DOES RS11191580 NT5C2 AND DRD2-141C INS/DEL POLYMOPRHIMSM AFFECT SCHIZOPHRENIA SYMPTOMS SEVERITY IN BATAK POPULATION

Introduction

Schizophrenia is a chronic and severe psychiatric disorder characterized by disturbances in perception, thought processes, emotions, and behavior. It affects approximately 1% of the global population and contributes substantially to disability, social dysfunction, and healthcare burden worldwide.¹ Clinical manifestations are heterogeneous and commonly categorized into positive symptoms, negative symptoms, cognitive impairment, and affective disturbances. The severity of these symptoms varies considerably among individuals, suggesting that genetic factors may contribute not only to disease susceptibility but also to clinical presentation and symptom severity.²

Accumulating evidence indicates that schizophrenia has a strong genetic component, with heritability estimates approaching 80%. Genome-wide association studies (GWAS) have identified numerous susceptibility loci associated with schizophrenia. Among these, the rs11191580 polymorphism located near the NT5C2 gene has emerged as a significant genetic variant.^3,4 The NT5C2 gene encodes cytosolic 5′-nucleotidase II, an enzyme involved in purine metabolism and neuronal cellular function. Several GWAS and replication studies have demonstrated an association between rs11191580 and schizophrenia susceptibility across different populations.⁵ Furthermore, a study in a South Chinese Han population reported that rs11191580 was associated not only with schizophrenia risk but also with symptom severity, particularly negative symptoms and total Positive and Negative Syndrome Scale (PANSS) scores.⁴

The dopaminergic hypothesis remains one of the most influential biological theories explaining schizophrenia pathogenesis. Dopamine dysregulation, particularly involving dopamine D2 receptors, has been implicated in the development of psychotic symptoms and constitutes the primary target of antipsychotic medications. The dopamine receptor D2 gene (DRD2) contains several functional polymorphisms, including the promoter-region variant -141C insertion/deletion (rs1799732). This polymorphism influences transcriptional activity and receptor expression, potentially affecting dopaminergic neurotransmission. Previous studies have suggested that DRD2 polymorphisms may influence schizophrenia susceptibility, symptom profiles, treatment response, and antipsychotic resistance, although findings remain inconsistent across ethnic populations.^6,7

Genetic associations in schizophrenia often demonstrate substantial ethnic variation due to differences in allele frequencies, linkage disequilibrium patterns, and gene-environment interactions. Consequently, findings observed in European, Chinese, Japanese, or other populations may not be directly applicable to Indonesian ethnic groups. The Batak population of North Sumatra represents a genetically distinct ethnic group with limited psychiatric genetic research. To date, data regarding the influence of rs11191580 NT5C2 and DRD2-141C Ins/Del polymorphisms on schizophrenia symptom severity among Batak individuals remain scarce.

Understanding the relationship between these genetic variants and clinical manifestations may provide insight into the biological mechanisms underlying symptom heterogeneity in schizophrenia. Such knowledge could contribute to the development of precision psychiatry approaches, including improved prognostic assessment and individualized treatment strategies. Therefore, this study aims to investigate the association between rs11191580 NT5C2 and DRD2-141C Ins/Del polymorphisms and schizophrenia symptom severity among Batak patients diagnosed with schizophrenia. We hypothesize that these genetic variants are associated with differences in PANSS scores and may influence the severity of positive, negative, and general psychopathology symptoms in this population.

Methods

Results

Discussion

This study included 100 ethnically homogeneous Batak individuals from North Sumatra, comprising 50 patients with schizophrenia and 50 healthy controls. The use of a genetically homogeneous population represents a major strength because population stratification is a recognized source of bias in genetic association studies. By minimizing ethnic heterogeneity, the observed associations between genetic polymorphisms and schizophrenia are less likely to be confounded by differences in ancestral allele frequencies.

The present study demonstrated a significant association between the NT5C2 rs11191580 polymorphism and schizophrenia in the Batak population. The heterozygous TC genotype was identified exclusively among patients with schizophrenia, whereas all healthy controls carried the CC genotype. This distinct genotype distribution suggests that the minor T allele may confer increased susceptibility to schizophrenia within this ethnic population.

