Thyroid Function and Mood Disorders: A Mendelian Randomization Study.
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ABSTRACT:
SUBMITTER: Kus A
PROVIDER: S-EPMC7612998 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hypothyroidism and hyperthyroidism are observationally associated with sex hormone concentrations and sexual dysfunction, but causality is unclear. We investigated whether TSH, fT4, hypo- and hyperthyroidism are causally associated with sex hormones and sexual function. We used publicly available summary statistics from genome-wide association studies on TSH and fT4 and hypo- and hyperthyroidism from the ThyroidOmics Consortium (N ≤ 54,288). Outcomes from UK Biobank (women ≤ 194,174/men ≤ 167,020) and ReproGen (women ≤ 252,514) were sex hormones (sex hormone binding globulin [SHBG], testosterone, estradiol, free androgen index [FAI]) and sexual function (ovulatory function in women: duration of menstrual period, age at menarche and menopause, reproductive lifespan, and erectile dysfunction in men). We performed two-sample Mendelian randomization (MR) analyses on summary level, and unweighted genetic risk score (GRS) analysis on individual level data. One SD increase in TSH was associated with a 1.332 nmol/L lower (95% CI: - 0.717,- 1.946; p = 2 × 10-5) SHBG and a 0.103 nmol/l lower (- 0.051,V0.154; p = 9 × 10-5) testosterone in two-sample MR, supported by the GRS approach. Genetic predisposition to hypothyroidism was associated with decreased and genetic predisposition to hyperthyroidism with increased SHBG and testosterone in both approaches. The GRS for fT4 was associated with increased testosterone and estradiol in women only. The GRS for TSH and hypothyroidism were associated with increased and the GRS for hyperthyroidism with decreased FAI in men only. While genetically predicted thyroid function was associated with sex hormones, we found no association with sexual function.
| S-EPMC7612952 | biostudies-literature
Project description:To clarify the role of thyroid function in ischemic heart disease (IHD) we assessed IHD risk and risk factors according to genetically predicted thyroid stimulating hormone (TSH), free thyroxine (FT4) and thyroid peroxidase antibody (TPOAb) positivity. Separate-sample instrumental variable analysis with genetic instruments (Mendelian randomization) was used in an extensively genotyped case (n?=?64,374)-control (n?=?130,681) study, CARDIoGRAMplusC4D. Associations with lipids, diabetes and adiposity were assessed using the Global Lipids Genetics Consortium Results (n?=?196,475), the DIAbetes Genetics Replication And Meta-analysis case (n?=?34,380)-control (n?=?114,981) study, and the Genetic Investigation of ANthropometric Traits (body mass index in 152,893 men and 171,977 women, waist-hip ratio in 93,480 men and 116,741 women). Genetically predicted thyroid function was not associated with IHD (odds ratio (OR) per standard deviation for TSH 1.05, 95% confidence interval (CI) 0.97 to 1.12; for FT4 1.01, 95% CI 0.91 to 1.12; for TPOAb positivity 1.10, 95% CI 0.83 to 1.46) or after Bonferroni correction with risk factors, except for an inverse association of FT4 with low-density lipoprotein-cholesterol. The associations were generally robust to sensitivity analyses using a weighted median method and MR Egger. This novel study provides little indication that TSH, FT4 or TPOAb positivity affects IHD, despite potential effects on its risk factors.
