1Eur. J. Pharmacol. 2000 Dec 410: 165-181
PMID11134668
TitlePharmacogenetics and the serotonin system: initial studies and future directions.
AbstractSerotonin (5-hydroxytryptamine, 5-HT) appears to play a role in the pathophysiology of a range of neuropsychiatric disorders, and serotonergic agents are of central importance in neuropharmacology. Genes encoding various components of the 5-HT system are being studied as risk factors in depression, schizophrenia, obsessive-compulsive disorder, aggression, alcoholism, and autism. Recently, pharmacogenetic research has begun to examine possible genetic influences on therapeutic response to drugs affecting the serotonin system. Genes regulating the synthesis (TPH), storage (VMAT2), membrane uptake (HTT), and metabolism (MAOA) of 5-HT, as well as a number of 5-HT receptors (HTR1A, HTR1B, HTR2A, HTR2C, and HTR5A), have been studied and this initial research is reviewed here. After a brief introduction to serotonin neurobiology and a general discussion of appropriate genetic methodology, each of the major 5-HT-related genes and their encoded proteins are reviewed in turn. For each gene, relevant polymorphisms and research on functional variants are discussed; following brief reviews of the disorder or trait association and linkage studies, pharmacogenetic studies performed to date are covered. The critical and manifold roles of the serotonin system, the great abundance of targets within the system, the wide range of serotonergic agents-available and in development-and the promising preliminary results suggest that the serotonin system offers a particularly rich area for pharmacogenetic research.
SCZ Keywordsschizophrenia, schizophrenic
2Schizophr. Res. 2001 Jan 47: 49-58
PMID11163544
TitleLack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia.
AbstractThe affinity of clozapine for 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, and 5-HT1A receptors has been suggested to contribute to various aspects of its complex clinical actions. This study examined the hypothesis that genetic variation in 5-HT1A, 5-HT6, and 5-HT7 receptor genes is involved in the variability observed in response to clozapine. We employed a pharmacogenetic approach in a group (n=185) of schizophrenia patients that have been clinically well characterized for clozapine response. Polymorphisms in the 5-HT6 (HTR6), 5-HT1A (HTR1A) and 5-HT7 (HTR7) receptor genes were genotyped. No evidence for either an allelic or genotypic association of the T-->C 267 HTR6 polymorphism with response to clozapine was found in our sample (allele: chi(2)=0.06, 1 df, P=0.80; genotype: chi(2)=1.21, 2 df, P=0.55). The pro16leu HTR1A polymorphism was not observed in our sample; all individuals genotyped were pro/pro 16 homozygotes. With respect to the pro279leu HTR7 polymorphism, one Caucasian male responder to clozapine was observed to be heterozygous (pro/leu 279 genotype). This individual was clinically similar to the other clozapine responders. Overall, our findings do not support a role for the T-->C 267 polymorphism of the 5-HT6 receptor gene in response to clozapine, although replication is required to confirm this finding.
SCZ Keywordsschizophrenia, schizophrenic
3J. Neuroimmunol. 2003 Aug 141: 155-64
PMID12965267
TitleAutoantibodies against four kinds of neurotransmitter receptors in psychiatric disorders.
AbstractThere is a hypothesis that autoimmune abnormalities in neurotransmitter receptors might cause some psychiatric disorders. Using a sensitive radioligand assay, we detected serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 (CHRM1, 34.4%), mu-opioid receptor (OPRM1, 13.1%), 5-hydroxytryptamine receptor 1A (HTR1A, 7.4%), and dopamine receptor D2 (DRD2, 4.9%) in 122 psychiatric patients. Positive antibodies to CHRM1 were found in 34.1%, 34.9%, 33.3%, and 9.1% of patients with schizophrenic disorders (n=44), mood disorders (n=63), other psychiatric disorders (n=15) and autoimmune diseases (n=33), respectively. All three patients with neuroleptic maliganant syndrome had high activities of autoantibodies to CHRM1, OPRM1, and/or HTR1A. Our data suggest that autoimmunity to neurotransmitter receptors might be associated with the induction of psychiatric symptoms and have some relation to neuroleptic malignant syndrome.
SCZ Keywordsschizophrenia, schizophrenic
4Int. J. Neuropsychopharmacol. 2004 Dec 7: 441-51
PMID15469667
TitleHuman 5-HT1A receptor C(-1019)G polymorphism and psychopathology.
