Murat Eren ÖZEN, Miris DİKMEN, Duygu TAP, Sinan OZLER, Mehmet Bertan YILMAZ, Meral Urhan KÜÇÜK

Is there any role of G-protein estrogen receptor gene (GPR30) polymorphism in development of schizophrenia?

Objectives: Schizophrenia is a complex neuropsychiatric disorder that affects approximately 1% of the population. Estrogens may play an important role in the etiology and treatment of this disorder. They mediate effect by either estrogen receptors. GPR30 is an alternative G protein-coupled receptor distinct from the classical estrogen recep- tors (ER αα and ER ββ ). We aimed to investigate the association between GPR30 gene SNP rs3808350 and gonadal hormone (estrogen and testosterone) levels, and their association with development of schizophrenia, in a Turkish population. Methods: A total 117 schizophrenia patients and 123 control individuals were genotyped with method Real-Time PCR. Results: In the comparison of the patients and the control group with regard to the SNP genotype and allele frequencies did not show significant differences. However, there was a significant decrease in the pre- sence of AA+AG genotypes in the patient group. There were significant differences in terms of estrogen, testos- terone. In the patient group, estrogen and testosterone levels were lower than the control group. Conclusions: This is the first study examining allele and genotype frequencies of GPR30 gene SNP rs3808350 in schizophrenia patients. Because of effects of gene polymorphisms may differ in the population from the population, we may sug- gest that role of GPR30 gene SNP rs3808350 in development of schizophrenia must be investigated in different and wider populations. (Anatolian Journal of Psychiatry 2019; 20(1):13-19)

Şizofreni gelişiminde G-protein östrojen reseptör geni (GPR30) polimorfizminin rolü var mıdır?

Şizofreni, toplumun yaklaşık %1'ini etkileyen karmaşık bir nöropsikiyatrik bozukluktur. Bu bozukluğun etiyolojisi ve tedavisinde östrojenler önemli bir rol oynayabilir. Etkisini bir östrojen bir reseptörü tarafından etki yaratır. GPR30, klasik östrojen reseptörlerinden (ER αα ve ER ββ ) farklı bir alternatif G protein-bağlı reseptördür. Türk popülasyonunda GPR30 geni SNP rs3808350 polimorfizmi ile gonadal hormon (östrojen ve testosteron) düzeyleri ve şizofreni gelişimi arasındaki ilişkiyi araştırmayı amaçladık. Yöntem: Toplam 117 şizofreni hastası ve 123 kontrol hastası Real-Time PCR yöntemiyle genotiplendirildi. Sonuçlar: Hasta grubu kontrol grubuyla karşılaştırıldığında SNP genotip ve alel sıklıkları açısından anlamlı farklılıklar görülmedi. Ancak, hasta grubunda kontrole göre AA+AG genotip sıklığında bir anlamlı bir azalma görüldü. Bununla birlikte, östrojen ve testosteron açısından anlamlı fark lılıklar vardı. Hasta grubunda östrojen ve testosteron düzeyleri kontrol grubundan daha düşüktü. Tartışma: Bu çalış- ma, şizofreni hastalarında GPR30 geni SNP rs3808350'nin alel ve genotip frekanslarını inceleyen ilk çalışmadır. Gen polimorfizminin etkilerinin popülasyondan popülasyona farklılık göstermesi nedeniyle, GPR30 geni SNP rs3808350'nin şizofrenideki rolünün farklı ve daha geniş popülasyonlarda araştırılması önerilebilir. (Anadolu Psiki- yatri Derg 2019; 20(1):13-19)

PDF

___

McGrath J, Saha S, Chant D, Welham J. Schizo- phrenia: a concise overview of incidence, preva- lence, and mortality. Epidemiol Rev 2008; 30:67- 76.

Knapp M. Schizophrenia costs and treatment cost-effectiveness. Acta Psychiatr Scand 2000; (407):15-18.

Leung A, Chue P. Sex differences in schizophre- nia, a review of the literature. Acta Psychiatr Scand 2000; 101:3-38.

Abel KM, Drake R, Goldstein JM. Sex differences in schizophrenia. Int Rev Psychiatry 2010; 22:417- 428.

Markham JA. Sex steroids and schizophrenia. Rev Endocr Metab Disord 2012; 13:187-207.

Ochoa S, Usall J, Cobo J, Labad X, Kulkarni J. Gender differences in schizophrenia and first-epi- sode psychosis: a comprehensive literature re- view. Schizophr Res Treat 2012; 2012:916198.

Gogos A, Sbisa AM, Sun J, Gibbons A, Udawela M, Dean B. A role for estrogen in schizophrenia: clinical and preclinical findings. Int J Endocrinol 2015; 2015:615356.

Cohen RZ, Seeman MV, Gotowiec A, Kopala L. Earlier puberty as a predictor of later onset of Anatolian Journal of Psychiatry 2019; 20(1):13-19 schizophrenia in women. Am J Psychiatry 1999; 156:1059-1064.

Goldstein JM, Link BG. Gender and the expres- sion of schizophrenia. J Psychiatr Res 1988; 22:141-155.