| S-EPMC5561103 | biostudies-literature
Project description: Not available
| S-EPMC10995335 | biostudies-literature
Project description:BackgroundThe role of thyroid hormones in cancers has been discussed in observational studies; however, the causal relationship between them remains controversial.MethodsThe SNPs associated with hypothyroidism and hyperthyroidism were selected from a FinnGen biobank of 342,499 (190,879 females and 151,620 males) Finnish adult subjects. Data from the Thyroidomics Consortium on 72,167 individuals were used to assess genetically determined thyroid-stimulating hormone (TSH) and free thyroxine (FT4). Lung cancer, lung adenocarcinoma and squamous cell lung cancer GWAS data from the International Lung Cancer Consortium(ILCCO). Six different Mendelian randomization (MR) Methods, including Inverse variance weighted (IVW), MR-Egger, Simple mode, MR-Pleiotropy Residual Sum and Outlier methods (MR-PRESSO), Weighted mode and Weighted median were used to Two-Sample MR analysis. IVW was used as the primary estimate. Sensitivity analyses were examined via four aspects (Cochran's Q-test, MR Egger intercept analysis, Funnel plot and Leave-one-out sensitivity test).ResultsThe OR of hypothyroidism on lung cancer was 0.918 (95% CI, 0.859-0.982; p = 0.013) in MR analysis with IVW method. No evidence for effects of hyperthyroidism, TSH and FT4 on lung cancer risk was found via six MR methods. Meanwhile, there was no evidence for effects of lung cancer on hypothyroidism through six MR methods. Lung adenocarcinoma and squamous cell lung carcinoma were further analyzed on the basis of lung cancer. The OR of hypothyroidism on lung adenocarcinoma was 0.893(95% CI, 0.813-0.981; p = 0.019), the OR of hypothyroidism on squamous cell lung cancer was 0.888(95%CI,0.797-0.990, p = 0.032) in MR analysis with IVW method.ConclusionIn summary, hypothyroidism genetically had a protective causal association with lung cancer. Furthermore, hypothyroidism had protective effects both on lung adenocarcinoma and squamous cell lung cancer. Further work is needed to elucidate the potential mechanisms.
| S-EPMC10494366 | biostudies-literature
Project description:Schizophrenia is a chronic psychiatric disorder with inconsistent behavioral and cognitive abnormalities with profound effects on the individual and the society. Individuals with schizophrenia have altered thyroid function, but results from observational studies are conflicting. To date, it remains unclear whether and in which direction there is a causal relationship between thyroid function and schizophrenia. To investigate causal paths, a bidirectional two-sample Mendelian randomization (MR) study was conducted using summary statistics from genome-wide association studies including up to 330,132 Europeans. Thyroid function was described by the normal-range thyroid-stimulating hormone (TSH) and free thyroxine levels as well as an increased and decreased TSH status. The iterative radial inverse-variance weighted approach with modified second order weights was used as the main method. Based on a discovery and replication sample for schizophrenia, pooled effect estimates were derived using a fixed-effect meta-analysis. Robustness of results was assessed using both a range of pleiotropy robust methods and a network analysis that clustered genetic instruments potentially responsible for horizontal pleiotropy. Genetic liability for hypothyroidism was inversely associated with schizophrenia ([Formula: see text]; 95% CI: (-0.10; -0.02); [Formula: see text]). No notable associations were observed between other thyroid parameters and schizophrenia. Furthermore, no associations could be detected in the reverse direction. Our results suggest that an elevated level of TSH reduce the risk for schizophrenia. The role of thyroid function and the hypothalamic-pituitary-thyroid axis in the development of schizophrenia should be subject of further research.
| S-EPMC10570193 | biostudies-literature
Project description:BackgroundNumerous observational studies have indicated a link between the composition of gut microbiota and thyroid function. Nevertheless, the precise causal relationship between gut microbiota and thyroid function remains uncertain.MethodsIn this two-sample Mendelian randomization study, we utilized summary data from a genome-wide association study of gut microbiota composition in 18,340 participants from 24 cohorts, as well as summary statistics on thyroid hormones and thyroid-stimulating hormone from the ThyroidOmics Consortium and summary statistics on hypothyroidism and hyperthyroidism from the FinnGen R8 release. Five different methods, including inverse variance weighting, MR-Egger, weighted median, weighted mode, and simple mode, were employed to examine the causal relationship between gut microbiota and thyroid function. Reverse Mendelian randomization analysis was conducted for taxa identified as having a causal relationship with thyroid function in the Mendelian randomization analysis. To assess the robustness of the results, sensitivity analyses were conducted employing Cochran's Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis.ResultsThrough MR analysis of 211 microbial taxa and 4 phenotypes, we identified a total of 34 gut microbiota taxa that were associated with the outcomes. After using the bonferroni method for multiple testing correction, phylum Actinobacteria (id.400) had a protective effect on hypothyroidism (OR=0.883, 95% CI: 0.817-0.955, P=0.002), and class Deltaproteobacteria (id.3087) had a protective effect on hyperthyroidism (OR=0.549, 95% CI: 0.374-0.805, P=0.002). According to the results of reverse MR analysis, no significant causal effect of the four phenotypes was found on gut microbiota. No significant horizontal pleiotropy was detected based on MR-Egger intercept test and MR-PRESSO global test.ConclusionThrough two-sample MR analysis, we identified specific gut microbiota taxa at the genetic level that are predicted to have a causal relationship with thyroid function, which may serve as useful biomarkers for early disease diagnosis.
