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|Year : 2017
: 59 | Issue : 4 | Page
|No genetic association between A118G polymorphism of μ-opioid receptor gene and schizophrenia and bipolar disorders
Shaghayegh Yazdani1, Vahid Salimi1, Mohammad Reza Eshraghian2, Mohammad Shayestehpour1, Alireza Pourtalebi-Firoozabadi3, Bizhan Romani4, Azadeh Shadab1, Mohammad Reza Aghasadeghi5, Jila Yavarian1
1 Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Epidemiology and Biostatistics, Tehran University of Medical Sciences, Tehran, Iran
3 Genomic Research Center, Birjand University of Medical Sciences; Department of Molecular Medicine, Birjand University of Medical Sciences, Birjand, Iran; Department of Cellular and Molecular Medicine, Mehrvarzan-e-Saba Gostar Medical Rehabilitation and Maintenance Center of Chronic Mental Patients, Karaj, Alborz Province, Canada
4 Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; Cellular and Molecular Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
5 Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
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|Date of Web Publication||18-Jan-2018|
| Abstract|| |
Background: Schizophrenia (SZ) and bipolar disorder (BD) are chronic and multifactorial psychiatric disorders that might be affected by different genes in combination with environmental factors. There is evidence of association between polymorphisms of μ-opioid receptor gene (OPRM1) with these disorders.
Objectives: The aim of this study was to investigate the genetic association between OPRM1 A118G SNP in SZ and BD patients in comparison with healthy controls (HCs).
Materials and Methods: One single-nucleotide polymorphism in OPRM1 was genotyped using TaqMan real-time PCR assay in 203 SZ and BD patients and 389 HCs.
Results: There was no statistically significant difference in genotypic and allelic frequencies of OPRM1 A118G SNP between HCs and SZ/BD patients.
Conclusions: To find the underlying genetic factors associated with these complex disorders, further studies need to be conducted using larger sample size, different genetic populations, and different gene variations.
Keywords: μ-opioid receptor gene, bipolar disorder, schizophrenia, single-nucleotide polymorphism
|How to cite this article:|
Yazdani S, Salimi V, Eshraghian MR, Shayestehpour M, Pourtalebi-Firoozabadi A, Romani B, Shadab A, Aghasadeghi MR, Yavarian J. No genetic association between A118G polymorphism of μ-opioid receptor gene and schizophrenia and bipolar disorders. Indian J Psychiatry 2017;59:483-6
|How to cite this URL:|
Yazdani S, Salimi V, Eshraghian MR, Shayestehpour M, Pourtalebi-Firoozabadi A, Romani B, Shadab A, Aghasadeghi MR, Yavarian J. No genetic association between A118G polymorphism of μ-opioid receptor gene and schizophrenia and bipolar disorders. Indian J Psychiatry [serial online] 2017 [cited 2020 Mar 30];59:483-6. Available from: http://www.indianjpsychiatry.org/text.asp?2017/59/4/483/217302
| Introduction|| |
Schizophrenia (SZ) and bipolar disorder (BD) are complex chronic psychiatric diseases which can cause disruptive psychopathologies, including difficulties in thought, understanding, behavior, movement, emotion, cognition, and mood functions. Genetic analyses of SZ and BD patients have shown that interactions between different genes along with environmental factors are important factors contributing to these disorders., In recent years, genome-wide association studies have found new evidence for SZ and BD genetic basis and shown that single-nucleotide polymorphisms (SNPs) affect the function of certain receptors and corresponding neurotransmitters and contribute to SZ and BD development.,,, The μ-opioid receptor (MOR) encoded by μ-opioid receptor gene (OPRM1) is widely distributed in the central nervous system,,, and its expression is very prominent in caudate, putamen, thalamus, and globus pallidus., The MOR has a high affinity for opioid drugs such as methadone, morphine, and heroin. The symptoms related to opiate drug withdrawal, euphoria and analgesia are believed to be caused by MORs.,, A number of studies have reported more than 250 SNPs in the OPRM1 gene.,,, A single-nucleotide polymorphism (A118G, rs1799971) in the OPRM1 gene results in replacement of asparagine (Asn) with aspartic acid (Asp) at amino acid position 40 which leads to a change at N-glycosylation site and decreased expression of the receptor.,, Studies on the association between this SNP and SZ/BD disorders have provided contradicting results.,,, The different literature findings for the A118G genotype report the distribution of alleles and genotypes. The genotypic and allelic frequencies are similar among different populations. The variant genotypes for A118G, AG and GG, are reported in 10.5% to 18.8% of the population (NCBI-rs1799971).
