41 intermediary inflammatory cytokines (n = 8293), were analyzed. Inverse variance weighting (IVW) method assessed the causal relationships, while summary MR analysis with pQTL datasets from decode and 91 inflammatory cytokines explored the cytokines' roles as biomarkers and therapeutic targets for OCPC. Multivariable MR (MVMR) analysis quantified the mediation effect of these cytokines in the TD-OCPC relationship., Results: UVMR analysis provided strong evidence for a causal relationship between TD (OR = 1.376, 95 % CI = 1.142-1.656, p = 0.001), hyperthyroidism (OR = 1.319, 95 % CI=1.129-1.541, p = 0.001), hypothyroidism (OR = 1.224, 95 % CI = 1.071-1.400, p = 0.003), and the risk of OCPC. CXCL9 was identified as a significant intermediary in mediating the risk of OCPC from TD and its two subtypes (OR = 1.218, 95 % CI = 1.016-1.461, P = 0.033), suggesting its potential as a predictive biomarker for OCPC. MVMR analysis further revealed that CXCL9 mediated 7.94 %, 14.4 %, and 18 % of the effects of TD, hyperthyroidism, and hypothyroidism on OCPC risk, respectively., Discussion: This study not only elucidated the potential causal relationships between TD including its two subtypes and OCPC risk, but also highlighted CXCL9 as a pivotal mediator in this association., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Vitiligo is an acquired autoimmune depigmented disorder characterized by the presence of white and well-defined patches on the skin, mucous membrane, or both. It is associated with a significant disease burden and has a profoundly impacts patients' quality of life. Autoimmune thyroid diseases (AITDs) result from an autoimmune system dysregulation, leading to an erroneous immune attack on the thyroid gland. Previous observational and epidemiological studies have suggested the association between vitiligo and AITDs. However, the bidirectional cause-effect relationship between vitiligo and AITDs has not been formally assessed., Method: Two-sample bidirectional Mendelian randomization (MR) analysis was conducted to explore potential causal relationships between genetically increased risk of vitiligo and AITDs, using summary statistics from genome-wide association studies in European populations. Causal effects were primarily estimated using the inverse variance weighted method, and additional quality control was performed using the MR-Egger, weighted median, simple mode, and weight mode methods. Sensitivity analysis was conducted to assess the robustness of the results., Results: The forward MR analysis showed a positive causal relationship between vitiligo and autoimmune thyroiditis (AIT), autoimmune hyperthyroidism (AIH), and Graves' disease (GD). The odds ratio (OR) were 1.17 (95% CI, 1.01-1.35; p = 0.04), 1.12 (95% CI, 1.03-1.22; p = 0.01), and 1.13 (95% CI, 1.06-1.20; p < 0.01), respectively. In the reverse MR analysis, a positive causal relationship was found between AIT and vitiligo, with an OR of 1.10 (95% CI, 1.01-1.35; p = 0.04). However, no causal relationship was observed between AIH (p = 0.10) or GD (p = 0.61) and vitiligo. Sensitivity analysis revealed no evidence of horizontal pleiotropy or heterogeneity., Conclusions: The genetic-level investigation provides evidence of a genetic causal association between susceptibility to vitiligo and an increased risk of AITDs. Additionally, the results demonstrate a genetic causal association between susceptibility to AIT and an increased risk of vitiligo, while not indicating a similar association with susceptibility to AIH or GD., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Evidence from observational researches have suggested that mental diseases are able to affect thyroid diseases. However, the causal relationship between mental diseases and the risk of thyroid diseases still remains unclear. Herein, we conducted a two-sample Mendelian randomization (MR) statistical analysis method to assess the causality between mental diseases and thyroid diseases. Initially, publicly available genome-wide association studies summary data were leveraged to obtain single-nucleotide polymorphisms based on set parameters. Subsequently, a two-sample MR was utilized to analyze causal relationships between mental diseases (Alzheimer disease, bipolar disorder, major depressive disorder, Parkinson disease, schizophrenia) and thyroid diseases (hyperthyroidism/thyrotoxicosis, hypothyroidism) with removing outliers based on MR-PRESSO method. Finally, 8 regression MR methods (inverse variance weighted [IVW], IVW fixed effects, c, MR Egger, weighted median, penalized weighted median, simple mode, weighted mode) were performed to evaluate bias and effectiveness, of which IVW was considered as the primary method. Our results demonstrated that most of mental diseases have no causal relationships with thyroid diseases except bipolar disorder and hyperthyroidism/thyrotoxicosis based on IVW method [odds ratio: 0.999, 95% confidence interval: 0.998-1.000, P = .028], and bipolar disorder and hypothyroidism based on IVW method [odds ratio: 0.997, 95% confidence interval: 0.995-0.999, P = .002]. Then we subsequently conducted a consistent robustness analysis to assess heterogeneity and horizontal pleiotropy. Our method reports causal relationships exist mental diseases and the risk of thyroid diseases. Subsequent researches are still warranted to determine how mental diseases influence the development of thyroid diseases., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Significant progress has been made in the understand-ing of many human diseases, especially cancers, which has contributed to improved and increased survival. The Human Genome Project and The Cancer Genome Atlas project brought about a new era, with an understanding of inherited diseases at a molecular level, which subsequently facilitated the option of precision medicine. Precision medicine has helped tailor treatment decisions at an individual level, for instance in terms of surgical treatments or targeted therapies in advanced diseases. Despite the increasing advances in genetic-lead precision medicine, this has not translated into increasing uptake among patients. Reasons for this may be potential knowledge gaps among clinicians; on reasons for poor uptake of genetic testing such as for cultural, religious or personal beliefs; and on financial implications such as lack of support from insurance companies. In this review, we look at the current scenario of genetic screening for common inherited endocrine conditions affecting the thyroid, parathyroid and adrenal glands in Singapore, and the implications associated with it., Competing Interests: No conflict of interests to declare.

