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Published in: BMC Psychiatry 1/2018

Open Access 01-12-2018 | Research article

Polymorphisms in the human serotonin receptor 1B (HTR1B) gene are associated with schizophrenia: a case control study

Authors: Xi Xia, Mei Ding, Jin-feng Xuan, Jia-xin Xing, Hao Pang, Bao-jie Wang, Jun Yao

Published in: BMC Psychiatry | Issue 1/2018

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Abstract

Background

Schizophrenia is associated with multiple neurotransmitter disorders, including serotonin (5-hydroxytryptamine, 5-HT). The neuromodulatory action of serotonin on brain function largely depends on the action of specific subtypes of serotonin receptors. The serotonin receptor 1B (HTR1B) gene has been proposed to play putative roles in the development of multiple emotional and psychiatric disorders.

Methods

To study the relationship of HTR1B polymorphisms and schizophrenia, gene information was drawn from a cohort of 310 schizophrenic patients (152 men and 158 women) and 313 healthy controls (153 men and 160 women) of northern Han Chinese descent. The χ2 test was used to compare allele and genotype distributions between case and control groups. The haplotype and linkage equilibrium were also assessed in two group comparisons.

Results

We detected 14 SNPs. Male patients were observed to have higher frequencies of the A-allele and AA+AG genotype at rs1778258 than female patients (p = 0.012 and p = 0.015, respectively). Both the A-allele and AA+AG genotype were associated with schizophrenia risk (OR = 1.986 and OR = 2.061, respectively), although the statistical significance of the genotype was lost after Bonferroni correction. Linkage analysis showed that rs17273700, rs11568817, rs9361234 and rs58138557 polymorphisms exhibit strong linkage disequilibrium (LD). In addition, schizophrenic patients show stronger linkage between 11,568,817 and rs130058 than healthy controls.