Since there is a body of conflicting and controversial evidence regarding the basic role of opioid receptors and their SNPs in psychotic disorders, this case–control study was designed to investigate the relationship between OPRM1 SNP (rs1799971, A118G) and SZ/BD patients in the Iranian population.
| Materials and Methods|| |
The sample size of this case–control study consisted of 134 patients with SZ (94 females and 40 males; mean age: 38.01 ± 10.57 years old) and 69 patients with BD (39 females and 30 males; mean age: 37.84 ± 11.92 years old) and 389 healthy controls (HCs) (215 females and 174 males; mean age: 41.67 ± 22.06 years old). All the patients were hospitalized at one of the psychiatry hospitals of Iran University and Mehrvarzan-e-Saba Gostar Medical, Rehabilitation and Maintenance Centre of chronic mental patients, Karaj. Two certified psychiatrists made the consensus diagnosis with regard to the diagnostic and manual of Mental Disorder-Forth edition IV diagnostic criteria. Individuals with a history of severe medical diseases such as neurological disorders, diabetes, hypertension, cardiovascular diseases, and substance dependence were excluded from this study. The HC volunteers participated in this study were from Tehran University of Medical Sciences. The HCs were first interviewed using a neuropsychiatric approach and then by a psychiatrist. All individuals with a history of SZ, BD, or addiction were excluded from the HCs. Informed consent forms were signed by all the participants for joining the study. The control and patient groups were matched for gender and age.
DNA was extracted from peripheral blood mononuclear cells using the High Pure Viral Nucleic Acid Kit (Roche, Germany) according to the manufacturer's instructions. A commercial kit from Thermo Fisher Scientific (4351379) was used to detect the OPRM1 polymorphism (rs1799971). The assay takes advantage of specific primers to amplify OPRM1 gene and 2 probes to specifically detect the two SNPs. A VIC-labeled probe detects the A/A allele and the FAM-labeled probe detects A/G allele. The TaqMan real-time PCR was performed using automated ABI one plus system (Applied Biosystems, Foster City, CA). The reaction mixture of a total volume of 20 μl was comprised of 10 μl of TaqMan universal PCR master mix (Applied Biosystems, Foster City, CA), 5 μl of the extracted DNA, 4.8 μl of distilled water, and 0.2 μl of primers and probes mix. The condition for real-time PCR SNP detection consisted of an initial denaturation phase at 95°C for 10 min followed by 50 cycles at 95°C for 15 s and annealing/extension at 60°C for 90 s.
The real-time PCR data obtained from the patients and HCs were compared for genotype and allele frequencies using SPSS version 22 software. Using Chi-square distribution of a 2 × 2 table, genotype distribution and allele frequency variation between patients and HCs, and the deviation from Hardy-Weinberg equilibrium was surveyed for SNP analysis.
| Results|| |
The OPRM1 A118G SNP (rs1799971) was tested in 203 SZ and BD patients together with 389 HCs. No significant deviation from the Hardy–Weinberg equilibrium was observed in either of the patient groups or the HCs for this SNP. The OPRM1 SNP analyses based on gender and in case and control groups are shown in [Table 1], and the results of genotyping of the OPRM1 gene polymorphism are demonstrated in [Table 2]. The total of 152 patients had AA genotype, 46 patients carried AG genotype, and five patients were GG homozygotes. In the HCs, 276 individuals carried the AA genotype, 97 individuals were AG heterozygotes and 16 individuals were GG homozygotes.
|Table 1: The polymorphisms of μ-opioid receptor gene single-nucleotide polymorphism analysis based on gender in case and control groups|
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|Table 2: Genotype and alleles of polymorphisms of μ-opioid receptor gene single nucleotide polymorphism in case and healthy control groups|
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Comparison of genotype frequencies showed no significant difference between the studied groups (P = 0.451). No significant difference was also found when the allelic frequencies between the two groups were compared, suggesting that the distribution of the OPRM1 A118G SNP is similar between the healthy individuals and BD/SZ patients. Taken together, our results did not support the previous studies reporting the contribution of this specific SNP in BD/SZ development.