Backgroud: Gastric cancer is one of the most common cancers worldwide, and its development is associated with a variety of factors. Previous observational studies have reported that thyroid dysfunction is associated with the development of gastric cancer. However, the exact relationship between the two is currently unclear. We used a two-sample Mendelian randomization (MR) study to reveal the causal relationship between thyroid dysfunction and gastric cancer for future clinical work., Materials and Methods: This study is based on a two-sample Mendelian randomization design, and all data are from public GWAS databases. We selected hyperthyroidism, hypothyroidism, free thyroxine (FT4), and thyroid-stimulating hormone (TSH) as exposures, with gastric cancer as the outcome. We used three statistical methods, namely Inverse-variance weighted (IVW), MR-Egger, and weighted median, to assess the causal relationship between thyroid dysfunction and gastric cancer. The Cochran's Q test was used to assess the heterogeneity among SNPs in the IVW analysis results, and MR-PRESSO was employed to identify and remove IVs with heterogeneity from the analysis results. MR-Egger is a weighted linear regression model, and the magnitude of its intercept can be used to assess the horizontal pleiotropy among IVs. Finally, the data were visualized through the leave-one-out sensitivity test to evaluate the influence of individual SNPs on the overall causal effect. Funnel plots were used to assess the symmetry of the selected SNPs, forest plots were used to evaluate the confidence and heterogeneity of the incidental estimates, and scatter plots were used to assess the exposure-outcome relationship. All results were expressed as odds ratios (OR) and 95% confidence intervals (95% CI). P<0.05 represents statistical significance., Results: According to IVW analysis, there was a causal relationship between hypothyroidism and gastric cancer, and hypothyroidism could reduce the risk of gastric cancer (OR=0.936 (95% CI:0.893-0.980), P=0.006).This means that having hypothyroidism is a protective factor against stomach cancer. This finding suggests that hypothyroidism may be associated with a reduced risk of gastric cancer.Meanwhile, there was no causal relationship between hyperthyroidism, FT4, and TSH and gastric cancer., Conclusions: In this study, we found a causal relationship between hypothyroidism and gastric cancer with the help of a two-sample Mendelian randomisation study, and hypothyroidism may be associated with a reduced risk of gastric cancer, however, the exact mechanism is still unclear. This finding provides a new idea for the study of the etiology and pathogenesis of gastric cancer, and our results need to be further confirmed by more basic experiments in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Mu, Jiang, Zhao, Wang and Shen.)

Introduction: Given the clinical association between thyroid dysfunction and iron deficiency anemia (IDA), as well as their shared association with iron status, this study aimed to investigate the causal relationship between iron status and thyroid dysfunction, while also examining the risk of IDA in relation to thyroid dysfunction., Methods: A two-sample mendelian randomization (MR) study was conducted to identify the causal relationship of iron status on thyroid dysfunction, as well as thyroid dysfunction on IDA. Large-scale European population-based genome-wide association study databases were utilized (Genetics of Iron Status consortium, ThyroidOmics consortium, FinnGen consortium, and UK Biobank). Inverse variance-weighted (IVW) was used as the main analysis. In addition, we used weighted median and MR-Egger to enhance the robustness. Sensitivity analysis was conducted to evaluate the robustness of MR results., Results: The IVW estimates did not reveal any significant causal relationship between serum iron status markers and thyroid dysfunction. However, a significant causal relationship was observed between hypothyroidism and IDA (odds ratio [OR] = 1.101, 95% confidence interval [CI] = 1.048-1.157, p < 0.001). Repeated analyses also demonstrated a similar trend (OR = 1.023, 95% CI = 1.011-1.035, p < 0.001). Sensitivity analysis supported that the MR estimates were robust., Conclusion: In our MR study, an upregulation of the hypothyroidism-associated gene was found to be significantly associated with an elevated risk of IDA in the European population. These findings may offer novel therapeutic insights for clinicians managing patients with hypothyroidism, IDA, or their comorbidities., (© 2024 S. Karger AG, Basel.)