Conclusions

HTR1B polymorphisms are associated with schizophrenia in the northern Han Chinese population, which provides an etiological reference for schizophrenia.
Literature
1.
go back to reference Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60(12):1187–92.CrossRef Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60(12):1187–92.CrossRef
2.
go back to reference Liy-Salmeron G, Meneses A. Role of 5-HT1-7 receptors in short- and long-term memory for an autoshaping task: intrahippocampal manipulations. Brain Res. 2007;1147:140–7.CrossRef Liy-Salmeron G, Meneses A. Role of 5-HT1-7 receptors in short- and long-term memory for an autoshaping task: intrahippocampal manipulations. Brain Res. 2007;1147:140–7.CrossRef
3.
go back to reference Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38(8):1083–152.CrossRef Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38(8):1083–152.CrossRef
4.
go back to reference Guimaraes AP, Schmitz M, Polanczyk GV, Zeni C, Genro J, Roman T, Rohde LA, Hutz MH. Further evidence for the association between attention deficit/hyperactivity disorder and the serotonin receptor 1B gene. J Neural Transm. 2009;116(12):1675–80.CrossRef Guimaraes AP, Schmitz M, Polanczyk GV, Zeni C, Genro J, Roman T, Rohde LA, Hutz MH. Further evidence for the association between attention deficit/hyperactivity disorder and the serotonin receptor 1B gene. J Neural Transm. 2009;116(12):1675–80.CrossRef
5.
go back to reference Moul C, Dobson-Stone C, Brennan J, Hawes DJ, Dadds MR. Serotonin 1B receptor gene (HTR1B) methylation as a risk factor for callous-unemotional traits in antisocial boys. PLoS One. 2015;10(5):e0126903.CrossRef Moul C, Dobson-Stone C, Brennan J, Hawes DJ, Dadds MR. Serotonin 1B receptor gene (HTR1B) methylation as a risk factor for callous-unemotional traits in antisocial boys. PLoS One. 2015;10(5):e0126903.CrossRef
6.
go back to reference Hakulinen C, Jokela M, Hintsanen M, Merjonen P, Pulkki-Raback L, Seppala I, Lyytikainen LP, Lehtimaki T, Kahonen M, Viikari J, et al. Serotonin receptor 1B genotype and hostility, anger and aggressive behavior through the lifespan: the young Finns study. J Behav Med. 2013;36(6):583–90.CrossRef Hakulinen C, Jokela M, Hintsanen M, Merjonen P, Pulkki-Raback L, Seppala I, Lyytikainen LP, Lehtimaki T, Kahonen M, Viikari J, et al. Serotonin receptor 1B genotype and hostility, anger and aggressive behavior through the lifespan: the young Finns study. J Behav Med. 2013;36(6):583–90.CrossRef
7.
go back to reference Lopez-Figueroa AL, Norton CS, Lopez-Figueroa MO, Armellini-Dodel D, Burke S, Akil H, Lopez JF, Watson SJ. Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biol Psychiatry. 2004;55(3):225–33.CrossRef Lopez-Figueroa AL, Norton CS, Lopez-Figueroa MO, Armellini-Dodel D, Burke S, Akil H, Lopez JF, Watson SJ. Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biol Psychiatry. 2004;55(3):225–33.CrossRef
8.
go back to reference Veldman ER, Svedberg MM, Svenningsson P, Lundberg J. Distribution and levels of 5-HT1B receptors in anterior cingulate cortex of patients with bipolar disorder, major depressive disorder and schizophrenia - an autoradiography study. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2017;27(5):504–14.CrossRef Veldman ER, Svedberg MM, Svenningsson P, Lundberg J. Distribution and levels of 5-HT1B receptors in anterior cingulate cortex of patients with bipolar disorder, major depressive disorder and schizophrenia - an autoradiography study. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2017;27(5):504–14.CrossRef
9.
go back to reference Cao J, LaRocque E, Li D: Associations of the 5-hydroxytryptamine (serotonin) receptor 1B gene (HTR1B) with alcohol, cocaine, and heroin abuse. American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2013, 162B(2):169–176.CrossRef Cao J, LaRocque E, Li D: Associations of the 5-hydroxytryptamine (serotonin) receptor 1B gene (HTR1B) with alcohol, cocaine, and heroin abuse. American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2013, 162B(2):169–176.CrossRef
10.
go back to reference Pal P, Mihanovic M, Molnar S, Xi H, Sun G, Guha S, Jeran N, Tomljenovic A, Malnar A, Missoni S, et al. Association of tagging single nucleotide polymorphisms on 8 candidate genes in dopaminergic pathway with schizophrenia in Croatian population. Croatian medical journal. 2009;50(4):361–9.CrossRef Pal P, Mihanovic M, Molnar S, Xi H, Sun G, Guha S, Jeran N, Tomljenovic A, Malnar A, Missoni S, et al. Association of tagging single nucleotide polymorphisms on 8 candidate genes in dopaminergic pathway with schizophrenia in Croatian population. Croatian medical journal. 2009;50(4):361–9.CrossRef
11.
go back to reference Ambrosio AM, Kennedy JL, Macciardi F, Coelho I, Soares MJ, Oliveira CR, Pato CN. Lack of association or linkage disequilibrium between schizophrenia and polymorphisms in the 5-HT1Dalpha and 5-HT1Dbeta autoreceptor genes: family-based association study. American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatr Genet. 2004;128B(1):1–5.CrossRef Ambrosio AM, Kennedy JL, Macciardi F, Coelho I, Soares MJ, Oliveira CR, Pato CN. Lack of association or linkage disequilibrium between schizophrenia and polymorphisms in the 5-HT1Dalpha and 5-HT1Dbeta autoreceptor genes: family-based association study. American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatr Genet. 2004;128B(1):1–5.CrossRef
