Genetic variants in purine metabolism and treatment resistance in schizophrenia : a pilot study

Pjevac, Milica (author), Blagus, Tanja (author), Oblak, Aleš (author), Vogrinc, David (author), Terzić, Tea (author), Bon, Jurij (author), Dolžan, Vita (author)

Background: The adenosine hypothesis of schizophrenia provides an integrative framework in which reduced adenosinergic signalling contributes to dopaminergic hyperactivity and glutamatergic hypofunction. Enzymes regulating purine metabolism, including inosine triphosphatase (ITPA), adenosine monophosphate deaminase 1 (AMPD1), and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), may influence adenosine availability and thereby modulate disease susceptibility and treatment response. As part of a pilot pharmacogenetic investigation, we investigated whether functional polymorphisms in these genes are associated with schizophrenia risk, treatment resistance, and symptom severity. Methods: A total of 249 patients with schizophrenia (including 47 with treatment-resistant schizophrenia - TRS) and 93 healthy controls were genotyped for ITPA rs1127354, AMPD1 rs17602729, and ATIC rs2372536 in this exploratory, hypothesis-generating study. Case-control and TRS analyses were conducted using χ2 tests and logistic regression with Bonferroni correction. Symptom severity (BPRS), global functioning (GAF), and positive and negative symptom subscales were examined using two-way ANOVA with false discovery rate (FDR) adjustment for multiple exploratory comparisons. Results: ITPA rs1127354 showed a nominally significant recessive association with schizophrenia risk based on a very small genotype count (OR = 0.09, p = 0.033), driven by rare AA homozygosity, but did not remain significant after Bonferroni correction. No significant case-control associations were observed for AMPD1 or ATIC. In contrast, ATIC rs2372536 was significantly associated with TRS (χ2 = 10.86, p = 0.004; CG vs. CC OR = 2.68, 95% CI 1.20-6.55), remaining significant after Bonferroni correction. In exploratory dimensional analyses, uncorrected genotype-related effects were observed for global functioning and overall symptom severity; after FDR adjustment, only the association between ATIC rs2372536 and negative symptoms remained statistically supported at q < 0.10. AMPD1 rs17602729 showed associations with overall symptom burden at the unadjusted level. Conclusion: Our findings provide preliminary evidence that genetic variation in purine metabolism may contribute to clinical heterogeneity in schizophrenia. In particular, ATIC rs2372536 was associated with treatment resistance and negative symptom severity, supporting a potential role of adenosinergic mechanisms in antipsychotic response. Associations with schizophrenia risk and other dimensions were exploratory and require replication in larger, independent cohorts. Integration of genetic data with biochemical measures of purine and adenosine metabolism will be important to establish clinical relevance and support precision-oriented therapeutic strategies.

• Language: English
• Keywords: AMPD1, ATIC, ITPA, adenosine hypothesis, genetic polymorphism, purine metabolism, schizophrenia, treatment-resistant schizophrenia
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: 11 str.
• Numbering: Vol. 17, art. 1876365
• PID: 20.500.12556/RUL-185778
• UDC: 577.2:616.89
• ISSN on article: 1663-9812
• DOI: 10.3389/fphar.2026.1876365
• COBISS.SI-ID: 288022531
• Publication date in RUL: 20.08.2026

Record is a part of a journal

• Title: Frontiers in pharmacology
• Shortened title: Front Pharmacol
• Publisher: Frontiers Media
• ISSN: 1663-9812
• COBISS.SI-ID: 29551833

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: adenozinska hipoteza, genetski polimorfizem, presnova purinov, shizofrenija, na zdravljenje odporna shizofrenija

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P5-0110
• Name: Psihološki in nevroznanstveni vidiki kognicije

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P1-0170
• Name: Molekulski mehanizmi uravnavanja celičnih procesov v povezavi z nekaterimi boleznimi pri človeku