Min J-A, Kim JJ, Pae C-U, Kim KH, Lee C-U, Lee C-Paik I-H. Association of estrogen receptor genes and schizophrenia: A preliminary study. Prog Neuro-Psychopharmacol Biol Psychiatry 2012; 36:1-4.

Wang S, Li W, Zhao J, Zhang H, Yang Y, Wang X, et al. Association of estrogen receptor alpha gene polymorphism with age at onset, general psychopathology symptoms, and therapeutic ef- fect of schizophrenia. Behav Brain Func 2013; 9:1-8.

Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signalling. Science 2005; 307:1625-1630.

Seeman MV. Interaction of sex, age, and neuro- leptic dose. Compr Psychiatry 1983; 24:125-128.

McEwen BS, Alves SE. Estrogen actions in the central nervous system. Endocr Rev 1999; 20(3):279-307.

McEwen B, Akama K, Alves S, Brake WG, Bulloch K, Lee S, et al. Tracking the estrogen receptor in neurons: implications for estrogen-induced syn- apse formation. Proc Natl Acad Sci U S A. 2001; 98:7093-7100.

Thomas P, Pang Y, Filardo EJ, Dong J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrino- logy 2005; 146:624-632.

Tang H, Zhang Q, Yang L, Dong Y, Khan M, Yang F, et al. Reprint of GPR30 mediates estrogen rapid signaling and neuroprotection. Mol Cell Endocrinol 2014; 389:92-98.

Maggiolini M, Picard D. The unfolding stories of GPR30, a new membrane-bound estrogen recep- tor. J Endocrinol 2010; 204:105-114.

Noel SD, Keen KL., Baumann DL, Filardo EJ, Terasawa E. Involvement of G protein-coupled receptor 30 (GPR30) in rapid action of estrogen in primate LHRH neurons. Mol Endocrinol 2009; 23:349-359.

Weickert CS, Miranda-Angulo AL, Wong J, Perl- man WR, Ward SE, Radhakrishna V, et al. Vari- ants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia. Hum Mol Genet 2008; 17:2293-2309.

Kasap B, Turhan NÖ, Edgünlü T, Duran M, Akba- ba E, Öner G. G-protein-coupled estrogen recep- tor-30 gene polymorphisms are associated with uterine leiomyoma risk. Bosn J Basic Med Sci 2016; 16:39-45.

Prossnitz ER, Arterburn JB, Smith HO, Oprea TI, Sklar LA, Hathaway HJ. Estrogen signaling through the Transmembrane G Protein-Coupled Receptor GPR30. Annu Rev Physiol 2008; 70:165-190.

Fink G, Sumner BE, Rosie R, Grace O, Quinn JP. Estrogen control of central neurotransmission: effect on mood, mental state, and memory. Cell Mol Neurobiol 1996; 16:325-344.

Carmeci C, Thompson DA, Ring HZ, Francke U, Weigel RJ. Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics 1997; 45:607-617.

Giess M, Lattrich C, Springwald A, Goerse R, Ortmann O, Treeck O. GPR30 gene polymor- phisms are associated with progesterone receptor status and histopathological characteristics of breast cancer patients. J Steroid Biochem Mol Biol 2010; 118:7-12.

O'Dowd BF, Nguyen T, Marchese A, Cheng R, Lynch KR, Heng HH, et al. Discovery of three novel G-protein-coupled receptor genes. Geno- mics 1998; 47(2):310-313.

Chevalier N, Paul-Bellon R, Camparo P, Michiels J-F, Chevallier Dl, Fénichel P. Genetic variants of GPER/GPR30, a Novel Estrogen-Related G Pro- tein Receptor, are associated with human semi- noma. Int J Mol Sci 2014; 15:1574-1589.

Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. Fourth ed., New York: Garland Science, 2002.

https://ghr.nlm.nih.gov/primer/genomicresearch/ snp. (Access: July, 18 th 2018)

Bergemann N, Parzer P, Nagl I, Salbach B, Runnebaum B, Mundt C, et al. Acute psychiatric admission and menstrual cycle phase in women with schizophrenia. Arch Womens Ment Health 2002; 5:119-126.

Zhang-Wong JH, Seeman MV. Antipsychotic drugs, menstrual regularity and osteoporosis risk. Arch Womens Ment Health 2002; 5:93-98.

Montgomery J, Winterbottom E, Jessani M, Kohegyi E, Fulmer J, Seamonds B, et al. Preva- lence of hyperprolactinemia in schizophrenia: association with typical and atypical antipsychotic treatment. J Clin Psychiatry 2004; 65:1491-1498.

Perkins DO. Antipsychotic-induced hyperprolac- tinemia: pathophysiology and clinical consequ- ences. Adv Stud Med 2004; 4:982-986.

Chavez C, Hollaus M, Scarr E, Pavey G, Gogos A, van den Buuse M. The effect of estrogen on dopamine and serotonin receptor and transporter levels in the brain: an autoradiography study. Brain Res 2010; 1321:51-59.

Sanchez MG, Bourque M, Morissette M, Di Paolo T. Steroids-dopamine interactions in the patho- physiology and treatment of cns disorders. CNS Neurosci Ther 2010; 16:e43-71.