| S-EPMC10562735 | biostudies-literature
Project description:Background: Untreated hypothyroidism is associated with acquired von Willebrand syndrome, and hyperthyroidism is associated with increased thrombosis risk. However, the causal effects of thyroid function on hemostasis, coagulation, and fibrinolysis are unknown. Methods: In a two-sample Mendelian randomization (MR) study with genome-wide association variants, we assessed causality of genetically predicted hypothyroidism (N = 134,641), normal-range thyrotropin (TSH; N = 54,288) and free thyroxine (fT4) (N = 49,269), hyperthyroidism (N = 51,823), and thyroid peroxidase antibody positivity (N = 25,821) on coagulation (activated partial thromboplastin time, von Willebrand factor [VWF], factor VIII [FVIII], prothrombin time, factor VII, fibrinogen) and fibrinolysis (D-dimer, tissue plasminogen activator [TPA], plasminogen activator inhibitor-1) from the CHARGE Hemostasis Consortium (N = 2583-120,246). Inverse-variance-weighted random effects were the main MR analysis followed by sensitivity analyses. Two-sided p < 0.05 was nominally significant, and p < 0.0011[ = 0.05/(5 exposures × 9 outcomes)] was Bonferroni significant for the main MR analysis. Results: Genetically increased TSH was associated with decreased VWF [β(SE) = -0.020(0.006), p = 0.001] and with decreased fibrinogen [β(SE) = -0.008(0.002), p = 0.001]. Genetically increased fT4 was associated with increased VWF [β(SE) = 0.028(0.011), p = 0.012]. Genetically predicted hyperthyroidism was associated with increased VWF [β(SE) = 0.012(0.004), p = 0.006] and increased FVIII [β(SE) = 0.013(0.005), p = 0.007]. Genetically predicted hypothyroidism and hyperthyroidism were associated with decreased TPA [β(SE) = -0.009(0.024), p = 0.024] and increased TPA [β(SE) = 0.022(0.008), p = 0.008], respectively. MR sensitivity analyses showed similar direction but lower precision. Other coagulation and fibrinolytic factors were inconclusive. Conclusions: In the largest genetic studies currently available, genetically increased TSH and fT4 may be associated with decreased and increased synthesis of VWF, respectively. Since Bonferroni correction may be too conservative given the correlation between the analyzed traits, we cannot reject nominal associations of thyroid traits with coagulation or fibrinolytic factors.
| S-EPMC8558080 | biostudies-literature
Project description:ObjectiveLow back pain is a prevalent and debilitating condition worldwide, with significant implications for individuals' quality of life and productivity. The aim of this study was to assess the relationship between mood instability and the risk of developing chronic low back pain, using a rigorously designed mendelian randomization methodology.MethodThe study incorporated both univariate and multivariate mendelian randomization to analysis the causal relationship between mood instability and the risk of developing chronic low back pain. The data on mood instability from the Integrative Epidemiology Unit (IEU) opened Genome-Wide Association Studies (GWAS) project (IEU-opened GWAS project). Data on low back pain were collected from two sources: One source is the IEU open GWAS project (discovery data). Another source is a GWAS meta-analysis (replication data). Inverse variance weighted method, weighted median method, MR-Egger regression, and mendelian randomization pleiotropy residual sum and outlier method were used for mendelian randomization analysis.ResultThe univariable mendelian randomization analysis shows a statistically significant correlation between mood instability and the risk of low back pain. Several methods were performed, including inverse variance weighting (discovery data: odds ratio = 3.544, 95% confidence interval = 1.785-7.039, p = 0.000; replication data: odds ratio = 3.167, 95% confidence interval = 2.476-4.052, p = 0.000), MR-Egger (discovery data: odds ratio = 7.178, 95% confidence interval = 0.057-909.525, p = 0.429; replication data: odds ratio = 2.262, 95% confidence interval = 0.580-8.825, p = 0.246), weighted median (discovery data: odds ratio = 2.730, 95% confidence interval = 1.112-6.702, p = 0.028; replication data: odds ratio = 3.243, 95% confidence interval = 2.378-4.422, p = 0.000), MR-PRESSO (discovery data: odds ratio = 3.544, 95% confidence interval = 1.785-7.039, p = 0.001; replication data: odds ratio = 3.167, 95% confidence interval = 2.476-4.052, p = 0.000) methods. The results were consistent across these methods. The results obtained from discovery data are consistent with those obtained from discovery data. In the multivariable mendelian randomization, after adjusting for various covariates such as body mass index, current tobacco smoking, alcohol intake frequency, Total body bone mineral density, and vigorous physical activity, there is a consistent correlation between mood instability and chronic low back pain.ConclusionThis study provides robust evidence supporting a causal relationship between mood instability and the development of low back pain. Our findings suggest that addressing mood instability may play a crucial role in prevention and management strategies for individuals experiencing low back pain.
