1Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Apr 144B: 341-3
PMID17034020
TitleNo association between ADRA2A polymorphisms and schizophrenia.
AbstractThere is evidence to suggest that the alpha(2A)-adrenergic receptor may be involved in schizophrenia. With attention directed at the upstream regulatory region of the gene which codes for this receptor (ADRA2A), we proposed that single nucleotide polymorphisms (SNPs) within this region influences susceptibility to schizophrenia by altering the expression of this receptor. We opted to test for an influence on susceptibility by association study using 112 schizophrenic/schizoaffective disorder patients and 159 controls. The region of interest was screened for SNPs using a combination of bioinformatic searches and sequencing. A total of nine SNPs were discovered, of which four (-5972-G/A, -2211-A/T, -1291-C/G and -261-G/A) were genotyped in the entire clinical sample. No associations were evident, suggesting no influence for these SNPs in susceptibility to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
2Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Apr 144B: 341-3
PMID17034020
TitleNo association between ADRA2A polymorphisms and schizophrenia.
AbstractThere is evidence to suggest that the alpha(2A)-adrenergic receptor may be involved in schizophrenia. With attention directed at the upstream regulatory region of the gene which codes for this receptor (ADRA2A), we proposed that single nucleotide polymorphisms (SNPs) within this region influences susceptibility to schizophrenia by altering the expression of this receptor. We opted to test for an influence on susceptibility by association study using 112 schizophrenic/schizoaffective disorder patients and 159 controls. The region of interest was screened for SNPs using a combination of bioinformatic searches and sequencing. A total of nine SNPs were discovered, of which four (-5972-G/A, -2211-A/T, -1291-C/G and -261-G/A) were genotyped in the entire clinical sample. No associations were evident, suggesting no influence for these SNPs in susceptibility to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
3Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Apr 33: 499-502
PMID19439247
TitleAssociation analysis between the C-1291G polymorphism in the promoter region of the adrenergic alpha2A receptor gene and polydipsia in schizophrenia.
AbstractSeveral lines of studies have shown the existence of an important inhibitory mechanism for the control of water intake involving adrenergic alpha2A receptors (ADRA2A). A human study using patients with schizophrenia demonstrated an exacerbation of polydipsia by the administration of clonidine, an ADRA2A-agonist, and a relief of polydipsia by mianserin, an ADRA2A-antagonist, suggesting the involvement of the central adrenergic system in the drinking behavior of patients with schizophrenia. Based on these findings we examined a possible association between the C-1291G polymorphism in the promoter region of the ADRA2A gene and polydipsia in schizophrenia using a Japanese case-control sample. Our sample includes 348 patients with schizophrenia (DSM-IV) (84 with polydipsia and 264 without polydipsia). No significant association between the ADRA2A C-1291G polymorphism and polydipsia was found. Our result suggests that the ADRA2A C-1291G polymorphism may not confer susceptibility to polydipsia in schizophrenia in our sample. Further studies with larger samples are warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
4J Clin Psychopharmacol 2010 Dec 30: 667-71
PMID21105277
TitleAssociation between the 1291-C/G polymorphism in the adrenergic ?-2a receptor and the metabolic syndrome.
AbstractThe prevalence of the metabolic syndrome is increased in patients with schizophrenia compared with the general population. The strong interindividual differences in susceptibility to developing the metabolic syndrome suggests that the genetic makeup is a modulating factor. Part of the genetic puzzle can possibly be explained by variations in the gene coding for the adrenergic ?-2a receptor (ADRA2A) because this receptor plays an important role in lipolysis. Three studies have found an association between the ?-2a 1291-C/G polymorphism and antipsychotic induced weight gain, with conflicting results between whites and Asians. No studies have been published investigating the association between the 1291-C/G polymorphism and the metabolic syndrome. The primary objective of this cross-sectional study was to investigate the association between the ADRA2A 1291-C/G polymorphism and the metabolic syndrome in 470 patients using antipsychotic drugs. There was no significant association between carriership of the variant 1291-G allele and prevalence of the metabolic syndrome (odds ratio, 0.73; 95% confidence interval, 0.49-1.15). Exploratory analysis showed an association between carriership of the variant 1291-G allele and a reduced prevalence of the metabolic syndrome in patients not currently using antipsychotics (odds ratio, 0.05; 95% confidence interval, 0.003-0.97; P = 0.048). In conclusion, this study shows that the ADRA2A 1291-C/G polymorphism does not seem to be a strong predictor for long-term occurrence of the metabolic syndrome in antipsychotic using patients. Studies investigating this association using a prospective, or retrospective, design, as well as studies investigating this association in a nonpsychiatric population, are warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
5Hum Psychopharmacol 2011 Aug 26: 386-91
PMID21823169
TitleGenetic interactions in the adrenergic system genes: analysis of antipsychotic-induced weight gain.