These findings are consistent with recent genome-wide association studies that identified chromosome 10q24.32, which harbors NT5C2, as a susceptibility locus for schizophrenia. NT5C2 encodes cytosolic 5′-nucleotidase II, an enzyme involved in intracellular purine metabolism and nucleotide homeostasis. Beyond its metabolic function, NT5C2 participates in adenosine signaling, glutamatergic neurotransmission, neuronal differentiation, and neuroinflammatory pathways, all of which have been implicated in the pathophysiology of schizophrenia.^10,11

Some studies further support this biological mechanism. Reduced NT5C2 expression has been shown to induce schizophrenia-like behavioral abnormalities, impaired synaptic electrophysiological function, and increased sensitivity to dopaminergic stimulation in animal models. The concordance between genome-wide association studies, experimental findings, and the present clinical observations strengthens the hypothesis that NT5C2 contributes to schizophrenia susceptibility. Therefore, rs11191580 may represent a promising population-specific genetic marker for schizophrenia among individuals of Batak ancestry.⁴

Similarly, this study demonstrated a significant association between the DRD2 − 141C Ins/Del polymorphism and schizophrenia. Patients with schizophrenia exhibited a substantially higher frequency of the Ins/Del genotype, whereas the Ins/Ins genotype predominated among healthy controls. These findings further support the dopamine hypothesis, which proposes that dysregulated dopaminergic neurotransmission plays a central role in schizophrenia pathophysiology.

The −141C Ins/Del polymorphism is located within the promoter region of DRD2 and has been shown to influence transcriptional activity. Functional studies have demonstrated that the deletion allele reduces promoter activity, resulting in decreased expression of dopamine D2 receptors in the prefrontal cortex and striatum, two regions critically involved in executive function, reward processing, and psychosis. Reduced receptor expression may contribute to altered dopaminergic signaling and increase vulnerability to schizophrenia.^12,13

The present findings are also consistent with previous studies reporting a significant association between the DRD2 − 141C Ins/Del polymorphism and schizophrenia in Asian populations. The magnitude of association observed in this study may reflect the relatively homogeneous genetic background of the Batak population, suggesting that ethnic-specific allele frequencies or gene–environment interactions contribute to disease susceptibility. These findings highlight the importance of conducting genetic association studies within well-characterized local populations rather than extrapolating data from genetically heterogeneous cohorts.¹⁴

Interestingly, despite the observed associations with schizophrenia susceptibility, neither NT5C2 nor DRD2 polymorphisms were significantly associated with PANSS severity or its individual symptom domains. Patients carrying different genotypes demonstrated comparable total PANSS scores, as well as positive symptom, negative symptom, and general psychopathology scores. These findings suggest that although these variants may contribute to disease susceptibility, they are unlikely to exert a major influence on clinical severity after disease onset.

The absence of genotype–phenotype associations may be explained by several factors. First, schizophrenia symptom severity is a highly polygenic trait influenced by numerous common genetic variants, each contributing only a modest effect.¹⁵ Second, clinical manifestations are substantially modified by environmental exposures, illness duration, antipsychotic treatment, medication adherence, and psychosocial factors, which may overshadow the contribution of individual polymorphisms.¹⁶ Third, the relatively small sample size limits statistical power to detect modest genetic effects on quantitative clinical phenotypes. Consequently, larger multicenter studies incorporating polygenic risk scores, transcriptomic analyses, and longitudinal clinical assessments are needed to further elucidate the contribution of these variants to disease progression and treatment response.

This study has several limitations. The relatively small sample size may have limited the statistical power to detect modest genetic effects, particularly in the analysis of genotype–phenotype associations with PANSS scores. In addition, the cross-sectional case–control design precludes causal inference regarding the relationship between NT5C2 and DRD2 polymorphisms and schizophrenia. Only two candidate polymorphisms were investigated, whereas schizophrenia is a highly polygenic disorder influenced by multiple genetic variants and gene–environment interactions. Although the use of an ethnically homogeneous Batak population reduced population stratification and strengthened the internal validity of the genetic association analysis, the findings may not be directly generalizable to other ethnic populations. Furthermore, functional studies were not performed to elucidate the biological mechanisms underlying the observed associations. Therefore, larger multicenter studies involving diverse populations and functional genomic analyses are warranted to validate and expand upon the present findings.

Conclusion

This study demonstrated that the NT5C2 rs11191580 and DRD2 − 141C Ins/Del polymorphisms were significantly associated with schizophrenia susceptibility in the Batak population, suggesting that both variants may contribute to genetic predisposition to the disorder. However, neither polymorphism was associated with schizophrenia symptom severity as measured by PANSS scores. These findings highlight the potential role of NT5C2 and DRD2 as genetic susceptibility markers for schizophrenia while suggesting a limited contribution to clinical symptom severity.

AI use disclosure

The authors used ChatGPT (GPT-5.5, OpenAI) solely for grammar and language editing to improve the clarity and readability of the manuscript. The AI tool was not used to generate, interpret, or analyze scientific content. The authors reviewed and edited all outputs and take full responsibility for the final content of the manuscript.