Thyroid hormones (THs) are crucial in bodily functions, while iron is essential for processes like oxygen transport. Specialized proteins maintain iron balance, including ferritin, transferrin, ferroportin, and hepcidin. Research suggests that THs can influence iron homeostasis by affecting mRNA and protein expression, such as ferritin and transferrin. Our study focused on male rats to assess mRNA expression of iron homeostasis-related proteins and metabolomics in thyroid dysfunction. We found altered gene expression across various tissues (liver, duodenum, spleen, and kidney) and identified disrupted metabolite patterns in thyroid dysfunction. These findings highlight tissue-specific effects of thyroid dysfunction on essential iron homeostasis proteins and provide insights into associated metabolic changes. Our research contributes to understanding the intricate interplay between thyroid hormones and iron balance. By unveiling tissue-specific gene expression alterations and metabolic disruptions caused by thyroid dysfunction, our work lays a foundation for future investigations to explore underlying mechanisms and develop targeted strategies for managing iron-related complications in thyroid disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Small extracellular vesicles (sEVs) contain microRNAs (miRNAs) which have potential to act as disease-specific biomarkers. The current study uses an established method to maintain human thyroid tissue ex vivo on a tissue-on-chip device, allowing the collection, isolation and interrogation of the sEVs released directly from thyroid tissue. sEVs were analysed for differences in miRNA levels released from benign thyroid tissue, Graves' disease tissue and papillary thyroid cancer (PTC), using miRNA sequencing and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to identify potential biomarkers of disease. Thyroid biopsies from patients with benign tissue (n = 5), Graves' disease ( n = 5) and PTC ( n = 5) were perfused with medium containing sEV-depleted serum for 6 days on the tissue-on-chip device. During incubation, the effluents were collected and ultracentrifuged to isolate sEVs; miRNA was extracted and sequenced (miRNASeq). Out of the 15 samples, 14 passed the quality control and miRNASeq analysis detected significantly higher expression of miR-375-3p, miR-7-5p, miR-382-5p and miR-127-3p in the sEVs isolated from Graves' tissue compared to those from benign tissue (false discovery rate; FDR p < 0.05). Similarly, miR-375-3p and miR-7-5p were also detected at a higher level in the Graves' tissue sEVs compared to the PTC tissue sEVs (FDR p < 0.05). No significant differences were observed between miRNA in sEVs from PTC vs. those from benign tissue. These results were supported by Quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR). The novel findings demonstrate that the tissue-on-chip technology is a robust method for isolating sEVs directly from the tissue of interest, which has permitted the identification of four miRNAs, with which further investigation could be used as biomarkers or therapeutic targets within thyroid disease.

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases., (© 2023. Springer Nature Limited.)

Background: Human blood metabolites have demonstrated close associations with thyroid disorders in observational studies. However, it's essential to determine whether these correlations imply causation. Mendelian Randomization (MR) offers a promising approach to investigate these patterns., Aims: The primary aim of our investigation is to establish causality between blood metabolites and three thyroid disorders: TC, GD, and HT., Methods: We employed a two-sample bidirectional MR analysis approach to assess the relationships between 452 blood metabolites and the three aforementioned thyroid disorders. Causal links were estimated using the IVW method, with sensitivity analyses conducted via MR-Egger, Weighted Median, and MR-PRESSO. We assessed potential heterogeneity and pleiotropy using MR-Egger intercept and Cochran's Q statistic. Additionally, we conducted pathway analysis to identify potential metabolic pathways., Results: We found 46 metabolites that showed suggestive associations with thyroid disease risk, especially Aspartate (OR IVW =7.41; 95%CI: 1.51-36.27; P IVW =0.013) and C-glycosyltryptophan (OR IVW =0.04; 95%CI: 0.00-0.29; P IVW =0.001) impacted TC, Kynurenine (OR IVW =2.69; 95%CI: 1.08-6.66; P IVW =0.032) and 4-androsten-3beta,17beta-diol disulfate 2 (OR IVW =0.78; 95%CI: 0.48-0.91; P IVW =0.024) significantly impacted GD, and Alpha-ketoglutarate (OR IVW =46.89; 95%CI: 4.65-473.28; P IVW =0.001) and X-14189-leucylalanine (OR IVW =0.31; 95%CI: 0.15-0.64 P IVW =0.001) significantly impacted HT. We also detected 23 metabolites influenced by TC and GD. Multiple metabolic pathways have been found to be involved in thyroid disease., Conclusion: Our MR findings suggest that the identified metabolites and pathways can serve as biomarkers for clinical thyroid disorder screening and prevention, while also providing new insights for future mechanistic exploration and drug target selection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Zhou, Xie, Li, Hu, He and Li.)