AbstractAtypical antipsychotics (AP) have high affinity for many neurotransmitter receptors. Among these receptors, APs are antagonist at ?-adrenergic and ?-adrenergic receptors, and this pharmacological property has been postulated to be involved in the mechanism of action of these drugs with respect to both clinical response and adverse effects.
We tested the hypotheses that AP-induced weight gain is associated with genetic variation in adrenergic receptors and pathway enzymes. We analyzed nine genetic polymorphisms across seven adrenergic genes (ADRA1A, ADRA2A, ADRA2C, ADRB3, DBH, MAOA and COMT).
One hundred thirty-nine patients with schizophrenia were prospectively assessed for AP-induced weight gain. The HelixTree software (Golden Helix, Bozeman, MT, USA) was employed to detect differences in genotypic distribution between weight gainer and non-weight gainer groups. Furthermore, for the dopamine ?-hydroxylase haplotype, we were able to obtain both the molecular and the statistical phases, analyzing the phenotype considering both phases.
Weight gain was not associated with any adrenergic gene.
Our results suggest that genetic polymorphisms in the adrenergic system may not play a major role in AP-induced weight gain; however, adrenergic 2A receptor gene that produced previously the most consistent associations with this phenotype showed a significant interaction with the monoamine oxidase A in weight gainers.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
6Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Jan 36: 205-10
PMID22037178
TitleAssociation of the ADRA1A gene and the severity of metabolic abnormalities in patients with schizophrenia.
AbstractPatients with schizophrenia have a higher risk of developing metabolic abnormalities and their associated diseases. Some studies found that the accumulative number of metabolic syndrome components was associated with the severity of metabolic abnormalities. The purpose of this study was to examine the roles of the ADRA1A, ADRA2A, ADRB3, and 5HT2A genes in the risk of having more severe metabolic abnormalities among patients with schizophrenia. We studied a sample of 232 chronic inpatients with schizophrenia (120 males and 112 females) to explore the associations between the four candidate genes and the severity of metabolic syndrome by accumulative number of the components. Four single nucleotide polymorphisms in the candidate genes were genotyped, including the Arg347Cys in ADRA1A, the C1291G in ADRA2A, the Try64Arg in ADRB3, and the T102C in 5HT2A. An association between the accumulative number of metabolic syndrome components and the ADRA1A gene was found after adjusting age, sex, and other related variables (p-value=0.036). Presence of the Arg347 allele in the ADRA1A gene is a risk factor for having more severe metabolic abnormalities. These findings suggest a medical attention of closely monitoring metabolic risks for schizophrenia patients with high-risk genotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
7Neuro Endocrinol. Lett. 2013 -1 34: 792-7
PMID24522021
TitleInteractive effect of MTHFR and ADRA2A gene polymorphisms on pathogenesis of schizophrenia.
AbstractIncreasing evidences support the importance of epigenetic control in schizophrenia pathogenesis. One of the enzymes involved in DNA methylation process through homocysteine metabolism is methylenetetrahydrofolate reductase (MTHFR). The most extensively studied variant in the MTHFR gene is the C677T polymorphism, resulting in reduced enzyme activity and elevated homocysteine level.
In sample of 192 schizophrenics and 213 healthy controls an increasing risk of schizophrenia associated with MTHFR 677 CT+TT genotype was found (OR=1.6, p=0.021). Association was also evaluated by considering the C677T polymorphism as an interaction with COMT Val158Met and ADRA2A C-1291G polymorphisms previously associated with schizophrenia risk using a logistic regression analysis.
Previous studies of MTHFR*COMT (C677T*Val158Met) interaction in relation to schizophrenia resulted in inconsistent results. In our sample this interaction did not significantly differ between schizophrenics and control subjects. On the other hand analysis of MTHFR*ADRA2A (C677T*C-1291G) interaction revealed significant association between ADRA2A CC+CG genotype in the MTHFR TC+TT carriers (p=0.008).
Our results support role of noradrenergic functions as well as previously proposed role of epigenetic control in the pathogenesis of schizophrenia. Further relevant studies including larger sample size and more markers are needed to prove our results.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
8Neuro Endocrinol. Lett. 2013 -1 34: 792-7
PMID24522021
TitleInteractive effect of MTHFR and ADRA2A gene polymorphisms on pathogenesis of schizophrenia.
AbstractIncreasing evidences support the importance of epigenetic control in schizophrenia pathogenesis. One of the enzymes involved in DNA methylation process through homocysteine metabolism is methylenetetrahydrofolate reductase (MTHFR). The most extensively studied variant in the MTHFR gene is the C677T polymorphism, resulting in reduced enzyme activity and elevated homocysteine level.
