Abstract
The pathogenesis of schizophrenia involves complex interactions between the environmental and genetic factors. Poly(ADP-ribose) polymerase-1 is activated in response to deoxyribonucleic acid damage. This study aimed to investigate the possible relationship between poly(ADP-ribose) polymerase-1 polymorphism and schizophrenia. The study included 320 participants, consisting of 140 individuals diagnosed with schizophrenia and 180 healthy controls. Haplotype analysis indicated that carrying the TT genotype for the rs7527192 polymorphism increased the risk of disease by 17 times compared to the CC genotype (odds ratio: 17.361, 95% confidence interval: 2.178–138.409, P < .0001). Individuals with the CT genotype had a 1.86-fold higher risk of developing schizophrenia than those with the CC genotype (P < .0001). Additionally, the T allele was found to increase the risk of schizophrenia by 2.09 times compared with the C allele (P < .0001). Identifying genetic risk factors in the etiology of schizophrenia may improve clinical follow-up and contribute to the treatment of this disorder.
Keywords: gene polymorphism, PARP-1, schizophrenia, SNP
1. Introduction
Schizophrenia is a neurodevelopmental disorder that is typically diagnosed during early adulthood.[1] It is a chronic disorder affecting approximately 1% of the global population.[2] The mortality risk among individuals with schizophrenia is 2 to 4 times higher than that in the general population.[3]
Schizophrenia is a complex disorder affected by various genetic and environmental factors.[1,4] Genetic variations increase the risk of developing schizophrenia through interactions with environmental factors.[5] The inheritance of schizophrenia involves genes with diverse functions, and the number of genes linked to the disorder continues to increase with ongoing research. Recent comprehensive genetic studies have identified over 100 gene regions that are associated with schizophrenia.[6,7]
Poly(adenosine diphosphate-ribose) polymerases (PARPs) are involved in deoxyribonucleic acid (DNA) repair, cell death, cell division and differentiation, inflammation, and immune response.[8] Among the 17 PARP family members have been identified, among which PARP-1 is the prototypical enzyme. PARP-1 is a multifunctional enzyme that regulates DNA repair, chromatin remodeling, gene expression, and cell death.[8] When overactivated in response to DNA damage, it can deplete cellular nicotinamide adenine dinucleotide and adenosine triphosphate stores, ultimately leading to cell death.[9,10]
PARP-1 may play a role in dysregulation of neurodevelopmental pathways that are frequently associated with schizophrenia. Schizophrenia is characterized by impaired neurogenesis, and PARP-1 is known to regulate the proliferation and differentiation of neural cells.[11,12] In addition, evidence has shown that PARP-1 regulates the proliferation and differentiation of cells in the nervous system. Preclinical animal studies have examined the association between PARP-1 polymorphism and schizophrenia. The absence of PARP-1 results in impaired neurogenesis and behavioral deficits in mice, which is reminiscent of schizophrenia.[13]
Primarily known for its protective function in DNA repair, PARP-1 plays a regulatory role in inflammatory processes. Excessive PARP-1 activity has been linked to various tumors and inflammatory conditions, including asthma, sepsis, arthritis, atherosclerosis, and neurodegenerative diseases.[13,14] Autoimmune disorders are more prevalent in patients with schizophrenia and their relatives than in the general population. Therefore, schizophrenia has been described as a systemic disorder characterized by immune system dysfunction.[15] It has been proposed that inflammatory responses in the brain contribute to neurodegeneration and drive the pathogenesis of schizophrenia to contribute to neurodegeneration and drive the pathogenesis of schizophrenia. Seventeen PARP-1 genes, a prototypical member of this family, have been identified.[16,17] Genetic polymorphisms help to identify individual differences in susceptibility to certain diseases. This study aimed to investigate the potential association between PARP gene polymorphisms and schizophrenia.
2. Materials and methods
2.1. Study population
The study included patients with schizophrenia who were admitted to the outpatient psychiatry clinics of the University of Health Sciences, Bursa Yuksek Ihtisas Training and Research Hospital between September 2023 and March 2024. Schizophrenia diagnosis was made according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria by trained psychiatrists. The control group comprised hospital staff and their relatives, matched for age and sex. Inclusion criteria for the patient group were: a diagnosis of schizophrenia based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria, and absence of comorbid neurological or major medical conditions. Exclusion criteria included: a history of substance use disorder, presence of an active infectious disease, a diagnosis of another psychiatric or neurological disorder, or a family history of hereditary metabolic diseases. All participants were informed about the research process and provided written informed consent prior to participation, in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of the University of Health Sciences (Approval No: 2011-KAEK-25 2021/03-23). Two milliliters of peripheral venous blood were collected from each participant. Genomic DNA was extracted from leukocytes using a commercial DNA extraction kit (Qiagen, Germany), following the manufacturer’s protocol.
2.2. Genotype analysis
The selection of single nucleotide polymorphisms (SNPs) adhered to the following fundamental principles detailed in our previously published study.[18] Initially, a total of 18.875 SNPs for the PARP-1 gene were identified within the National Center for Biotechnology Information-dbSNP database. Application of a minor allele frequency filter, ranging from 0.14 to 0.4, narrowed this down to 248 SNPs, among which 3 were classified as missense variants. Despite all missense variants being predicted as tolerable according to the SIFT database, the rs1136410 polymorphism was prioritized due to its identification as “possibly damaging” by the PolyPhen-2 database. Upon evaluating untranslated region variants, 6 were located within the promoter region. A subsequent search in the SNPbase 3.0 database revealed that 5 of these 6 SNPs contained transcription factor binding sites. The rs7527192 promoter variant was chosen for inclusion in the study based on literature indicating its association with Hashimoto thyroiditis in the Turkish population and its demonstrated influence on PARP-1 expression in a breast cancer study. Furthermore, examination of 3′-untranslated region variants from the Ensembl database, following filtering with a minor allele frequency of 0.14 to 0.4, resulted in the detection of a single SNP, rs8679. The miRNA DB database predicted that this SNP would enhance miR-7 binding while diminishing miR-124a/miR-223 binding.
The obtained genomic DNA was measured by spectrophotometry at a wavelength of 280 nm to determine the suitability of the DNA quality. Specific primers were designed using National Center for Biotechnology Information Primer-BLAST and PerlPrimer to amplify regions containing PARP-1 gene polymorphisms (rs1136410, rs7527192, and rs8679). Primer specificity and efficiency were evaluated using OligoCalc software. Polymerase chain reactions (PCR) were performed in a 25 μL volume containing 20 to 100 ng of genomic DNA, 100 μM dNTPs, 20 pmol of each primer, 1X DreamTaq Buffer, and DreamTaq DNA polymerase (Thermo Fisher Scientific, Waltham). The PCR cycling conditions for each polymorphism are listed in Table 1. PCR products digested with the appropriate restriction enzymes (Table 2) were separated on a 3% or 3.5% agarose gel at 120 V for 50 minutes and visualized under UV light using a Vilber Lourmat E-BOX VX5.
Table 1.
Primer sequences and annealing temperatures for PCR.
| SNP ID | Primer sequences (5′–3′) | Annealing temperature (°C) |
|---|---|---|
| rs1136410 T>C | Forward primer: 5′-GTACGAGAGGAAAGACAGTTCT-3′ Reverse primer: 5′-CCTGACCCTGTTACCTTAATGT-3′ |
55 |
| rs7527192 C>T | Forward primer: 5′-AGTAGCTCTTTGGAGGACCC-3′ Reverse primer: 5′-ACTATATTCCCGAGGCGGGG-3′ |
62 |
| rs8679 T>C | Forward primer: 5′-GAGCTTTCCTTCTCCAGGTA-3′ Reverse primer: 5′-TATTTGCTGCCTGGCACGTT-3′ |
62 |
PCR = polymerase chain reaction, SNP = single nucleotide polymorphism.
Table 2.
Enzymes and restriction conditions specific to polymorphisms.
| SNP ID | Restriction enzyme | Restriction conditions |
|---|---|---|
| rs1136410 T>C | AciI (Thermo Scientific) | Overnight incubation at 37°C |
| rs7527192 C>T | BstUI (Thermo Scientific) | Overnight incubation at 37°C |
| rs8679 T>C | BstZ17I (Thermo Scientific) | Overnight incubation at 37°C |
SNP = single nucleotide polymorphism.
Genotyping of the rs1136410 polymorphism involved digestion with AciI, producing 2 fragments of 253 and 135 bp for the C allele, while the T allele remained undigested at 388 bp (Fig. 1). For rs7527192, digestion of the 457 bp PCR product with BstUI produced 2 fragments of 332 and 127 bp for the C allele, while the T allele remained undigested at 457 bp (Fig. 2). For rs8679, digestion with BstZ17I produced 2 fragments of 298 and 20 bp for the T allele, whereas the C allele remained undigested at 318 bp (Fig. 3).
Figure 1.
Gel image of PARP-1 rs1136410 polymorphism (1st lane: 100 bp DNA marker, 2nd and 3rd lane TC, 4th lane TT, and 11th lane CC).
Figure 2.
Gel image of PARP-1 rs7527192 polymorphism (1st lane: TC, 2nd lane: CC, 6th lane: 100 bp DNA marker, and 8th lane: TT).
Figure 3.
Gel image of PARP-1 rs8679 polymorphism (1st lane: 100 bp DNA marker, 2nd lane: TT, 3rd lane: CC, and 5th lane: TC).
2.3. Statistical analysis
Age and sex distributions between patients with schizophrenia and healthy controls were compared across each SNP subgroup (rs1136410, rs7527192, and rs8679) using the χ² test for categorical variables and the independent-samples t test for continuous variables. The χ² test was also used to compare genotype and allele frequencies between patients and controls. Logistic regression analysis was performed to evaluate the association between the polymorphisms and the risk of schizophrenia. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to quantify the magnitude of this association. Statistical significance was set at P < .05. All statistical analyses were conducted using Statistical Package for the Social Sciences version 22 software (SPSS Inc., Chicago, IL). A post hoc power analysis was conducted using G*Power 3.1 to evaluate the adequacy of the sample size. For the chi-square test of independence applied to the total sample (n = 320), assuming a medium effect size (w = 0.3) and a significance level of α = 0.05, the statistical power was estimated to exceed 95%, indicating that the sample size was sufficient to detect meaningful associations.
3. Results
This study included 320 participants: 140 individuals with schizophrenia (70 males and 70 females) and 180 healthy controls (96 females and 84 males). There were no statistically significant sex differences between the 2 groups (P = .574). The schizophrenia group had a mean age of 27.08 ± 7.71 years (range: 13–46 years), while the control group had a mean age of 29.36 ± 9.89 years (range: 17–68 years). No significant age difference was found between the 2 groups (P = .101). When age and sex distributions were analyzed separately for each SNP subgroup (rs1136410, rs7527192, and rs8679), no statistically significant demographic differences were observed between patients and controls (P > .05).
The distribution of genotypes and allele frequencies of the PARP-1 gene polymorphisms (rs1136410, rs7527192, and rs8679) in each group are shown in Table 3. The distribution of PARP-1 (rs7527192, T/C) genotypes differed significantly between schizophrenia and control groups. When genotype frequencies were compared, the CC genotype was markedly higher in the schizophrenia group than in the control group (schizophrenia vs control, 7.1% vs 0.6%). The risk of schizophrenia was more than 17.361 times higher in individuals with the rs7527192 TT genotype than in those with the CC genotype (OR: 17.361; 95% CI: 2.178–138.409; P < .0001). Additionally, the risk of schizophrenia was 1.86 times higher in individuals with the rs7527192 CT genotype compared to those with the CC genotype (OR: 1.86, 95% CI: 1.239–2.791, P < .0001). Analysis of the allelic distribution of the rs7527192 polymorphism revealed that the T allele frequency was significantly higher in the patient group than in the control group (P < .0001; OR: 2.096; 95% CI = 1.424–3.086, Table 3), indicating a 2.09-fold increased risk of schizophrenia in carriers of the T allele compared to those with the C allele.