12.
go back to reference Rujescu D, Giegling I, Sato T, Moller HJ. Lack of association between serotonin 5-HT1B receptor gene polymorphism and suicidal behavior. American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2003;116B(1):69–71.CrossRef Rujescu D, Giegling I, Sato T, Moller HJ. Lack of association between serotonin 5-HT1B receptor gene polymorphism and suicidal behavior. American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2003;116B(1):69–71.CrossRef
13.
go back to reference Cordeiro Q, Vallada H. Lack of association between the G681C polimorphism in the 5-HT1D(beta) autoreceptor gene and schizophrenia. Arq Neuropsiquiatr. 2005;63(2B):380–2.CrossRef Cordeiro Q, Vallada H. Lack of association between the G681C polimorphism in the 5-HT1D(beta) autoreceptor gene and schizophrenia. Arq Neuropsiquiatr. 2005;63(2B):380–2.CrossRef
14.
go back to reference Sanders AR, Cao Q, Taylor J, Levin TE, Badner JA, Cravchik A, Comeron JM, Naruya S, Del Rosario A, Salvi DA, et al. Genetic diversity of the human serotonin receptor 1B (HTR1B) gene. Genomics. 2001;72(1):1–14.CrossRef Sanders AR, Cao Q, Taylor J, Levin TE, Badner JA, Cravchik A, Comeron JM, Naruya S, Del Rosario A, Salvi DA, et al. Genetic diversity of the human serotonin receptor 1B (HTR1B) gene. Genomics. 2001;72(1):1–14.CrossRef
15.
go back to reference Gilabert-Juan J, Ivorra JL, Tolosa A, Gratacos M, Costas J, Sanjuan J, Molto MD. Potential involvement of serotonin receptor genes with age of onset and gender in schizophrenia: a preliminary study in a Spanish sample. Psychiatry Res. 2011;186(1):153–4.CrossRef Gilabert-Juan J, Ivorra JL, Tolosa A, Gratacos M, Costas J, Sanjuan J, Molto MD. Potential involvement of serotonin receptor genes with age of onset and gender in schizophrenia: a preliminary study in a Spanish sample. Psychiatry Res. 2011;186(1):153–4.CrossRef
16.
go back to reference Kramvis A, Bukofzer S, Kew MC. Comparison of hepatitis B virus DNA extractions from serum by the QIAamp blood kit, GeneReleaser, and the phenol-chloroform method. J Clin Microbiol. 1996;34(11):2731–3.PubMedPubMedCentral Kramvis A, Bukofzer S, Kew MC. Comparison of hepatitis B virus DNA extractions from serum by the QIAamp blood kit, GeneReleaser, and the phenol-chloroform method. J Clin Microbiol. 1996;34(11):2731–3.PubMedPubMedCentral
17.
go back to reference Zhu F, Yan CX, Wang Q, Zhu YS, Zhao Y, Huang J, Zhang HB, Gao CG, Li SB. An association study between dopamine D1 receptor gene polymorphisms and the risk of schizophrenia. Brain Res. 2011;1420:106–13.CrossRef Zhu F, Yan CX, Wang Q, Zhu YS, Zhao Y, Huang J, Zhang HB, Gao CG, Li SB. An association study between dopamine D1 receptor gene polymorphisms and the risk of schizophrenia. Brain Res. 2011;1420:106–13.CrossRef
18.
go back to reference Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21(2):263–5.CrossRef Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21(2):263–5.CrossRef
19.
go back to reference Duan S, Yin H, Chen W, Xing Q, chen Q, Guo T, Gao J, Li X, Gao R, Liu Z, et al. No association between the serotonin 1B receptor gene and schizophrenia in a case-control and family-based association study. Neurosci Lett. 2005;376(2):93–7.CrossRef Duan S, Yin H, Chen W, Xing Q, chen Q, Guo T, Gao J, Li X, Gao R, Liu Z, et al. No association between the serotonin 1B receptor gene and schizophrenia in a case-control and family-based association study. Neurosci Lett. 2005;376(2):93–7.CrossRef
20.
go back to reference Thakkinstian A, McElduff P, D'Este C, Duffy D, Attia J. A method for meta-analysis of molecular association studies. Stat Med. 2005;24(9):1291–306.CrossRef Thakkinstian A, McElduff P, D'Este C, Duffy D, Attia J. A method for meta-analysis of molecular association studies. Stat Med. 2005;24(9):1291–306.CrossRef
21.
go back to reference Ratnu VS, Emami MR, Bredy TW. Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain. J Neurosci Res. 2017;95(1–2):301–10.CrossRef Ratnu VS, Emami MR, Bredy TW. Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain. J Neurosci Res. 2017;95(1–2):301–10.CrossRef
22.
go back to reference Ochoa S, Usall J, Cobo J, Labad X, Kulkarni J. Gender differences in schizophrenia and first-episode psychosis: a comprehensive literature review. Schizophr Res Treat. 2012;2012:916198. Ochoa S, Usall J, Cobo J, Labad X, Kulkarni J. Gender differences in schizophrenia and first-episode psychosis: a comprehensive literature review. Schizophr Res Treat. 2012;2012:916198.
23.
go back to reference Bryant NL, Buchanan RW, Vladar K, Breier A, Rothman M. Gender differences in temporal lobe structures of patients with schizophrenia: a volumetric MRI study. Am J Psychiatry. 1999;156(4):603–9.PubMed Bryant NL, Buchanan RW, Vladar K, Breier A, Rothman M. Gender differences in temporal lobe structures of patients with schizophrenia: a volumetric MRI study. Am J Psychiatry. 1999;156(4):603–9.PubMed