In sample of 192 schizophrenics and 213 healthy controls an increasing risk of schizophrenia associated with MTHFR 677 CT+TT genotype was found (OR=1.6, p=0.021). Association was also evaluated by considering the C677T polymorphism as an interaction with COMT Val158Met and ADRA2A C-1291G polymorphisms previously associated with schizophrenia risk using a logistic regression analysis.
Previous studies of MTHFR*COMT (C677T*Val158Met) interaction in relation to schizophrenia resulted in inconsistent results. In our sample this interaction did not significantly differ between schizophrenics and control subjects. On the other hand analysis of MTHFR*ADRA2A (C677T*C-1291G) interaction revealed significant association between ADRA2A CC+CG genotype in the MTHFR TC+TT carriers (p=0.008).
Our results support role of noradrenergic functions as well as previously proposed role of epigenetic control in the pathogenesis of schizophrenia. Further relevant studies including larger sample size and more markers are needed to prove our results.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
9Psychiatry Res 2013 Jan 205: 7-12
PMID22940547
TitlePreliminary evidence for association between schizophrenia and polymorphisms in the regulatory Regions of the ADRA2A, DRD3 and SNAP-25 Genes.
AbstractThe results of linkage and candidate gene association studies have led to a range of hypotheses about the pathogenesis of schizophrenia. We limited our study to polymorphisms in candidate genes involved in dopaminergic and noradrenergic systems, and in the 25KDa synaptosomal-associated protein (SNAP-25) gene that is related to neurotransmitter exocytosis. Eight single nucleotide polymorphisms (SNPs) in regulating or coding regions of genes for the alpha-2A adrenergic receptor (ADRA2A), dopamine receptors D1 and D3 (DRD1 and DRD3), dopamine ?-hydroxylase (DBH) and SNAP-25 were genotyped in male patients with schizophrenia (n=192) and in healthy controls (n=213). These polymorphisms were previously associated with schizophrenia. The allelic association between schizophrenia and ADRA2A rs1800544 polymorphism, SNAP-25 rs1503112 polymorphism, and DRD3 rs6280 polymorphism was found in our study. However, only observations for rs1503112 survived correction for multiple testing. Association was also evaluated by considering the polymorphisms as interactions; in this case, a likelihood ratio test (LRT) revealed evidence for association with schizophrenia in four polymorphism combinations: two DRD3*SNAP-25 combinations (rs6280*rs3746544 and rs6280*rs3746544, P=0.02), one ADRA2A*SNAP25 combination (rs1800544*rs3746544) and one ADRA2A*DBH combination (rs1800544*rs2519152). Our results are in agreement with the previously proposed role of DNA polymorphisms involved in dopaminergic, noradrenergic and synaptic functions in the pathogenesis of schizophrenia. Further relevant studies including larger sample size and more markers are needed to confirm our results.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
10Front 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, schizophrenics
11Hum Psychopharmacol 2014 Jan 29: 38-45
PMID24424705
TitleAssociation of ADRA2A and MTHFR gene polymorphisms with weight loss following antipsychotic switching to aripiprazole or ziprasidone.
AbstractVarious genetic polymorphisms have been reported to be associated with antipsychotic-induced weight gain. In this study, we aimed to determine whether risk polymorphisms in 12 candidate genes are associated with reduction in body mass index (BMI) of patients following switching of antipsychotics to aripiprazole or ziprasidone.
We recruited 115 schizophrenia patients with metabolic abnormalities and who have been on at least 1?year treatment with other antipsychotics; they were then switched to either aripiprazole or ziprasidone. They were genotyped, and their BMI monitored for 6 months.
Significant associations with reduction in BMI at 6?months following switching were found in two of these genes: with rs1800544 of the ADRA2A gene (CC?+?CG [-0.32??1.41?kg/m] vs GG [-1.04??1.63?kg/m], p?=?0.013) and with rs1801131 of the MTHFR gene (AA [-0.36??1.53] vs AC?+?CC [-1.07??1.53], p?=?0.015).
The study data indicated that carriage of the ADRA2A rs1800544 GG genotype and the MTHFR rs1801131 C allele are associated with BMI reduction in this population following switching of antipsychotics to aripiprazole and ziprasidone.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
12Hum Psychopharmacol 2014 Jul 29: 336-41
PMID25163438
TitlePolymorphism in alpha 2A adrenergic receptor gene is associated with sialorrhea in schizophrenia patients on clozapine treatment.
AbstractClozapine-induced sialorrhea (CIS) is a common, inconvenient and socially stigmatizing adverse effect. The pathophysiology of CIS may be related to the effect of clozapine on the muscarinic and adrenergic receptors as well as the disruption of the circadian rhythms. The aim of this study was to find out if polymorphisms in muscarinic M1 and M3 receptor genes (CHRM1 and CHRM3), adrenoceptor alpha 2A gene (ADRA2A) or clock circadian regulator gene (CLOCK) are associated with CIS.