Table 3.
Genotype and allele frequency distributions of PARP-1 gene polymorphisms in patients with schizophrenia and healthy controls.
| SNP | Healthy controls (n = 180/%) | Patients with schizophrenia (n = 140/%) | P | OR (95% CI) |
|---|---|---|---|---|
| rs1136410 | ||||
| Genotype frequency | ||||
| TT | 126 (70.0%) | 99 (70.7%) | .552 | Reference |
| TC | 48 (26.7%) | 39 (27.9%) | 1.034 (0.629–1.701) | |
| CC | 6 (3.3%) | 2 (1.4 %) | 0.424 (0.084–2.148) | |
| Allele frequency | ||||
| T | 300 (83.3%) | 237 (84.6%) | .666 | Reference |
| C | 60 (16.7%) | 43 (15.4%) | 0.907 (0.592–1.390) | |
| rs7527192 | ||||
| Genotype frequency | ||||
| CC | 125 (69.4%) | 72 (51.4%) | <.0001 | Reference |
| CT | 54 (30.0%) | 58 (41.4%) | 1.865 (1.165–2.985) | |
| TT | 1 (0.6%) | 10 (7.1%) | 17.361 (2.178–138.409) | |
| Allele frequency | ||||
| C | 304 (84.4%) | 202 (72.1%) | <.0001 | Reference |
| T | 56 (15.6%) | 78 (27.9%) | 2.096 (1.424–3.086) | |
| rs8679 | ||||
| Genotype frequency | ||||
| TT | 92 (51.1%) | 84 (60.0%) | .141 | Reference |
| TC | 76 (42.2%) | 52 (37.1%) | 0.749 (0.473–1.187) | |
| CC | 12 (6.7%) | 4 (2.9%) | 0.365 (0.113–1.176) | |
| Allele frequency | ||||
| T | 260 (72.2%) | 220 (78.6%) | .067 | Reference |
| C | 100 (27.8%) | 60 (21.4%) | 0.709 (0.491–1.023) |
CI = confidence interval, OR = odds ratio, PARP-1 = poly(ADP-ribose) polymerase-1, SNP = single nucleotide polymorphism.
The distributions of genotypes and allele frequencies of the rs1136410 and rs8679 polymorphisms were similar between the patient and control groups and were not statistically significant (P = .552 and P = .141 for rs1136410, and P = .666 and P = .067 for rs8679, respectively).
Haplotype analysis was conducted using the 3 SNPs: rs7527192 (C/T), rs8679 (T/C), and rs1136410 (T/C). Among the constructed haplotypes, the T–T–T combination (rs7527192-T/rs8679-T/rs1136410-T) was found to be significantly more frequent in the schizophrenia group compared to the healthy controls. This haplotype was associated with an increased risk of schizophrenia (OR: 2.978; 95% CI: 1.746–5.081) (Table 4).
Table 4.