AbstractDysfunction of the serotonin (5-HT1A) receptor (5-HTR1A) has been implicated in mood disorders, anxiety disorders, psychosis and the action of antidepressants. A common C(-1018)G [C(-1019)G] functional polymorphism in the promoter region of the human 5-HT1A receptor gene has been reported, which may be useful in identifying psychopathology associated with altered function of the human 5-HT1A receptor. We studied the relationship of this polymorphism to psychopathology and 5-HT1A binding in prefrontal cortex. The 5-HT1A receptor genotype for the C(-1019)G polymorphism was typed in 696 unrelated psychiatric subjects, 107 unrelated healthy volunteers, and in post-mortem brain samples from 241 cases. 5-HT1A receptor binding was assayed in post-mortem prefrontal cortex using [3H]8-OH-DPAT, and specific binding determined by 1 microM 5-HT. An association of genotype distribution and allele frequency of the 5-HTR1A C(-1019)G locus was observed in schizophrenia (chi2=9.51, d.f.=2, p=0.009; chi2=9.52, d.f.=1, p=0.002; Armitage's trend test: chi2=9.07, d.f.=1, p=0.003), in substance use disorder (chi2=8.41, d.f.=2, p=0.015; chi2=8.35, d.f.=1, p=0.004; Armitage's trend test: chi2=6.27, d.f.=1, p=0.0012), and in panic attack (chi2=6.31, d.f.=2, p=0.043; chi2=6.14, d.f.=1, p=0.013; Armitage's trend test: chi2=6.27, d.f.=1, p=0.012). An association of the 5-HTR1A C(-1019)G locus with schizophrenia, substance use disorder, and panic attack was suggested by our results. In post-mortem brain samples, 5-HT1A receptor binding in prefrontal cortex and suicide were not associated with genotype. The relationship does not appear to be explained by binding differences, although we cannot rule out altered receptor affinity and transduction.
SCZ Keywordsschizophrenia, schizophrenic
5Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Apr 144B: 291-9
PMID17192951
TitleHTR2C and HTR1A gene variants in German and Italian suicide attempters and completers.
AbstractThe serotonin 2C (HTR2C) and 1A (HTR1A) receptors have been involved in suicide-related behaviors. We studied gene variants of both receptors in suicide attempters and completers. The sample was composed of 167 German suicide attempters (affective spectrum n = 107, schizophrenia spectrum n = 35, borderline personality disorder n = 25), 92 Caucasian individuals who committed suicide, 312 German healthy subjects, 152 Italian suicide attempters (major depression n = 68 and bipolar disorder n = 84), and 131 Italian healthy volunteers. HTR2C (SNP: rs547536, rs2192372, rs6318, rs2428707, rs4272555, rs1801412) and HTR1A (SNP: rs1423691, rs878567, and rs6295) variants were analyzed in the German sample. HTR2C rs6318 and HTR1A rs6295 were analyzed in the Italian sample. Haplotype analysis in relation to suicidal behaviors did not reveal any significant association. Single markers and haplotypes were not or only marginally associated with other related features, such as violence of suicide attempt, family history for suicide attempt or State-Trait Anger Expression Inventory (STAXI) and Questionnaire for Measuring Factors of Aggression (FAF) scores. In conclusion, our study does not support the notion that HTR2C and HTR1A gene variants are major contributors to suicide-, anger-, or aggression-related behaviors in our sample.
SCZ Keywordsschizophrenia, schizophrenic
6Pharmacogenomics 2008 Oct 9: 1437-43
PMID18855532
TitleVariants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia.
AbstractAbnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics. We conducted a pharmacogenetic study to evaluate whether variants in dopamine-related genes (DRD1-DRD5, AKT1 and GSK3beta) and serotonin receptor genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR2C, HTR6 and HTR7) can be used to predict the efficacy of risperidone treatment for schizophrenia.
A total of 120 first-episode neuroleptic-naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale.
Among the 30 variants that we examined, two SNPs in DRD2 (-241A>G [rs1799978] and TaqIA [rs1800497]) and two SNPs in AKT1 (AKT1-SNP1 [rs3803300] and AKT1-SNP5 [rs2494732]) were significant predictors of treatment response to risperidone.
These data suggest that the SNPs in DRD2 and AKT1 may influence the treatment response to risperidone in schizophrenia patients.
SCZ Keywordsschizophrenia, schizophrenic
7J Neural Transm (Vienna) 2009 May 116: 607-13
PMID19352591
TitleGenetic variation of serotonin receptor function affects prepulse inhibition of the startle.
AbstractPrepulse inhibition (PPI) is the attenuation of the startle response towards an instantaneous and intense stimulus when preceded by a weaker non-startling stimulus. Deficits in this sensorimotor gating process have been associated with the pathophysiology of schizophrenia and other psychiatric disorders. Among the neurotransmitters involved in PPI modulation, serotonin (5-HT) has so far received comparably little attention. While a recent pharmacological study suggests an important role of different 5-HT receptor (5-HTR) subtypes in PPI modulation, the mechanisms by which 5-HTR impact on PPI remain to be further elucidated. Therefore, we employed a molecular genetic approach in order to examine whether PPI is associated with two functional 5-HTR gene polymorphisms, 5-HTR1A C-1019G and 5-HTR2A T102C. In a sample of 81 healthy volunteers, we found no significant main effects of the polymorphisms, but a significant interaction effect on PPI at short (50 ms) and mid-long (150 ms) pulse-prepulse intervals. The presence of the 5-HTR2A T allele (reported to result in higher 5-HTR2A expression) led to attenuated PPI only in the absence of the 5-HTR1A G allele (reported to result in reduced 5-HTR1A autoreceptor expression). Our results may indicate that a higher 5-HTR2A expression together with a reduced 5-HTR1A autoreceptor expression and consequently, elevated firing rates of serotonergic neurons results in elevated 5-HTR2A activation by serotonin which could potently attenuate PPI. While further research into the molecular mechanisms underlying this interaction is needed, our results underscore the role of 5-HTR in PPI modulation and further implicate the 5-HTR1A G-1019C and the 5-HTR2A T102C polymorphisms in the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
8Neuropharmacology 2010 Feb 58: 452-6
PMID19747927
TitleSerotonin 1A receptor gene is associated with Japanese methamphetamine-induced psychosis patients.
AbstractSeveral investigations have reported associations the serotonin 1A (5-HT1A) receptor to schizophrenia and psychotic disorders, making 5-HT1A receptor gene (HTR1A) an adequate candidate gene for the pathophysiology of schizophrenia and methamphetamine (METH)-induced psychosis. Huang and colleagues reported that rs6295 in HTR1A was associated with schizophrenia. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. It may indicate that METH-induced psychosis and schizophrenia have common susceptibility genes. In support of this hypothesis, we reported that the V-act murine thymoma viral oncogene homologue 1 (AKT1) gene was associated with METH-induced psychosis and schizophrenia in the Japanese population. Furthermore, we conducted an analysis of the association of HTR1A with METH-induced psychosis.
Using one functional SNP (rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients.
Rs878567 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this significance remained after Bonferroni correction. In addition, we detected an association between rs6295 and rs878567 in HTR1A and METH-induced psychosis patients in the haplotype-wise analysis. Although we detected an association between rs6295 and METH-induced psychosis patients, this significance disappeared after Bonferroni correction.
HTR1A may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population. However, because we did not perform a mutation scan of HTR1A, a replication study using a larger sample may be required for conclusive results.
SCZ Keywordsschizophrenia, schizophrenic
9Behav. Genet. 2011 Sep 41: 709-15
PMID21399903
TitleEffect of serotonin-related gene polymorphisms on pathogenesis and treatment response in Korean schizophrenic patients.
AbstractSerotonin has been implicated in the pathophysiology of several psychiatric disorders including schizophrenia. Serotonergic system-related genes may be good candidates in investigating the genetic basis of schizophrenia. We aimed to investigate the associations of HTR1A C-1019G, HTR2A-1438A/G, TPH1 218A/C, and TPH2-703G/T variants with schizophrenia. A total of 202 patients with schizophrenia and 165 normal controls were genotyped for HTR1A C-1019G, HTR2A-1438A/G, TPH1 218A/C, and TPH2-703G/T single nucleotide polymorphisms (SNPs). In order to assess the severity of a patient's psychiatric symptoms, the brief psychiatric rating scale (BPRS), the positive and negative symptom scale (PANSS), and the Calgary depression scale for schizophrenia (CDSS) were administered. Genotype and allele frequencies were compared between groups via ?(2) statistics. Associations between the genotypes of candidate SNPs with the severity of symptoms were examined with ANOVA by comparing the mean scores of BPRS, PANSS, and CDSS according to genotype. No significant differences in the genotype distributions and allele frequencies of four SNPs were found between patients with schizophrenia and normal controls. There was a trend towards association of HTR1A C-1019G polymorphism with negative symptom. Negative symptom score of PANSS was lower in the patients with CC genotype than in the G allele carriers. These results suggested that C allele might be associated with lesser negative symptom. More studies are needed to confirm these findings. In the future, we plan to study the associations between schizophrenia and other genetic polymorphisms.
SCZ Keywordsschizophrenia, schizophrenic
10Behav. Genet. 2011 Sep 41: 709-15
PMID21399903
TitleEffect of serotonin-related gene polymorphisms on pathogenesis and treatment response in Korean schizophrenic patients.
AbstractSerotonin has been implicated in the pathophysiology of several psychiatric disorders including schizophrenia. Serotonergic system-related genes may be good candidates in investigating the genetic basis of schizophrenia. We aimed to investigate the associations of HTR1A C-1019G, HTR2A-1438A/G, TPH1 218A/C, and TPH2-703G/T variants with schizophrenia. A total of 202 patients with schizophrenia and 165 normal controls were genotyped for HTR1A C-1019G, HTR2A-1438A/G, TPH1 218A/C, and TPH2-703G/T single nucleotide polymorphisms (SNPs). In order to assess the severity of a patient's psychiatric symptoms, the brief psychiatric rating scale (BPRS), the positive and negative symptom scale (PANSS), and the Calgary depression scale for schizophrenia (CDSS) were administered. Genotype and allele frequencies were compared between groups via ?(2) statistics. Associations between the genotypes of candidate SNPs with the severity of symptoms were examined with ANOVA by comparing the mean scores of BPRS, PANSS, and CDSS according to genotype. No significant differences in the genotype distributions and allele frequencies of four SNPs were found between patients with schizophrenia and normal controls. There was a trend towards association of HTR1A C-1019G polymorphism with negative symptom. Negative symptom score of PANSS was lower in the patients with CC genotype than in the G allele carriers. These results suggested that C allele might be associated with lesser negative symptom. More studies are needed to confirm these findings. In the future, we plan to study the associations between schizophrenia and other genetic polymorphisms.
SCZ Keywordsschizophrenia, schizophrenic
11Psychiatry Res 2011 Jan 185: 20-6
PMID20594600
TitleSerotonin 1A receptor gene, schizophrenia and bipolar disorder: an association study and meta-analysis.
AbstractSeveral investigations have reported associations between serotonin 1A (5-HT1A) receptor and major psychiatric disorders, such as schizophrenia and bipolar disorder (BP), making the 5-HT1A receptor gene (HTR1A) a good candidate gene for the pathophysiology of schizophrenia and BP. To evaluate the association between HTR1A and schizophrenia and BP, we conducted a case-control study of Japanese population samples with two single- nucleotide polymorphisms (SNPs), including rs6295 (C-1019G) in HTR1A. In addition, we conducted a meta-analysis of rs6295, which has been examined in other studies. Using one functional single- nucleotide polymorphism (SNP; rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (857 schizophrenic patients, 1028 BP patients and 1810 controls) in the Japanese population. Two association studies for schizophrenia and three association studies for BP, including this study, met our criteria for the meta-analysis of rs6295. We found an association between HTR1A and Japanese BP in a haplotype-wise analysis, the significance of which remained after Bonferroni correction. In addition, we detected an association between rs6295 and BP in the meta-analysis (fixed model: P(Z)=0.000400). However, we did not detect an association between HTR1A and schizophrenia in the allele/genotype-wise, haplotype-wise or meta-analysis. HTR1A may play an important role in the pathophysiology of BP, but not schizophrenia in the Japanese population. In the meta-analysis, rs6295 in HTR1A was associated with BP patients.
SCZ Keywordsschizophrenia, schizophrenic
12Psychiatry Res 2011 Jan 185: 20-6
PMID20594600
TitleSerotonin 1A receptor gene, schizophrenia and bipolar disorder: an association study and meta-analysis.
AbstractSeveral investigations have reported associations between serotonin 1A (5-HT1A) receptor and major psychiatric disorders, such as schizophrenia and bipolar disorder (BP), making the 5-HT1A receptor gene (HTR1A) a good candidate gene for the pathophysiology of schizophrenia and BP. To evaluate the association between HTR1A and schizophrenia and BP, we conducted a case-control study of Japanese population samples with two single- nucleotide polymorphisms (SNPs), including rs6295 (C-1019G) in HTR1A. In addition, we conducted a meta-analysis of rs6295, which has been examined in other studies. Using one functional single- nucleotide polymorphism (SNP; rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (857 schizophrenic patients, 1028 BP patients and 1810 controls) in the Japanese population. Two association studies for schizophrenia and three association studies for BP, including this study, met our criteria for the meta-analysis of rs6295. We found an association between HTR1A and Japanese BP in a haplotype-wise analysis, the significance of which remained after Bonferroni correction. In addition, we detected an association between rs6295 and BP in the meta-analysis (fixed model: P(Z)=0.000400). However, we did not detect an association between HTR1A and schizophrenia in the allele/genotype-wise, haplotype-wise or meta-analysis. HTR1A may play an important role in the pathophysiology of BP, but not schizophrenia in the Japanese population. In the meta-analysis, rs6295 in HTR1A was associated with BP patients.
SCZ Keywordsschizophrenia, schizophrenic
13Genes Brain Behav. 2013 Feb 12: 133-9
PMID23036158
TitleThe combined effects of the 5- HTTLPR and HTR1A rs6295 polymorphisms modulate decision making in schizophrenia patients.
AbstractDecision making ability has been reported to be impaired in schizophrenia patients, but no research has examined the genetic bases of this impairment. This study investigated how decision making was affected by the genetic variants in the serotonin transporter gene (triallelic 5- HTTLPR) and serotonin receptor 1A gene (rs6295) and their interaction in 465 schizophrenia patients and 448 healthy controls. The Iowa Gambling Task (IGT) was used to evaluate decision making under ambiguity (the first 40 trials) and decision making under risk (the last 60 trials). Results showed that, among the patients, the main effects of 5- HTTLPR (F(2) (,16) = 6.54, P = 0.002) and HTR1A rs6295 (F(2) (,16) = 3.87, P = 0.021) polymorphisms and their interaction effect (F(4) (,16) = 3.32, P = 0.005) were significant for the first 40 trials, with the GG genotype of HTR1A rs6295, the L'L' genotype of 5- HTTLPR and the GG-L'L' combination showing poorer IGT performance than their counterparts. Results for the healthy controls showed a similar pattern but did not reach statistical significance. No significant effects were found for the last 60 trials. These results are discussed in terms of their implications for our understanding of the genetic mechanisms of decision making in schizophrenia patients as well as healthy adults.
SCZ Keywordsschizophrenia, schizophrenic
14J. Mol. Neurosci. 2013 Mar 49: 625-31
PMID23192369
TitleRelationship between genetic polymorphisms in the HTR1A gene and paranoid schizophrenia in a northern Han Chinese population.
AbstractThe hypothesis for the etiology of schizophrenia involves various neurotransmitters, including 5-HT. Metabolic disorder of 5-HT is an important underlying neurobiochemical cause leading to the development of mental illness. Abnormality in the receptors involved in 5-HT synthesis and metabolism may affect the functioning of 5-HT in the central nervous system. There are seven types of 5-HT receptor families, with a total of 15 corresponding subtypes. HTR1A is the most abundantly expressed 5-HT receptor subtype in the mammalian brain. SNPs in HTR1A enhance or weaken the functioning of 5-HT by affecting HTR1A expression levels or ligand-binding activity, thereby placing HTR1A in an important role in the study of diseases of the nervous system. This study employed DNA sequencing to investigate HTR1A fragment lengths, including complete exons as well as 5' FR and 3' FR segments, for a total of 2,718 bp. Seven SNP loci (ss212928868, rs6295, rs6294, ss218178047, rs34118353, rs6449693, and rs878567) were found in 182 healthy volunteers and 161 patients. Among them, two SNP loci had not been reported in the National Center for Biotechnology Information (NCBI) database, promoter locus ss212928868 and exon locus ss218178047, which now have been approved by the NCBI database and assigned rs numbers, rs113195492 and rs112846276, respectively. ss212928868 and rs6294 were statistically different between control and paranoid schizophrenic women (P?HTR1A were different between paranoid schizophrenic and control group women. Although such differences were lost after statistical correction, studies with larger sample sizes have not been conducted. Combined with the newly discovered loci, these findings can point out possible directions for future investigations in different populations.
