Ukr.Biochem.J. 2020; Volume 92, Issue 1, Jan-Feb, pp. 12-20


Proline dehydrogenase (PRODH) gene polymorphisms and the risk of schizophrenia in Iranian populations

F. H. Moghadam1, Z. H. A. Mehrabani2, M. Amounajaf3,
S. Rahmanzadeh3, F. Ghasemvand3, A. S. Samghabadi3,
A. Nejadmoghaddam3, E. Omidinia3

1Department of Traditional Medicine, School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran;
2Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran;
3Enzyme Technology Lab., Genetics & Metabolism Research Group, Pasteur Institute of Iran, Tehran, Iran;
e-mail: or

Received: 10 August 2019; Accepted: 29 November 2019

Schizophrenia is a highly heritable mental disorder which can be occurred as a result of mutations or single nucleotide polymorphisms (SNPs) in various genes. Proline dehydrogenase (PRODH) gene is one of the most important genes which can be associated with increased risk of schizophrenia in several populations. Here, we considered the effect of PRODH gene polymorphisms on the incidence of schizophrenia in Iranian populations. This study was done using the analysis of 3 SNPs markers, including G1496A, G758A and C1482T. Molecular analysis was performed on 263 schizophrenic patients and 278 healthy individuals (control group). These examinations were executed by PCR-based restriction fragment length polymorphism (RFLP) technique. Statistical analysis was performed by SPSS software (16.0). Our findings showed that G1496A and C1482T polymorphisms in patients were significantly higher than controls and there were meaningful correlations between the occurrence of these polymorphisms and schizophrenia in the population (P < 0.001). However­, there was no significant relationship between G758A in the PRODH gene and schizophrenia. Haplotype analysis showed that AAT, AAC and GAT blocks (variation alleles are bold) had significant correlations with schizophrenia. PRODH gene can be considered as one of the important genes involved in schizophrenia development among the Iranian population.

