Year: 2007
Type: dissertation
Study design: Observational Study
Abstract: Evidence from multiple lines of research supports the hypothesis that schizophrenia arises from interactions between genetic and environmental factors during critical early periods of neuronal development. Abnormal levels of thyroid hormones or retinoids during fetal development have been suggested to contribute to the neurodevelopmental deviations found in schizophrenic patients. In fact, thyroid hormones and retinoids could constitute a functional link between genetic and environmental risk factors in schizophrenia. This is an attractive hypothesis capable of explaining several epidemiological features of the disease. Thyroid hormones and retinoids are involved in the regulation of central nervous system function probably through their capacity to modulate the expression of several genes. To investigate if genes involved in the metabolism of thyroid hormones and retinoids account for an increase in schizophrenia susceptibility, we performed association studies in four promising candidate genes, using three independent samples. The proteins encoded by these four genes are involved in molecular pathways implicated in schizophrenia. Human Nur-related receptor 1 (NR4A2) is an orphan nuclear receptor that regulates transcription by heterodimerization with retinoid nuclear receptors. NR4A2 is essential for the formation of the dopaminergic system, the neurotransmitter pathway targeted by most anti-psychotic drugs used in the treatment of schizophrenia. We did not find, in our samples, any of the NR4A2 mutations previously described, further confirming that they are rare. The Lipocalin-type of prostaglandin D2 synthase (PTGDS) transports thyroid hormones and retinoids, and the expression of the gene is regulated by both modulators. In addition, it is involved in lipid metabolism, which is altered in schizophrenia. We found four previously described polymorphisms, none of which was associated with schizophrenia. Transthyretin (TTR) is a transporter of both thyroid hormones and retinoids, and has been implicated in behavior. Neither a novel polymorphism, that we describe for the first time, nor another, previously identified, were associated to the disease. Similarly, serum TTR levels did not differ between patients and mentally healthy individuals. Neurogranin (NRGN) is a neurospecific protein whose expression is regulated by retinoids and thyroid hormones. Interestingly, NRGN is involved in glutamatergic transmission, known to be abnormal in schizophrenia. We report the association of a DNA variant near the thyroid hormone response element in the NRGN gene with schizophrenia in males. The gender specificity of this association is of particular interest since significant symptomatic differences in disease manifestation exist between sexes, such as earlier onset and more severe manifestation in male patients. NRGN joins several other genes already implicated in schizophrenia that are likewise involved in the glutamatergic pathway, such as dysbindin and neuregulin. Thus, our finding introduces an additional player into the glutamatergic hypothesis of schizophrenia. In a preliminary study, we evaluated thyroid hormone function in schizophrenic patients, which showed reduced levels of free triiodothyronine in males when compared with healthy individuals. Whether this alteration is related to the manifestation of symptoms still needs to be investigated. Together our data support the involvement of thyroid hormones in schizophrenia, which should be further explored in expression studies.
Author: Dina Ruana Neto
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2166734969