SCZ Keywordsschizophrenia, schizophrenic
15J. Mol. Neurosci. 2013 Mar 49: 625-31
PMID23192369
TitleRelationship between genetic polymorphisms in the HTR1A gene and paranoid schizophrenia in a northern Han Chinese population.
AbstractThe hypothesis for the etiology of schizophrenia involves various neurotransmitters, including 5-HT. Metabolic disorder of 5-HT is an important underlying neurobiochemical cause leading to the development of mental illness. Abnormality in the receptors involved in 5-HT synthesis and metabolism may affect the functioning of 5-HT in the central nervous system. There are seven types of 5-HT receptor families, with a total of 15 corresponding subtypes. HTR1A is the most abundantly expressed 5-HT receptor subtype in the mammalian brain. SNPs in HTR1A enhance or weaken the functioning of 5-HT by affecting HTR1A expression levels or ligand-binding activity, thereby placing HTR1A in an important role in the study of diseases of the nervous system. This study employed DNA sequencing to investigate HTR1A fragment lengths, including complete exons as well as 5' FR and 3' FR segments, for a total of 2,718 bp. Seven SNP loci (ss212928868, rs6295, rs6294, ss218178047, rs34118353, rs6449693, and rs878567) were found in 182 healthy volunteers and 161 patients. Among them, two SNP loci had not been reported in the National Center for Biotechnology Information (NCBI) database, promoter locus ss212928868 and exon locus ss218178047, which now have been approved by the NCBI database and assigned rs numbers, rs113195492 and rs112846276, respectively. ss212928868 and rs6294 were statistically different between control and paranoid schizophrenic women (P?HTR1A were different between paranoid schizophrenic and control group women. Although such differences were lost after statistical correction, studies with larger sample sizes have not been conducted. Combined with the newly discovered loci, these findings can point out possible directions for future investigations in different populations.
SCZ Keywordsschizophrenia, schizophrenic
16Front Behav Neurosci 2014 -1 8: 388
PMID25414651
TitleAddiction and reward-related genes show altered expression in the postpartum nucleus accumbens.
AbstractMotherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, HTR1A, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis (WGCNA) identified possible networks for transcription factors, including Nr1d1, Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions.
SCZ Keywordsschizophrenia, schizophrenic
17Int. J. Neuropsychopharmacol. 2014 Apr 17: 645-9
PMID24331356
TitleMethylation at a transcription factor-binding site on the 5-HT1A receptor gene correlates with negative symptom treatment response in first episode schizophrenia.
AbstractIndividual variability and inadequate response of negative symptoms are major limitations of antipsychotic treatment in schizophrenia. A functional polymorphism, rs6295, in the 5-HT1A-receptor gene (HTR1A) contributes to this variability in negative symptom response. The DNA sequence containing rs6295 is rich in cytosine methylation (CpG) sites; CpG methylation is an epigenetic factor that, like rs6295, can modify transcriptional control. To investigate whether DNA methylation influences response to antipsychotic treatment, we determined methylation at CpG sites close to rs6295 in DNA from 82 Chinese subjects with a first psychotic episode. Methylation of one CpG site within a recognition sequence for HES transcriptional repressors was found to correlate with changes in total PANSS score (p = 0.006) and negative factor sub-score (p < 0.001) following 10 wk initial antipsychotic treatment, as well as with baseline negative factor score (p = 0.019); the effect on symptom change remained after correction for this baseline score. An effect of rs6295 on negative symptom response was not seen in this sample, which may not have provided sufficient power for the pharmacogenetic association. These preliminary results indicate that epigenetic modification of transcriptional regulation by specific cytosine methylation may modulate HTR1A expression, resulting in effects on emotional dysfunction and negative symptom response to antipsychotic treatment.
SCZ Keywordsschizophrenia, schizophrenic
18J Psychiatr Res 2015 Jan 60: 1-13
PMID25287955
TitleSpecific and common genes implicated across major mental disorders: a review of meta-analysis studies.
AbstractMajor efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress.
SCZ Keywordsschizophrenia, schizophrenic
19Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Dec 168: 749-55
PMID26408209
TitleCommon variants of HTR1A and SLC6A4 confer the increasing risk of Schizophrenia susceptibility: A population-based association and epistasis analysis.
