DIO2 POLYMORPHISM AS A LESS-INVASIVE PERIPHERAL BIOMARKER INDEXING BRAIN THYROID HORMONE DYSREGULATION IN SCHIZOPHRENIA

Low levels of triiodothyronine (T3) in the brain increase dopaminergic receptor sensitivity, a mechanism strongly implicated in schizophrenia pathophysiology. Iodothyronine deiodinase type 2 (DIO2) is the sole enzyme responsible for the intracellular conversion of tetraiodothyronine (T4) to bioactive T3 in the brain. The functional polymorphism rs225014 in the DIO2 gene may reduce enzymatic activity, potentially causing localized cerebral hypothyroidism without affecting peripheral levels. This case-control study investigated the association of DIO2 rs225014 with schizophrenia and thyroid hormone levels in a Pakistani population (150 patients/150 controls).
Genomic DNA was extracted for PCR and Sanger sequencing (genotyped via MEGA X), while serum thyroid hormones were measured using chemiluminescent magnetic microparticle immunoassay. Statistical analyses included independent t-tests, chi-square tests, and Pearson’s correlation. Results revealed that the reference TT genotype and T allele were significantly more prevalent in controls (P < 0.05), indicating a protective association. While the polymorphism did not significantly influence disease severity or serum thyroid levels (P > 0.05), schizophrenia patients exhibited significantly lower serum T3 levels than controls (P < 0.001). Genotype-stratified analysis confirmed that controls with TT (P = 0.035) or CC (P = 0.001) genotypes maintained higher mean T3 levels than genotype-matched cases.
In conclusion, DIO2 rs225014 is associated with schizophrenia susceptibility and may contribute to altered central thyroid regulation despite normal peripheral homeostasis. This study highlights a distinct metabolic disconnect, though further research using cerebrospinal fluid or post-mortem tissue is required to definitively validate the intracerebral thyroid-dopamine axis.