| Discussion|| |
The MOR encoded by OPRM1 is widely distributed in the brain with different roles in diverse areas such as social status, stress, memory, drinking, eating, sexual activity, mental illness, mood, seizures, and neurologic disorders. MORs are believed to regulate many opioidergic actions such as analgesia, euphoria, and opiate drug withdrawal. There are high-affinity interactions between this receptor and the exogenous opioid drugs such as methadone, morphine, and heroin. The MOR controls the proliferation of oligodendrocyte progenitors and thickness of myelin sheaths and the volume of brain white matter. In SZ patients, there is an impairment of the myelination in the cortex., Genetic association studies have shown that certain SNPs in OPRM1 may contribute to disease pathogenesis by affecting the oligodendrocytes density and myelination rate., Among all SNPs, rs1799971 in coding region with a minor allele frequency of 20%, the 118A>G SNP (Asn40Asp) is the most important studied SNP of the OPRM1 gene. This polymorphism has been analyzed in different studies, for instance in one research by Hirasawa-Fujita et al., A118G and dopamine D2 receptor (DRD2) Taq1A (rs1800497) polymorphisms, smoking habits and sex differences among patients with SZ or BD were analyzed. The results showed that A118G increases smoking in patients with SZ and alteration of DRD2 receptor function also increases smoking in females with SC but not BD. The results of study by Wang et al. showed that Caucasians carrying the G allele of the A118G were susceptible for addiction to smoking in comparison with those with the AA homozygote. In a case–control study of 183 suicide cases and 374 HCs, it was shown that the A118G polymorphism was significantly different among the two groups suggesting the possible association between suicide and A118G. The present study was performed for detection of the A118G SNP in the OPRM1 gene of SZ and BD patients.
A number of studies have reported an association between the rs1799971 polymorphism in the OPRM1 gene and the increased risk of SZ in the males. It was also shown that the occurrence of the G allele was significantly lower in tardive dyskinesia patients. Another study confirmed the previous results by showing a less frequent G allele in participants with tardive dyskinesia among SZ patients. A study by Volk et al. depicted that the level of MOR mRNA in SZ patients was increased. Moreover, they showed that the G allele of rs1799971 can affect MOR function, resulting in decreased expression of this receptor.,, A recent study of OPRM1 polymorphism with SZ suggested that G allele of rs1799971 has decreased risk in these patients. Surprisingly, in our analysis, we did not find any association between OPRM1 rs1799971 SNP and the SZ and BD disorders. The incidence of complex disorders such as SZ is highly multifactorial which means no single gene may account for these disorders and multiple factors can play roles in their occurrences.,, Meanwhile, there are several possibilities for the contrast between our findings and previous studies. As requested we can write conclusions and from this part can move under the conclusion heading.
| Conclusion|| |
The lack of association between the studied SNP and BD and SZ disorders in this study can be the result of population characteristics, geographic location, and clinical heterogeneity. For adding more precious insights into the implications of the OPRM1 gene polymorphism and BD/SZ disorder association, further investigations using a larger sample size and family-based surveys are suggested.
The authors thank the entire staff of the Iranian National Influenza Centre (Tehran University of Medical Sciences).
Financial support and sponsorship
This study was financially supported by Research grant (94-02-27-28718) from the Tehran University of Medical Sciences.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Weis S, Llenos IC, Sabunciyan S, Dulay JR, Isler L, Yolken R, et al.
Reduced expression of human endogenous retrovirus (HERV)-W GAG protein in the cingulate gyrus and hippocampus in schizophrenia, bipolar disorder, and depression. J Neural Transm (Vienna) 2007;114:645-55.
Van Winkel R, Esquivel G, Kenis G, Wichers M, Collip D, Peerbooms O, et al.
REVIEW: Genome-wide findings in schizophrenia and the role of gene-environment interplay. CNS Neurosci Ther 2010;16:e185-92.
Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, et al.
Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: A population-based study. Lancet 2009;373:234-9.