Two hundred and thirty-seven clozapine-treated Finnish schizophrenia patients were genotyped for CHRM1, CHRM3, CLOCK and ADRA2A polymorphisms, and their salivary dysfunction was assessed with two questions. Twenty-six of these patients had previously been on medication to treat CIS. Comparisons of the genotypes between patients with excessive versus non-excessive salivation were analysed. Genotype distributions between patients and control group and haplotypes were also studied.
CHRM1, CHRM3 and CLOCK polymorphisms and haplotypes were not associated with CIS. ADRA2A (rs1800544) genotype was associated with CIS (p?=?0.029). In patients with CIS, CC genotype (n?=?103) was more common than in G-allele carriers (n?=?79) (p?=?0.013, OR 2.13, 95% CI: 1.17-3.88). No differences were found in the distributions of genotypes between patients and controls.
ADRA2A genotype was associated with CIS.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
13Brain Behav. Immun. 2015 May 46: 60-9
PMID25728234
TitleGadd45b is an epigenetic regulator of juvenile social behavior and alters local pro-inflammatory cytokine production in the rodent amygdala.
AbstractPrecise regulation of the epigenome during perinatal development is critical to the formation of species-typical behavior later in life. Recent data suggests that Gadd45b facilitates active DNA demethylation by recruiting proteins involved in base excision repair (BER), which will catalyze substitution of 5-methyl-cytosine (5mC) for an unmodified cytosine. While a role for Gadd45b has been implicated in both hippocampal and amygdalar learning tasks, to the best of our knowledge, no study has been done investigating the involvement of Gadd45b in neurodevelopmental programming of social behavior. To address this, we used a targeted siRNA delivery approach to transiently knock down Gadd45b expression in the neonatal rat amygdala. We chose to examine social behavior in the juvenile period, as social deficits associated with neurodevelopmental disorders tend to emerge in humans at an equivalent age. We find that neonatal Gadd45b knock-down results in altered juvenile social behavior and reduced expression of several genes implicated in psychiatric disorders, including methyl-CpG-binding protein 2 (MeCP2), Reelin, and brain derived neurotrophic factor (BDNF). We furthermore report a novel role for Gadd45b in the programmed expression of ?2-adrenoceptor (ADRA2A). Consistent with Gadd45b's role in the periphery, we also observed changes in the expression of pro-inflammatory cytokines interleukin-6 (Il-6) and interleukin-1beta (Il-1beta) in the amygdala, which could potentially mediate or exacerbate effects of Gadd45b knockdown on the organization of social behavior. These data suggest a prominent role for Gadd45b in the epigenetic programming of complex juvenile social interactions, and may provide insight into the etiology of juvenile behavioral disorders such as ADHD, autism, and/or schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
14Schizophr Bull 2016 May -1: -1
PMID27217270
TitlePharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis.
AbstractAlthough weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (?7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-nave youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
15Prog. Neuropsychopharmacol. Biol. Psychiatry 2016 Jan 64: 87-95
PMID26234518
TitlePerception of emotion in facial stimuli: The interaction of ADRA2A and COMT genotypes, and sex.
AbstractEmotional facial stimuli are important social signals that are essential to be perceived and recognized in order to make appropriate decisions and responses in everyday communication. The ability to voluntarily guide attention to perceive and recognize emotions, and react to them varies largely across individuals, and has a strong genetic component (Friedman et al., 2008). Two key genetic variants of the catecholamine system that have been related to emotion perception and attention are the catechol-O-methyl transferase genetic variant (COMT Val158Met) and the ?2A-receptor gene promoter polymorphism (ADRA2A C-1291G) accordingly. So far, the interaction of the two with sex in emotion perception has not been studied. Multilevel modeling method was applied to study how COMT Val158Met, ADRA2A C-1291G and sex are associated with measures of emotion perception in a large sample of young adults. Participants (n=506) completed emotion recognition and behavioral emotion detection tasks. It was found that COMT Val158Met genotype in combination with the ADRA2A C-1291G and sex predicts emotion detection, and perception of valence and arousal. In simple visual detection, the ADRA2A C-1291G G-allele leads to slower detection of a highly arousing face (scheming), which is modulated by each additional COMT Val158Met Met-allele and male sex predicting faster responses. The combination of G-allele, Met-allele and male sex also predicts higher perceived negativity in sad faces. No effects of C-1291G, Val158Met, and sex were found on verbal emotion recognition. Applying the findings to study the interplay between catecholamine-O-methyl transferase activity and ?2A-receptors in emotion perception disorders (such as ADHD, autism and schizophrenia) in men and women would be the next step towards understanding individual differences in emotion perception.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics