Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

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

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

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

131I-induced changes in rat thyroid gland function

Therapeutic doses of 131I administered to thyrotoxic patients may cause thyroid failure. The present study used a rat model to determine thyroid function after the administration of different doses of 131I (64-277 µCi). Thirty male Fisher rats in the experimental group and 30 in the control group (untreated) were followed for 6 months. The animals were 4 months old at the beginning of the experiment and were sacrificed at an age of 9 months. Hormone concentration was determined before 131I administration (4-month-old animals) and three times following 131I administration, when the animals were 7, 8, and 9 months old. The thyroid glands were removed and weighed, their volume was determined and histopathological examination was performed at the end of the experiment. Significant differences in serum triiodothyronine and thyroid-stimulating hormone concentration, measured at the age of 7, 8, and 9 months, were found in the experimental group. During aging of the animals, the concentration of thyroxin fell from 64.8 ± 8.16 to 55.0 ± 6.1 nM in the control group and from 69.4 ± 6.9 to 25.4 ± 3.2 nM in the experimental group. Thyroid gland volume and weight were significantly lower in the experimental than in the control group. Thyroid glands from the experimental group showed hyaline thickness of the blood vessel wall, necrotic follicles, a strong inflammatory reaction, and peeling of necrotic cells in the follicles. In conclusion, significant differences in hormone levels and histopathological findings indicated prolonged hypothyroidism after 131I administration to rats, which was not 131I dose dependent

Partial Instances via Subclassing

Abstract. The traditional notion of instantiation in Object-Oriented Modeling (OOM) requires objects to be complete, i.e., be fully certain about their existence and attributes. This paper explores the notion of partial instantiation of class diagrams, which allows the modeler to omit some details of objects depending on modeler’s intention. Partial instantiation allows modelers to express optional existence of some objects and slots (links) as well as uncertainty of values in some slots. We show that partial instantiation is useful and natural in domain modeling and requirements engineering. It is equally useful in architecture modeling with uncertainty (for design exploration) and with variability (for modeling software product lines). Partial object diagrams can be (partially) completed by resolving (some of) optional objects and replacing (some of) unknown values with actual ones. Under the Closed World Assumption (CWA), completion reduces uncertainty of already existing objects, or deletes them if their existence is optional. Under the Open World Assumption (OWA), completion may additionally introduce new elements, perhaps uncertain. The paper presents a simple theory of partial instantiation and completion under the CWA. It shows that partial object diagrams can be modeled by subclassing and multiplicity constraints. As a result, class diagrams can implement partial instances with the well-known notions of subtyping and inheritance.

Towards Extending the Validation Possibilities of ADOxx with Alloy

While ADOxx is a popular platform for the creation and use of enterprise modeling languages, it provides only limited support for a well-formedness check of created enterprise models. In this paper, we propose to complement the meta modeling platform ADOxx with Alloy, which natively provides extensive model checking capabilities, so as to enable a well-formedness check of enterprise models created in ADOxx. Using the e3value modeling language as a point of departure, we particularly provide (a) a partial ADOxx implementation of e3value, (b) a proof-of-concept XML2Alloy parser, which allows for converting e3value models created in ADOxx into Alloy format, so that (c) e3value well-formedness constraints stated in Alloy can be used to check the valid- ity of an e3value model with the Alloy Evaluator. Beyond the specific proof-of-concept, we also discuss further possibilities of using ADOxx in conjunction with Alloy, particularly in checking the soundness of meta models underlying an enterprise modeling language