Need AC, Ge D, Weale ME, Maia J, Feng S, Heinzen EL, et al.
Agenome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genet 2009;5:e1000373.
Williams HJ, Owen MJ, O'Donovan MC. New findings from genetic association studies of schizophrenia. J Hum Genet 2009;54:9-14.
Ding S, Chen B, Zheng Y, Lu Q, Liu L, Zhuge QC, et al.
Association study of OPRM1 polymorphisms with schizophrenia in Han Chinese population. BMC Psychiatry 2013;13:107.
Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, et al.
Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 2008;320:539-43.
Salimi V, Hennus MP, Mokhtari-Azad T, Shokri F, Janssen R, Hodemaekers HM, et al.
Opioid receptors control viral replication in the airways. Crit Care Med 2013;41:205-14.
Kieffer BL, Gavériaux-Ruff C. Exploring the opioid system by gene knockout. Prog Neurobiol 2002;66:285-306.
Delfs JM, Kong H, Mestek A, Chen Y, Yu L, Reisine T, et al.
Expression of mu opioid receptor mRNA in rat brain: An in situ
hybridization study at the single cell level. J Comp Neurol 1994;345:46-68.
Uhl GR, Sora I, Wang Z. The mu opiate receptor as a candidate gene for pain: Polymorphisms, variations in expression, nociception, and opiate responses. Proc Natl Acad Sci U S A 1999;96:7752-5.
Serý O, Prikryl R, Castulík L, St'astný F. A118G polymorphism of OPRM1 gene is associated with schizophrenia. J Mol Neurosci 2010;41:219-22.
Ide S, Kobayashi H, Ujike H, Ozaki N, Sekine Y, Inada T, et al.
Linkage disequilibrium and association with methamphetamine dependence/psychosis of mu-opioid receptor gene polymorphisms. Pharmacogenomics J 2006;6:179-88.
Ide S, Kobayashi H, Tanaka K, Ujike H, Sekine Y, Ozaki N, et al.
Gene polymorphisms of the Mu opioid receptor in methamphetamine abusers. Ann N
Y Acad Sci 2004;1025:316-24.
Ikeda K, Ide S, Han W, Hayashida M, Uhl GR, Sora I, et al.
How individual sensitivity to opiates can be predicted by gene analyses. Trends Pharmacol Sci 2005;26:311-7.
Ohmori O, Shinkai T, Hori H, Kojima H, Nakamura J. Polymorphisms of Mu and Delta opioid receptor genes and tardive dyskinesia in patients with schizophrenia. Schizophr Res 2001;52:137-8.
Tan EC, Chong SA, Mahendran R, Tan CH, Teo YY. Mu opioid receptor gene polymorphism and neuroleptic-induced tardive dyskinesia in patients with schizophrenia. Schizophr Res 2003;65:61-3.
Bodnar RJ. Endogenous opiates and behavior: 2013. Peptides 2014;62:67-136.
Hof PR, Haroutunian V, Friedrich VL Jr., Byne W, Buitron C, Perl DP, et al.
Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry 2003;53:1075-85.
Hirasawa-Fujita M, Bly MJ, Ellingrod VL, Dalack GW, Domino EF. Genetic variation of the Mu opioid receptor (OPRM1) and dopamine D2 receptor (DRD2) is related to smoking differences in patients with schizophrenia but not bipolar disorder. Clin Schizophr Relat Psychoses Spring 2017;11:39-48.
Wang J, Jin P, Wang WH, He M, Zhang ZT, Liu Y, et al.
Association of A118G polymorphism in the μ-opioid receptor gene with smoking behaviors: A meta-analysis. J Toxicol Sci 2015;40:711-8.
Hishimoto A, Cui H, Mouri K, Nushida H, Ueno Y, Maeda K, et al.
Afunctional polymorphism of the micro-opioid receptor gene is associated with completed suicides. J Neural Transm (Vienna) 2008;115:531-6.
Volk DW, Radchenkova PV, Walker EM, Sengupta EJ, Lewis DA. Cortical opioid markers in schizophrenia and across postnatal development. Cereb Cortex 2012;22:1215-23.
Zhang Y, Wang D, Johnson AD, Papp AC, Sadée W. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 2005;280:32618-24.
Dr. Jila Yavarian
Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]