Abstractschizophrenia (SZ) is a complex psychiatric disorder strongly influenced by genetic variants, some of which are associated with mood disorders. The neurotransmitter 5-hydoxytryptamine (5-HT) and its related biochemical factors have been shown to play a significant role in maintaining mood balance. Recent studies evaluating the association between SZ and genetic polymorphisms in a serotonin transporter (encoded by SLC6A4) and serotonin receptor 1A (encoded by HTR1A) show conflicting results. In this study, we performed a case-control association analysis using 4,000 individuals with Chinese-Han ancestry. Of these participants, 1,000 were SZ cases and 3,000 were healthy controls. Thirty-six single nucleotide polymorphisms (SNPs) located in SLC6A4 and HTR1A were genotyped in our 4,000 study samples. Of those, 33 polymorphic SNPs with a minor allele frequency >0.05 were used for further analysis. We found that rs878567 in HTR1A (asymptotic P-value?=?3.8910(-4) , corrected P-value?=?0.0106) was significantly associated with SZ. Further haplotype-based analyses revealed that a two-SNP haplotype, rs2054847-rs140701 (TG) in gene SLC6A4, was significantly associated with SZ (P-value?=?1.6310(-4) and corrected P-value?=?0.002799). We did not identify any significant epistatic interactions between the two genes. Our findings provide supportive evidence that genetic polymorphisms in SLC6A4 and HTR1A may influence the risk of SZ in Han Chinese individuals. 2015 Wiley Periodicals, Inc.
SCZ Keywordsschizophrenia, schizophrenic
20J Clin Psychopharmacol 2015 Jun 35: 220-7
PMID25822479
TitleHTR1A Gene Polymorphisms and 5-HT1A Receptor Partial Agonist Antipsychotics Efficacy in Schizophrenia.
AbstractIndividual differences in serotonin 1A (5-HT1A) receptor may result in variable response to antipsychotics with 5-HT1A receptor partial agonism. We investigated the relationship between 5-HT1A receptor gene (HTR1A) single nucleotide polymorphisms (SNPs) and efficacy of antipsychotics with 5-HT1A receptor partial agonism in Japanese patients with schizophrenia. Perospirone or aripiprazole was administered to 100 patients with schizophrenia in a randomized controlled study. Candidate SNPs were rs6295 (which affects HTR1A expression and function), rs1364043, rs878567, and rs10042486. Efficacy at week 12 of treatment was evaluated using the Positive and Negative Syndrome Scale (PANSS) 5-factor subscales (excitement/hostility, depression/anxiety, cognition, positive, and negative). Rs1364043 T allele was correlated with the percent change in the PANSS 5-factor negative score (P < 0.01). Haplotype analysis showed that the rs10042486-rs6295-rs1364043 T-C-G haplotype was correlated with worse negative score improvement (haplotype frequency, 0.675; P = 0.014), and the relatively rare T-G-T haplotype correlated with better efficacy (haplotype frequency, 0.05; P = 0.031). This is the first study to show that rs10042486-rs6295-rs1364043 HTR1A variants may be correlated with the improvement of the PANSS 5-factor negative score during treatment with 5-HT1A partial agonist antipsychotics. Studies with larger sample sizes and in different ethnic groups are warranted.
SCZ Keywordsschizophrenia, schizophrenic
21Int. J. Neuropsychopharmacol. 2016 May 19: -1
PMID26568455
TitleHTR1A Polymorphisms and Clinical Efficacy of Antipsychotic Drug Treatment in Schizophrenia: A Meta-Analysis.
AbstractThis meta-analysis was conducted to evaluate whether HTR1A gene polymorphisms impact the efficacy of antipsychotic drugs in patients with schizophrenia.
Candidate gene studies that were published in English up to August 6, 2015 were identified by a literature search of PubMed, Web of Science, and Google scholar. Data were pooled from individual clinical trials considering overall symptoms, positive symptoms and negative symptoms, and standard mean differences were calculated by applying a random-effects model.
The present meta-analysis included a total of 1281 patients from 10 studies. Three polymorphisms of HTR1A (rs6295, rs878567, and rs1423691) were selected for the analysis. In the pooled data from all studies, none of these HTR1A polymorphisms correlated significantly with either overall symptoms or positive symptoms. However, C allele carriers of the rs6295 polymorphism showed a significantly greater negative symptoms improvement than G allele carriers (P=.04, standardized mean difference =-0.14, 95?CI = 0.01 to 0.28).
