RESUMEN
BACKGROUND: Genome-wide association studies have reported a genetic overlap between borderline personality disorder (BPD) and schizophrenia (SCZ). Epidemiologically, the direction and causality of the association between thyroid function and risk of BPD and SCZ are unclear. We aim to test whether genetically predicted variations in TSH and FT4 levels or hypothyroidism are associated with the risk of BPD and SCZ. METHODS: We employed Mendelian Randomisation (MR) analyses using genetic instruments associated with TSH and FT4 levels as well as hypothyroidism to examine the effects of genetically predicted thyroid function on BPD and SCZ risk. Bidirectional MR analyses were employed to investigate a potential reverse causal association. RESULTS: Genetically predicted higher FT4 was not associated with the risk of BPD (OR: 1.18; P = 0.60, IVW) or the risk of SCZ (OR: 0.93; P = 0.19, IVW). Genetically predicted higher TSH was not associated with the risk of BPD (OR: 1.11; P = 0.51, IVW) or SCZ (OR: 0.98, P = 0.55, IVW). Genetically predicted hypothyroidism was not associated with BPD or SCZ. We found no evidence for a reverse causal effect between BPD or SCZ on thyroid function. CONCLUSIONS: We report evidence for a null association between genetically predicted FT4, TSH or hypothyroidism with BPD or SCZ risk. There was no evidence for reverse causality.
RESUMEN
To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.
Asunto(s)
Glándula Tiroides , Tiroxina , Humanos , Glándula Tiroides/metabolismo , Tiroxina/metabolismo , Estudio de Asociación del Genoma Completo , Triyodotironina/metabolismo , Tirotropina/metabolismoRESUMEN
Background: Observational studies suggest an association between thyroid function and risk of dementia, but the causality and direction of these effects are unclear. We aim to test whether genetically predicted variation within the normal range of thyroid function and hypothyroidism is causally associated with the risk of Alzheimer's disease (AD). Methods: Mendelian randomization (MR) analyses using genetic instruments are associated with normal range thyrotropin (TSH) and free thyroxine (fT4) levels. Secondary analyses included investigation of the role of hypothyroidism. Bidirectional MR was conducted to address the presence of a potential reverse causal association. Summary statistics were obtained from the ThyroidOmics Consortium involving up to 119,715 individuals and the latest AD genome-wide association study data including up to 71,880 cases. Results: MR analyses show an association between increased genetically predicted normal range TSH levels and a decreased risk of AD (p = 0.02). One standard deviation increased normal range TSH levels were associated with a decreased risk of AD in individuals younger than 50 years old (p = 0.04). There was no evidence for a causal association between fT4 (p = 0.54) and AD. We did not identify any effect of the genetically predicted full range TSH levels (p = 0.06) or hypothyroidism (p = 0.23) with AD. Bidirectional MR did not show any effect of genetic predisposition to AD on TSH or fT4 levels. Conclusions: This MR study shows that increased levels of genetically predicted TSH within the normal range and in younger individuals are associated with a decreased risk of AD. We observed a marginal association between genetically predicted full range TSH and AD risk. There was no evidence for an effect between genetically predicted fT4 or hypothyroidism on AD. Future studies should clarify the underlying pathophysiological mechanisms.