Haplotype frequencies of PARP-1 gene rs7527192(C/T)/rs1136410(T/C)/rs8679(T/C) polymorphisms between patients and healthy controls.
| Haplotype | Healthy controls, n = 180 (%) | Patients, n = 140 (%) | OR (95% CI) |
|---|---|---|---|
| rs7527192/rs1136410/ rs8679 | |||
| CTT | 193 (53.6) | 135 (48.2) | Reference |
| CTC | 61 (16.9) | 35 (12.5) | 0.820 (0.513–1.313) |
| CCT | 35 (9.7) | 24 (8.6) | 0.980 (0.558–1.723) |
| TTT | 24 (6.7) | 50 (17.9) | 2.978 (1.746–5.081) |
| CCC | 15 (4.2) | 8 (2.9) | 0.762 (0.314–1.849) |
| TTC | 22 (6.1) | 17 (6.1) | 1.105 (0.565–2.159) |
| TCT | 8 (3.2) | 11 (3.9) | 1.966 (0.770–5.017) |
| TCC | 2 (0.6) | 0 | * |
CI = confidence interval, OR = odds ratio, PARP-1 = poly(ADP-ribose) polymerase-1.
Odds ratio could not be calculated due to zero frequency in 1 group.
4. Discussion
Numerous genetic studies have been conducted to elucidate the pathophysiology of schizophrenia. Various pathogenic mechanisms have been implicated in the etiology of this disorder.[19]
PARP-1 is an enzyme involved in diverse cellular processes such as DNA repair and chromatin remodeling, and plays a role in the pathophysiology of schizophrenia. Our results demonstrated an association between PARP-1 expression and increased risk of schizophrenia. Our findings suggest that rs7527192 in the PARP-1 gene may play a role in the pathogenesis of schizophrenia, with the TT genotype and T allele of this locus being identified as risk factors for schizophrenia in the Turkish population. Also, the haplotype analysis revealed that the T–T–T combination of the rs7527192, rs8679, and rs1136410 polymorphisms was significantly associated with increased disease susceptibility. Specifically, individuals carrying this haplotype had nearly a threefold higher risk of developing schizophrenia compared to noncarriers (OR: 2.978, 95% CI: 1.746–5.081). These findings suggest a potential synergistic effect among these variants in the pathogenesis of the disorder. Notably, the T allele of rs7527192 was also individually associated with increased risk, and its presence within the risk haplotype further supports its possible role in schizophrenia susceptibility. A study conducted in a Han Chinese population yielded results consistent with those of a study conducted in Europe, demonstrating that rs2021722 at the HLA locus is associated with an increased risk of schizophrenia. This study found that individuals with the rs2021722 AG and A alleles had an increased risk of schizophrenia.[20] Schizophrenia is a neurodegenerative disorder, and animal models have reported impaired neurogenesis.[21,22] PARP-1 has been reported to regulate neurogenesis and is associated with schizophrenia.[13] Polymorphisms in PARP-1 promoter may influence PARP-1 protein expression.[22] Genotype and allele frequencies of PARP-1 polymorphisms may vary across races and regions. In the present study, 3 SNP regions of PARP-1 (rs1136410, rs7527192, and rs8679) were identified. The association between schizophrenia and PARP gene polymorphisms was examined. This study revealed significantly higher genotypic differences among patients with the rs7527192 polymorphism in the schizophrenia group. This is the first study to investigate the relationship between schizophrenia and rs1136410, rs7527192, and rs8679 polymorphisms in the Turkish population.
In recent years, numerous studies have investigated the mechanism of action of PARP-1 and consequences of its absence. It has been reported that the transcription factor NF-κB, which promotes the development of cancer and inflammation, is activated by PARP-1.[23,24] PARP-1 activation maintains the balance between cell death and survival.[25] Free oxygen radicals, generated as a result of oxidative stress, also lead to PARP activation. Poly(ADP-ribosyl)ation acts as a modulator under conditions such as DNA damage, excitotoxicity, and oxidative stress.[25,26] Increased levels of poly(ADP-ribosyl)ation have been reported to play a role in the pathogenesis of disorders, such as cancer and neurodegenerative disorders.[27] Neurodegenerative diseases are characterized by neuroinflammation and neuronal loss.[28]
In recent years, an increasing number of studies have focused on the therapeutic use of PARP-1 inhibitors. Such studies highlight the therapeutic potential of PARP-1 inhibitors for the treatment of malignant and inflammatory diseases.[29] Identifying shared genetic risks among schizophrenia, these diseases, and neurodegenerative disorders could lead to advancements in treatment and prevention.