The results of our present analysis indicate that the HTR1A rs6295 polymorphism may impact negative symptoms improvement but not on either overall symptoms or positive symptoms improvement. However, this meta-analysis was based on a small number of studies and patients, and the effect size on negative symptoms was small. Given this limitation, the results should be confirmed by further investigations.
SCZ Keywordsschizophrenia, schizophrenic
22Brain Behav. Immun. 2016 Jan 51: 119-30
PMID26254231
TitleDisruptions of sensorimotor gating, cytokines, glycemia, monoamines, and genes in both sexes of rats reared in social isolation can be ameliorated by oral chronic quetiapine administration.
AbstractThe pathogenesis of schizophrenia in patients with metabolic abnormalities remains unclear. Our previous study demonstrated that isolation rearing (IR) induced longitudinal concomitant changes of pro-inflammatory cytokine (pro-CK) levels and metabolic abnormalities with a developmental origin. However, the general consensus, believes that these abnormalities are caused by antipsychotic treatment in schizophrenic patients. The IR paradigm presents with face, construct, and predictive validity for schizophrenia. Therefore, we employed IR rats of both sexes to examine whether chronic quetiapine (QTP, a second-generation antipsychotic medication) treatment induces disruptions of metabolism (body weight, blood pressure, and the glycemic and lipid profiles) or cytokines [interleukin (IL)-1 beta, IL-6, IL-10, interferon-gamma, and tumor necrosis factor (TNF)-alpha], and further, whether it reverses deficits of behaviors [locomotor activity and prepulse inhibition (PPI)] and the expression of monoamines (dopamine and serotonin) and related genes (HTR1A, Htr2a, Htr3a, Drd1a, and Gabbr2). IR induced higher levels of pro-CK, dysglycemia, blood pressure, locomotor activity, and impaired PPI, simultaneously destabilizing cortico-striatal monoamines and relevant genes in both sexes, while QTP demonstrated dose-dependent reversal of these changes, suggesting that QTP might reduce the pro-CKs to regulate these abnormalities. Our data implied that antipsychotics may not be the solitary factor causing metabolic problems in schizophrenia and suggested that inflammatory changes may play a vital role in the developmental pathophysiology of schizophrenia and related metabolic abnormalities.
SCZ Keywordsschizophrenia, schizophrenic
23Brain Behav. Immun. 2016 Jan 51: 119-30
PMID26254231
TitleDisruptions of sensorimotor gating, cytokines, glycemia, monoamines, and genes in both sexes of rats reared in social isolation can be ameliorated by oral chronic quetiapine administration.
AbstractThe pathogenesis of schizophrenia in patients with metabolic abnormalities remains unclear. Our previous study demonstrated that isolation rearing (IR) induced longitudinal concomitant changes of pro-inflammatory cytokine (pro-CK) levels and metabolic abnormalities with a developmental origin. However, the general consensus, believes that these abnormalities are caused by antipsychotic treatment in schizophrenic patients. The IR paradigm presents with face, construct, and predictive validity for schizophrenia. Therefore, we employed IR rats of both sexes to examine whether chronic quetiapine (QTP, a second-generation antipsychotic medication) treatment induces disruptions of metabolism (body weight, blood pressure, and the glycemic and lipid profiles) or cytokines [interleukin (IL)-1 beta, IL-6, IL-10, interferon-gamma, and tumor necrosis factor (TNF)-alpha], and further, whether it reverses deficits of behaviors [locomotor activity and prepulse inhibition (PPI)] and the expression of monoamines (dopamine and serotonin) and related genes (HTR1A, Htr2a, Htr3a, Drd1a, and Gabbr2). IR induced higher levels of pro-CK, dysglycemia, blood pressure, locomotor activity, and impaired PPI, simultaneously destabilizing cortico-striatal monoamines and relevant genes in both sexes, while QTP demonstrated dose-dependent reversal of these changes, suggesting that QTP might reduce the pro-CKs to regulate these abnormalities. Our data implied that antipsychotics may not be the solitary factor causing metabolic problems in schizophrenia and suggested that inflammatory changes may play a vital role in the developmental pathophysiology of schizophrenia and related metabolic abnormalities.
SCZ Keywordsschizophrenia, schizophrenic