Keywords: , , ,


  1. Karayiorgou M, Gogos JA. A turning point in schizophrenia genetics. Neuron. 1997 Nov;19(5):967-79. PubMed, CrossRef
  2. Chow EW, Zipursky RB, Mikulis DJ, Bassett AS. Structural brain abnormalities in patients with schizophrenia and 22q11 deletion syndrome. Biol Psychiatry. 2002 Feb 1;51(3):208-15. PubMed, PubMedCentral, CrossRef
  3. Kirkpatrick B, Buchanan RW, Breier A, Carpenter WT Jr. Depressive symptoms and the deficit syndrome of schizophrenia. J Nerv Ment Dis. 1994 Aug;182(8):452-5. PubMed, CrossRef
  4. Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry. 2005 Mar;162(3):441-9. PubMed, CrossRef
  5. Karayiorgou M, Gogos JA. The molecular genetics of the 22q11-associated schizophrenia. Brain Res Mol Brain Res. 2004 Dec 20;132(2):95-104. PubMed, CrossRef
  6. McDermid HE, Morrow BE. Genomic disorders on 22q11. Am J Hum Genet. 2002 May;70(5):1077-88. PubMed, PubMedCentral, CrossRef
  7. Phang JM, Hu C, Valle D. Disorders of proline and hydroxyproline metabolism. Metab Mol Bases Inherit Dis. 2001;3:1821-1838.
  8. Fallin MD, Lasseter VK, Avramopoulos D, Nicodemus KK, Wolyniec PS, McGrath JA, Steel G, Nestadt G, Liang KY, Huganir RL, Valle D, Pulver AE. Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am J Hum Genet. 2005 Dec;77(6):918-36.  PubMed, PubMedCentral, CrossRef
  9. Humbertclaude V, Rivier F, Roubertie A, Echenne B, Bellet H, Vallat C, Morin D. Is hyperprolinemia type I actually a benign trait? Report of a case with severe neurologic involvement and vigabatrin intolerance. J Child Neurol. 2001 Aug;16(8):622-3. PubMed, CrossRef
  10. Aleman A, Kahn RS, Selten JP. Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch Gen Psychiatry. 2003 Jun;60(6):565-71. PubMed, CrossRef
  11. Ghasemvand F, Omidinia E, Salehi Z, Rahmanzadeh S. Relationship between polymorphisms in the proline dehydrogenase gene and schizophrenia risk. Genet Mol Res. 2015 Oct 2;14(4):11681-91.  PubMed, CrossRef
  12. Ghasemvand F, Rahman Zadeh S, Salehi Z, Fakour Y, Heidari Keshel S, Omidinia E.  Association of 757 C/T polymorphismin PRODH gene with Schizophrenia in Iranian population. J Paramed Sci. 2013;4(1):97-104.
  13. Heidari Keshel S, Sadough N,Omidinia S, Rahmanzadeh S. Quantitative determination of immunoglobulin IgM and apolipoprotein A1 in schizophrenia population. J Paramed Sci. 2013;4(1):107-111.
  14. Rahman Zadeh A, Mohammadi HS, Karimipour M, Heidari Keshel S, Omidinia E. Investigation of genetic association between PRODH gene and schizophrenia in Iranian population. J Paramed Sci. 2012;3(1):7-16.
  15. Bender HU, Almashanu S, Steel G, Hu CA, Lin WW, Willis A, Pulver A, Valle D. Functional consequences of PRODH missense mutations. Am J Hum Genet. 2005 Mar;76(3):409-20. PubMed, PubMedCentral, CrossRef
  16. Liu H, Abecasis GR, Heath SC, Knowles A, Demars S, Chen YJ, Roos JL, Rapoport JL, Gogos JA, Karayiorgou M. Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proc Natl Acad Sci USA. 2002 Dec 24;99(26):16859-64. PubMed, PubMedCentral, CrossRef
  17. Liu H, Heath SC, Sobin C, Roos JL, Galke BL, Blundell ML, Lenane M, Robertson B, Wijsman EM, Rapoport JL, Gogos JA, Karayiorgou M Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci USA. 2002 Mar 19;99(6):3717-22. PubMed, PubMedCentral, CrossRef
  18. Hoogendoorn B, Coleman SL, Guy CA, Smith SK, O’Donovan MC, Buckland PR. Functional analysis of polymorphisms in the promoter regions of genes on 22q11. Hum Mutat. 2004 Jul;24(1):35-42. PubMed, CrossRef
  19. Jacquet H, Raux G, Thibaut F, Hecketsweiler B, Houy E, Demilly C, Haouzir S, Allio G, Fouldrin G, Drouin V, Bou J, Petit M, Campion D, Frébourg T. PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. Hum Mol Genet. 2002 Sep 15;11(19):2243-9. PubMed, CrossRef
  20. Williams NM, O’Donovan MC, Owen MJ. Chromosome 22 deletion syndrome and schizophrenia. Int Rev Neurobiol. 2006;73:1-27.  PubMed, CrossRef
  21. Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM. Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer. Cancer Res. 2007 Oct 15;67(20):9609-12. PubMed, CrossRef
  22. Kempf L, Nicodemus KK, Kolachana B, Vakkalanka R, Verchinski BA, Egan MF, Straub RE, Mattay VA, Callicott JH, Weinberger DR, Meyer-Lindenberg A. Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function. PLoS Genet. 2008 Nov;4(11):e1000252.  PubMed, PubMedCentral, CrossRef
  23. Jacquet H, Demily C, Houy E, Hecketsweiler B, Bou J, Raux G, Lerond J, Allio G, Haouzir S, Tillaux A, Bellegou C, Fouldrin G, Delamillieure P, Ménard JF, Dollfus S, D’Amato T, Petit M, Thibaut F, Frébourg T, Campion D. Hyperprolinemia is a risk factor for schizoaffective disorder. Mol Psychiatry. 2005 May;10(5):479-85. PubMed, CrossRef
  24. Li T, Ma X, Sham PC, Sun X, Hu X, Wang Q, Meng H, Deng W, Liu X, Murray RM, Collier DA. Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population. Am J Med Genet B Neuropsychiatr Genet. 2004 Aug 15;129B(1):13-5. PubMed, CrossRef
  25. Roussos P, Giakoumaki SG, Bitsios P. A risk PRODH haplotype affects sensorimotor gating, memory, schizotypy, and anxiety in healthy male subjects. Biol Psychiatry. 2009 Jun 15;65(12):1063-70.  PubMed, CrossRef
  26. Li T, Ma X, Hu X, Wang Y, Yan C, Meng H, Liu X, Toulopoulou T, Murray RM, Collier DA. PRODH gene is associated with executive function in schizophrenic families. Am J Med Genet B Neuropsychiatr Genet. 2008 Jul 5;147B(5):654-7.  PubMed, CrossRef

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