Objectives: To clarify the controversy between systemic lupus erythematosus (SLE) and thyroid disease, our study was designed to determine whether or not thyroid problems are associated with SLE., Methods: We obtained the IEU GWAS database for summary information on genome-wide association studies (GWAS) of SLE and thyroid disease (hypothyroidism and hyperthyroidism) in people with European ancestry. Three approaches were employed to assess the causal link between SLE and thyroid disease: MR-Egger, weighted median (WM), and inverse variance weighted (IVW). The pleiotropy and heterogeneity were examined using a variety of techniques, including the MR-Egger intercept, the MR-PRESSO approach, and the Cochran's Q test., Results: MR analysis revealed a relationship between SLE and an elevated incidence of hypothyroidism (IVW OR: 1.004, 95% CI: [1.003, 1.005], P = 8.45E-16) and hyperthyroidism (IVW OR: 1.0009, 95% CI: [1.0005, 1.0010], P = 1.30E-5). Neither horizontal pleiotropy nor heterogeneity was detected in the sensitivity analysis., Conclusion: Our MR study presents strong evidence demonstrating a link between SLE and an elevated risk of thyroid illness. This could help us learn more about what causes SLE and give people with SLE more thorough thyroid function tests and evaluations. Key points • We did not discover modest heterogeneity and pleiotropy in our study. •The findings of this study indicate that SLE is related to an elevated risk of hypothyroidism and hyperthyroidism., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Purpose: PTEN hamartoma tumor syndrome (PHTS) comprises a group of rare genetic conditions caused by germline mutations in PTEN gene and characterized by development of both benign and malignant lesions in many body tissues. In this study, we aimed to evaluate the incidence of thyroid findings in both adult and pediatric PHTS patients., Methods: A retrospectively analysis conducted in 19 (13 adult and 6 pediatric) patients with PHTS, all confirmed with genetic testing, observed from 2015 to 2021 at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico., Results: We found a thyroid involvement in 12 adult patients (92%): 11 patients had benign lesions (85%) and the remaining developed a follicular thyroid carcinoma (8.3%). The median age at time of the first available record was 30 years. Among benign lesions, multinodular goiter was the most observed finding (10/11, 91%). Only 1 out of 6 (16%) pediatric patients was diagnosed with a thyroid lesion (unifocal lesion in mild lymphocytic thyroiditis) at the age of 8 years., Conclusions: Thyroid disorders affected nearly all adult PHTS patients, but a much lower proportion of pediatric patients. We discuss about the natural history of thyroid involvement, age of PHTS clinical onset, and optimized surveillance., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The current study aimed to assess the connection between the mixture of lead (Pb), cadmium (Cd), arsenic (As), methylmercury (MeHg) and decabrominated diphenyl ether (decaBDE) and thyroid function, by using in silico toxicogenomic data-mining approach. To obtain the linkage between investigated toxic mixture and thyroid diseases (TDs), the Comparative Toxicogenomics Database (CTD) was used, while gene ontology (GO) enrichment analysis was performed by ToppGeneSuite portal. The analysis has shown 10 genes connected to all chemicals present in the mixture and TDs (CAT, GSR, IFNG, IL1B, IL4, IL6, MAPK1, SOD2, TGFB1, TNF), most of which were in co-expression (45.68%), or belonged to the same pathway (30.47%). Top 5 biological processes and molecular functions affected by the investigated mixture emphasized the role of two common mechanisms - oxidative stress and inflammation. Cytokines and inflammatory response was listed as the main molecular pathway that may be triggered by simultaneous exposure to toxic metal(oid)s and decaBDE and connected to TDs. The direct relations between Pb/decaBDE and redox status impairment in thyroid tissue was confirmed by our chemical-phenotype interaction analysis, while the strongest linkage between Pb, As and decaBDE and thyroid disorders was found. The obtained results provide better understanding of molecular mechanisms involved in the thyrotoxicity of the investigated mixture, and can be used to direct further research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The most common cause of acquired thyroid dysfunction is autoimmune thyroid disease, which is an organ-specific autoimmune disease with two presentation phenotypes: hyperthyroidism (Graves-Basedow disease) and hypothyroidism (Hashimoto's thyroiditis). Hashimoto's thyroiditis is distinguished by the presence of autoantibodies against thyroid peroxidase and thyroglobulin. Meanwhile, autoantibodies against the TSH receptor have been found in Graves-Basedow disease. Numerous susceptibility genes, as well as epigenetic and environmental factors, contribute to the pathogenesis of both diseases. This review summarizes the most common genetic, epigenetic, and environmental mechanisms involved in autoimmune thyroid disease.