24.
go back to reference Gobinath AR, Choleris E, Galea LA. Sex, hormones, and genotype interact to influence psychiatric disease, treatment, and behavioral research. J Neurosci Res. 2017;95(1–2):50–64.CrossRef Gobinath AR, Choleris E, Galea LA. Sex, hormones, and genotype interact to influence psychiatric disease, treatment, and behavioral research. J Neurosci Res. 2017;95(1–2):50–64.CrossRef
25.
go back to reference Weiss LA, Abney M, Cook EH Jr, Ober C. Sex-specific genetic architecture of whole blood serotonin levels. Am J Hum Genet. 2005;76(1):33–41.CrossRef Weiss LA, Abney M, Cook EH Jr, Ober C. Sex-specific genetic architecture of whole blood serotonin levels. Am J Hum Genet. 2005;76(1):33–41.CrossRef
26.
go back to reference 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.CrossRef 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.CrossRef
27.
go back to reference Conner TS, Jensen KP, Tennen H, Furneaux HM, Kranzler HR, Covault J. Functional polymorphisms in the serotonin 1B receptor gene (HTR1B) predict self-reported anger and hostility among young men. American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatr Genet. 2010;153B(1):67–78. Conner TS, Jensen KP, Tennen H, Furneaux HM, Kranzler HR, Covault J. Functional polymorphisms in the serotonin 1B receptor gene (HTR1B) predict self-reported anger and hostility among young men. American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatr Genet. 2010;153B(1):67–78.
28.
go back to reference Li R, Ma X, Wang G, Yang J, Wang C. Why sex differences in schizophrenia? Journal of translational neuroscience. 2016;1(1):37–42.PubMedPubMedCentral Li R, Ma X, Wang G, Yang J, Wang C. Why sex differences in schizophrenia? Journal of translational neuroscience. 2016;1(1):37–42.PubMedPubMedCentral
29.
go back to reference Di Giovanni G, Esposito E, Di Matteo V. Role of serotonin in central dopamine dysfunction. CNS neuroscience & therapeutics. 2010;16(3):179–94.CrossRef Di Giovanni G, Esposito E, Di Matteo V. Role of serotonin in central dopamine dysfunction. CNS neuroscience & therapeutics. 2010;16(3):179–94.CrossRef
30.
go back to reference Duan J, Sanders AR, Molen JE, Martinolich L, Mowry BJ, Levinson DF, Crowe RR, Silverman JM, Gejman PV. Polymorphisms in the 5′-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression. Mol Psychiatry. 2003;8(11):901–10.CrossRef Duan J, Sanders AR, Molen JE, Martinolich L, Mowry BJ, Levinson DF, Crowe RR, Silverman JM, Gejman PV. Polymorphisms in the 5′-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression. Mol Psychiatry. 2003;8(11):901–10.CrossRef
31.
go back to reference Jensen KP, Covault J, Conner TS, Tennen H, Kranzler HR, Furneaux HM. A common polymorphism in serotonin receptor 1B mRNA moderates regulation by miR-96 and associates with aggressive human behaviors. Mol Psychiatry. 2009;14(4):381–9.CrossRef Jensen KP, Covault J, Conner TS, Tennen H, Kranzler HR, Furneaux HM. A common polymorphism in serotonin receptor 1B mRNA moderates regulation by miR-96 and associates with aggressive human behaviors. Mol Psychiatry. 2009;14(4):381–9.CrossRef
32.
go back to reference de Bartolomeis A, Buonaguro EF, Iasevoli F. Serotonin-glutamate and serotonin-dopamine reciprocal interactions as putative molecular targets for novel antipsychotic treatments: from receptor heterodimers to postsynaptic scaffolding and effector proteins. Psychopharmacology. 2013;225(1):1–19.CrossRef de Bartolomeis A, Buonaguro EF, Iasevoli F. Serotonin-glutamate and serotonin-dopamine reciprocal interactions as putative molecular targets for novel antipsychotic treatments: from receptor heterodimers to postsynaptic scaffolding and effector proteins. Psychopharmacology. 2013;225(1):1–19.CrossRef
33.
go back to reference Ohi K, Shimada T, Yasuyama T, Uehara T, Kawasaki Y. Variability of 128 schizophrenia-associated gene variants across distinct ethnic populations. Transl Psychiatry. 2017;7(1):e988.CrossRef Ohi K, Shimada T, Yasuyama T, Uehara T, Kawasaki Y. Variability of 128 schizophrenia-associated gene variants across distinct ethnic populations. Transl Psychiatry. 2017;7(1):e988.CrossRef
34.
go back to reference Drago A, Alboni S, Brunello N, De Ronchi D, Serretti A. HTR1B as a risk profile maker in psychiatric disorders: a review through motivation and memory. Eur J Clin Pharmacol. 2010;66(1):5–27.CrossRef Drago A, Alboni S, Brunello N, De Ronchi D, Serretti A. HTR1B as a risk profile maker in psychiatric disorders: a review through motivation and memory. Eur J Clin Pharmacol. 2010;66(1):5–27.CrossRef
Metadata
Title
Polymorphisms in the human serotonin receptor 1B (HTR1B) gene are associated with schizophrenia: a case control study
Authors
Xi Xia
Mei Ding
Jin-feng Xuan
Jia-xin Xing
Hao Pang
Bao-jie Wang
Jun Yao
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Psychiatry / Issue 1/2018
Electronic ISSN: 1471-244X
DOI
https://doi.org/10.1186/s12888-018-1849-x

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