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<p>Background: This study was designed to evaluate the genetic association of three specific intronic Single Nucleotide Polymorphisms (SNPs) within the Dopamine Receptor D2 (DRD2) gene—rs2005313, rs4274224, and rs4938019—with schizophrenia susceptibility in a Pakistani population. The primary objective was to identify population-specific biomarkers that could inform early intervention and personalized treatment strategies. Methods: Genotyping was conducted on a matched case-control cohort of 208 participants (104 cases; 104 controls) using High-Resolution Melting (HRM) PCR. Genetic associations were quantified using Odds Ratios (OR) and 95% Confidence Intervals (CI), representing the standard coefficient and its margin of error to ensure statistical precision. Functional annotation of the investigated polymorphisms was performed using GTEx, FORGEdb and RegulomeDB to assess regulatory potential and tissue-specific expression effects. Results: The research identified highly significant associations across multiple inheritance models, validating the technical robustness of the findings. The rs4938019 polymorphism emerged as the most potent genetic risk factor, particularly under the recessive model (OR: 9.60; 95% CI: 3.92–23.52; p &lt; 0.0001), where the rare GG genotype was found in 44% of cases compared to only 7.2% of controls. Conversely, rs4274224 demonstrated a significant protective effect, with a co-dominant OR of 0.23 (95% CI: 0.09–0.59; p = 0.0022), suggesting that the T allele confers genetic resilience. Furthermore, among the investigated DRD2 variants, rs2005313 demonstrated significance primarily under the over-dominant inheritance model, whereas rs4938019 exhibited the strongest association under the recessive model (OR: 2.13; 95% CI: 1.15–3.94; p = 0.014). All variants in the control group maintained Hardy-Weinberg Equilibrium (p &gt; 0.05), confirming the absence of population bias. Functional annotation revealed that rs4274224 showed the strongest direct regulatory evidence for DRD2 (FORGEdb score: 6; RegulomeDB Rank 1f), while rs4938019 demonstrated the highest overall regulatory potential (FORGEdb score: 9), with rs2005313 exhibiting substantial regulatory evidence (FORGEdb score: 7) supported by extensive GTEx cis-eQTLs across multiple tissues including brain regions. Conclusion: These findings establish DRD2 intronic polymorphisms as critical determinants of schizophrenia risk. The high-risk rs4938019 GG genotype provides a clear translational biomarker for rapid genetic screening, potentially improving clinical outcomes through genotype-guided therapeutic interventions.</p> Graphical Abstract <p></p>

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Dopamine Receptor D2 gene Polymorphisms rs2005313, rs4274224, and rs4938019 in Pakistani Patients with Schizophrenia:a Diagnostic Tool for Schizophrenia

  • 期刊论文

  • 发表日期：

    2026年8月5日

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  • Ishrat Yaseen,
  • Saleem Ahmad,
  • Muhammad Ghalib,
  • Muhammad Shahbaz Aslam,
  • Rabbia Tariq,
  • Osheen Sajjad,
  • Faisal Yaseen

摘要

Background: This study was designed to evaluate the genetic association of three specific intronic Single Nucleotide Polymorphisms (SNPs) within the Dopamine Receptor D2 (DRD2) gene—rs2005313, rs4274224, and rs4938019—with schizophrenia susceptibility in a Pakistani population. The primary objective was to identify population-specific biomarkers that could inform early intervention and personalized treatment strategies. Methods: Genotyping was conducted on a matched case-control cohort of 208 participants (104 cases; 104 controls) using High-Resolution Melting (HRM) PCR. Genetic associations were quantified using Odds Ratios (OR) and 95% Confidence Intervals (CI), representing the standard coefficient and its margin of error to ensure statistical precision. Functional annotation of the investigated polymorphisms was performed using GTEx, FORGEdb and RegulomeDB to assess regulatory potential and tissue-specific expression effects. Results: The research identified highly significant associations across multiple inheritance models, validating the technical robustness of the findings. The rs4938019 polymorphism emerged as the most potent genetic risk factor, particularly under the recessive model (OR: 9.60; 95% CI: 3.92–23.52; p < 0.0001), where the rare GG genotype was found in 44% of cases compared to only 7.2% of controls. Conversely, rs4274224 demonstrated a significant protective effect, with a co-dominant OR of 0.23 (95% CI: 0.09–0.59; p = 0.0022), suggesting that the T allele confers genetic resilience. Furthermore, among the investigated DRD2 variants, rs2005313 demonstrated significance primarily under the over-dominant inheritance model, whereas rs4938019 exhibited the strongest association under the recessive model (OR: 2.13; 95% CI: 1.15–3.94; p = 0.014). All variants in the control group maintained Hardy-Weinberg Equilibrium (p > 0.05), confirming the absence of population bias. Functional annotation revealed that rs4274224 showed the strongest direct regulatory evidence for DRD2 (FORGEdb score: 6; RegulomeDB Rank 1f), while rs4938019 demonstrated the highest overall regulatory potential (FORGEdb score: 9), with rs2005313 exhibiting substantial regulatory evidence (FORGEdb score: 7) supported by extensive GTEx cis-eQTLs across multiple tissues including brain regions. Conclusion: These findings establish DRD2 intronic polymorphisms as critical determinants of schizophrenia risk. The high-risk rs4938019 GG genotype provides a clear translational biomarker for rapid genetic screening, potentially improving clinical outcomes through genotype-guided therapeutic interventions.

Graphical Abstract