Thyroid Hormone Dynamics and DIO2 Variants in Schizophrenia: Exploring Genetic Links to Neuroendocrine Imbalance

Thyroid hormone modulates multiple neurotransmitter systems, including dopaminergic, serotonergic, glutamatergic and GABAergic pathways, which are implicated in schizophrenia (SCH) pathophysiology. The Type II deiodinase (DIO2) enzyme plays a critical role in thyroid metabolism, converting thyroxine (T4) into the biologically active triiodothyronine (T3). This study aimed to investigate the potential association between DIO2 gene polymorphisms, Thr92Ala and ORFa-Gly3Asp, with serum levels of free triiodothyronine (fT3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) in SCH susceptibility and symptomatology. The cohort included 582 unrelated patients diagnosed with SCH and 603 healthy controls. Genotyping of Thr92Ala and ORFa-Gly3Asp single nucleotide polymorphisms (SNPs) of the DIO2 gene was conducted along with serum measurements of TSH, fT4 and fT3 levels. The genotype distribution of Thr92Ala and ORFa-Gly3Asp genotypes differed significantly between SCH group and the controls (p < 0.001). Furthermore, patients with SCH exhibited significantly lower levels of fT3 (p < 0.001) and TSH (p < 0.001) compared with controls. Notably, the Thr92Ala genotypes displayed a significant association with altered fT3 and TSH levels in SCH patients (p < 0.05, respectively). This study identified a significant association between DIO2 polymorphisms and decreased levels of fT3 and TSH in Turkish patients with SCH. Given the impact of thyroid hormones on neurotransmitter systems involved in SCH, these results highlight the potential for thyroid hormone modulation as a therapeutic avenue. Further research could lead to more personalised treatment strategies, particularly for patients with genetic predispositions to altered thyroid hormone metabolism, improving clinical outcomes and offering new approaches to managing symptoms in schizophrenia.