Background and Objective: The recurrence risk ratio (λ) expresses the risk ratio of index patients' first-degree relatives developing a disease as compared to the general population and is a quantitative measure of the genetic contribution to the disease. This paper offers the results of a specialized center as well as a review of the pertinent literature., Methods: Data from 3315 consecutive subjects followed at an ORPHAN academic tertiary referral expert center for endocrine autoimmunity as well as 419 unrelated German families were collected. λ was assessed based on 806 well-documented subjects, 299 index patients with autoimmune glandular (AIGD) and non-endocrine diseases and 507 of their first-degree relatives (328 children, 179 siblings)., Results: As many as 36% of relatives of patients with autoimmune diseases (AID) were affected by various autoimmune conditions. Twenty-five percent and 23% of all relatives had an AIGD or an autoimmune thyroid disease (AITD), respectively. Furthermore, 29% and 25% of relatives of index cases with polyglandular (PGA) and monoglandular (MGA) autoimmunity were affected. The recurrence risk for AITD was increased 16-fold in both children and siblings compared to the general population (λ, 95% CI 16, 11-21 and 16, 12-19, respectively). Furthermore, λ for AITD/AIGD was 21.62 (95% CI 14.17-30.69)/17.57 (11.80-24.36) and 13.48 (8.42-20.52)/10.68 (6.76-16.02) for siblings of patients with PGA and MGA, respectively. Overall, a strong genetic component for AITD and AIGD with a significant genetic impact on the development of PGA was demonstrated., Conclusion: These novel results strongly recommend the screening for AITD and AIGD in children and siblings of index patients with AITD., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level. They are emerging as potential biomarkers and as therapeutic targets for several diseases including autoimmune thyroid diseases (AITD). They control a wide range of biological phenomena, including immune activation, apoptosis, differentiation and development, proliferation and metabolism. This function makes miRNAs attractive as disease biomarker candidates or even as therapeutic agents. Because of their stability and reproducibility circulating miRNAs have been an interesting area of research in many diseases, and studies describing their role in the immune response and in autoimmune diseases have progressively developed. The mechanisms underlying AITD remain elusive. AITD pathogenesis is characterized by a multifactorial interplay based on the synergy between susceptibility genes and environmental stimulation, together with epigenetic modulation. Understanding the regulatory role of miRNAs could lead to identify potential susceptibility pathways, diagnostic biomarkers and therapeutic targets for this disease. Herein we update our present knowledge on the role of microRNAs in AITD and discuss on their importance as possible diagnostic and prognostic biomarkers in the most prevalent AITDs: Hashimoto's thyroiditis (HT), Graves' disease (GD) and Graves' Ophthalmopathy (GO). This review provides an overview of the state of the art in the pathological roles of microRNAs as well as in possible novel miRNA-based therapeutic approaches in AITD., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.

Zebrafish is a useful model for understanding human genetics and diseases and has evolved into a prominent scientific research model. The genetic structure of zebrafish is 70% identical to that of humans. Its small size, low cost, and transparent embryo make it a valuable tool in experimentation. Zebrafish and mammals possess the same molecular mechanism of thyroid organogenesis and development. Thus, thyroid hormone signaling, embryonic development, thyroid-related disorders, and novel genes involved in early thyroid development can all be studied using zebrafish as a model. Here in this review, we emphasize the evolving role of zebrafish as a possible tool for studying the thyroid gland in the context of physiology and pathology. The transcription factors nkx2.1a, pax2a, and hhex which contribute a pivotal role in the differentiation of thyroid primordium are discussed. Further, we have described the role of zebrafish as a model for thyroid cancer, evaluation of defects in thyroid hormone transport, thyroid hormone (TH) metabolism, and as a screening tool to study thyrotoxins. Hence, the present review highlights the role of zebrafish as a novel approach to understand thyroid development and organogenesis., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)