In this study, no significant differences were found between the patient and healthy control groups in terms of rs1136410 and rs8679 polymorphisms. This finding suggests that there may be no association between rs1136410 and rs8679 polymorphisms and schizophrenia. Our findings provide data regarding the relationship between polymorphisms in the PARP-1 promoter region and schizophrenia. Determining the genotypic and allelic frequencies of these patients may provide valuable information for both patients and their families. Investigating polymorphisms may be important for identifying the risk of schizophrenia. To the best of our knowledge, this is the first study to analyze PARP-1 expression in patients with schizophrenia. Our study had some limitations. The relationships between PARP-1 polymorphisms and clinical characteristics such as age of onset, treatment response, family history, and symptom profiles were not evaluated. In addition, demographic analysis was limited to age and sex; variables such as socioeconomic status or educational background were not collected. These limitations may restrict the interpretability of the findings. Future research should aim to include broader clinical and demographic profiling, which could enhance the interpretability of findings.
Identifying genes and gene polymorphisms associated with the development of a disorder or susceptibility may contribute to early diagnosis and treatment. PARP-1 is known for its protective role in DNA repair and regulation of inflammatory processes. New therapeutic approaches, particularly anti-inflammatory drugs, have been developed for schizophrenia treatment. Further studies are required to confirm the association between PARP-1 and schizophrenia. Future studies supporting the relationship between PARP-1 and schizophrenia will shed light on the genetic background of schizophrenia.
5. Conclusions
In conclusion, schizophrenia is a heterogeneous disorder in which both genetic and environmental factors play a role in its etiology. A detailed history and genetic investigations may be beneficial for the evaluation of this disorder. When a genetic risk is identified, genetic susceptibility can be investigated among family members. Further genetic research on this disorder may contribute to clinical management and treatment. Our findings contribute to the growing body of evidence supporting a potential genetic risk factor for schizophrenia.
Acknowledgments
The authors would also like to thank all participants for their contribution to the study.
Author contributions
Conceptualization: Ömer Şenormanci, Çetin Turan, Salih Metin, Güliz Şenormanci, Süheyla Ünal.
Data curation: Ömer Şenormanci, Çetin Turan, Salih Metin, Sevim Karakaş Çelik, Büşra Yilmaz.
Formal analysis: Sevim Karakaş Çelik, Büşra Yilmaz.
Methodology: Sevim Karakaş Çelik.
Resources: Çetin Turan.
Supervision: Ömer Şenormanci.
Writing – original draft: Ömer Şenormanci, Çetin Turan, Salih Metin, Güliz Şenormanci, Süheyla Ünal.
Writing – review & editing: Ömer Şenormanci, Sevim Karakaş Çelik, Büşra Yilmaz, Güliz Şenormanci, Süheyla Ünal.
Abbreviations:
- CI
- confidence interval
- DNA
- deoxyribonucleic acid
- OR
- odds ratio
- PARP-1
- poly(ADP-ribose) polymerase-1
- PCR
- polymerase chain reaction
- SNP
- single nucleotide polymorphism
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to cite this article: Şenormanci Ö, Turan Ç, Metin S, Karakaş Çelik S, Yilmaz B, Şenormanci G, Ünal S. Poly(ADP-ribose) polymerase-1 (PARP-1) gene polymorphisms in schizophrenia: A case-control study in the Turkish population. Medicine 2025;104:22(e42679).
Contributor Information
Çetin Turan, Email: cetin.turan@hotmail.com.
Salih Metin, Email: drsalihmetin@gmail.com.
Sevim Karakaş Çelik, Email: sevimkarakas@hotmail.com.
Büşra Yilmaz, Email: bsry1mz555@gmail.com.
Güliz Şenormanci, Email: gulizsenormanci@yahoo.com.
Süheyla Ünal, Email: suheylaunal@gmail.com.
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