| S-EPMC10541504 | biostudies-literature
Project description:ContextObservational studies suggest that variations in normal range thyroid function are associated with cardiovascular diseases. However, it remains to be determined whether these associations are causal or not.ObjectiveTo test whether genetically determined variation in normal range thyroid function is causally associated with the risk of stroke and coronary artery disease (CAD) and investigate via which pathways these relations may be mediated.Design, setting, and participantsMendelian randomization analyses for stroke and CAD using genetic instruments associated with normal range thyrotropin (TSH) and free thyroxine levels or Hashimoto's thyroiditis and Graves' disease. The potential mediating role of known stroke and CAD risk factors was examined. Publicly available summary statistics data were used.Main outcome measuresStroke or CAD risk per genetically predicted increase in TSH or FT4 levels.ResultsA 1 standard deviation increase in TSH was associated with a 5% decrease in the risk of stroke (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99; P = 0.008). Multivariable MR analyses indicated that this effect is mainly mediated via atrial fibrillation. MR analyses did not show a causal association between normal range thyroid function and CAD. Secondary analyses showed a causal relationship between Hashimoto's thyroiditis and a 7% increased risk of CAD (OR, 1.07; 95% CI, 1.01-1.13; P = 0.026), which was mainly mediated via body mass index.ConclusionThese results provide important new insights into the causal relationships and mediating pathways between thyroid function, stroke, and CAD. We identify variation in normal range thyroid function and Hashimoto's thyroiditis as risk factors for stroke and CAD, respectively.
| S-EPMC7316221 | biostudies-literature
Project description:BackgroundThyroid dysfunction is associated with cardiovascular diseases. However, the role of thyroid function in lipid metabolism remains partly unknown. The present study aimed to investigate the causal association between thyroid function and serum lipid metabolism via a genetic analysis termed Mendelian randomization (MR).MethodsThe MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial. A two-sample MR was performed to assess the causal association, using summary statistics from the Atrial Fibrillation Genetics Consortium (n = 537,409) and the Global Lipids Genetics Consortium (n = 188,577). The clinical measures of thyroid function include thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels, FT3:FT4 ratio and concentration of thyroid peroxidase antibodies (TPOAb). The serum lipid metabolism traits include total cholesterol (TC) and triglycerides, high-density lipoprotein, and low-density lipoprotein (LDL) levels. The MR estimate and MR inverse variance-weighted method were used to assess the association between thyroid function and serum lipid metabolism.ResultsThe results demonstrated that increased TSH levels were significantly associated with higher TC (β = 0.052, P = 0.002) and LDL (β = 0.041, P = 0.018) levels. In addition, the FT3:FT4 ratio was significantly associated with TC (β = 0.240, P = 0.033) and LDL (β = 0.025, P = 0.027) levels. However, no significant differences were observed between genetically predicted FT4 and TPOAb and serum lipids.ConclusionTaken together, the results of the present study suggest an association between thyroid function and serum lipid metabolism, highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility.
| S-EPMC8116035 | biostudies-literature