Illi A, etal., Neuroreport. 2009 Aug 5;20(12):1125-8. doi: 10.1097/WNR.0b013e32832eb708.
Genes that regulate the serotonin signalling system are potential targets for research in the aetiology of mood disorders and also in the treatment response of serotonin reuptake inhibitors. In this study, we evaluated the association of seven serotonin signal transduction-linked single nucleotide p
olymorphisms [HTR1A (rs6295), HTR2A (rs6313, rs6311 and rs7997012), HTR6 (rs1805054), TPH1 (rs1800532) and TPH2 (rs1386494)] with major depressive disorder and/or treatment outcome with serotonin reuptake inhibitors. Patients who met the criteria for major depressive disorder were treated for 6 weeks with fluoxetine, paroxetine or citalopram. The treatment response was evaluated with the Montgomery-Asberg Depression Rating Scale, and according to predefined response criteria, the patients were divided into responders, nonresponders, remitters and nonremitters. Altogether, 86 patients completed the entire study according to the study protocol. We had also a control population (N = 395) of healthy blood donors. None of the seven single nucleotide polymorphisms was associated with major depressive disorder or with treatment response in our study population of Finnish individuals.
Lin H, etal., Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):749-55. doi: 10.1002/ajmg.b.32380. Epub 2015 Sep 26.
Schizophrenia (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. R
ecent 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 = 3.89x10(-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 = 1.63x10(-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. (c) 2015 Wiley Periodicals, Inc.
BACKGROUND: Alcohol and nicotine codependence can be considered as a more severe subtype of alcohol dependence. A portion of its risk may be attributable to genetic factors. METHODS: We searched for significant risk genomic regions specific for this disorder using a genome-wide
association study. A total of 8,847 subjects underwent gene-disease association analysis, including (i) a discovery cohort of 818 European American cases with alcohol and nicotine codependence and 1,396 European American controls, (ii) a replication cohort of 5,704 Australian family subjects with 907 affected offspring, and (iii) a replication cohort of 449 African American cases and 480 African American controls. Additionally, a total of 38,714 subjects of European or African descent in 18 independent cohorts with 10 other nonalcoholism neuropsychiatric disorders were analyzed as contrast. Furthermore, 90 unrelated HapMap CEU individuals, 93 European brain tissue samples, and 80 European peripheral blood mononuclear cell samples underwent cis-acting expression quantitative locus (cis-eQTL) analysis. RESULTS: We identified a significant risk region for alcohol and nicotine codependence between IPO11 and HTR1A on chromosome 5q that was reported to be suggestively associated with alcohol dependence previously. In the European American discovery cohort, 381 single nucleotide polymorphisms (SNPs) in this region were nominally associated with alcohol and nicotine codependence (p < 0.05); 57 associations of them survived region- and cohort-wide correction (α = 3.6 × 10(-6) ); and the top SNP (rs7445832) was significantly associated with alcohol and nicotine codependence at the genome-wide significance level (p = 6.2 × 10(-9) ). Furthermore, associations for 34 and 11 SNPs were replicated in the Australian and African American replication cohorts, respectively. Among these replicable associations, 4 reached genome-wide significance level in the meta-analysis of European Americans and European Australians: rs7445832 (p = 9.6 × 10(-10) ), rs13361996 (p = 8.2 × 10(-9) ), rs62380518 (p = 2.3 × 10(-8) ), and rs7714850 (p = 3.4 × 10(-8) ). Cis-eQTL analysis showed that many risk SNPs in this region had nominally significant cis-acting regulatory effects on HTR1A or IPO11 mRNA expression. Finally, no markers were significantly associated with any other neuropsychiatric disorder examined. CONCLUSIONS: We speculate that this IPO11-HTR1A region might harbor a causal variant for alcohol and nicotine codependence.
Takekita Y, etal., J Clin Psychopharmacol. 2015 Jun;35(3):220-7. doi: 10.1097/JCP.0000000000000304.
Individual 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 eff
icacy 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.
Qiu Y, etal., BMC Neurosci. 2016 Oct 19;17(1):66. doi: 10.1186/s12868-016-0300-9.
BACKGROUND: Limited surveys have assessed the performance of 5-hydroxytreptamine receptor 1A and its antagonist WAY-100635 in pharmacological manipulations targeting delirium therapies. The purpose of this paper was to assess the central pharmacological activity of WAY-100635 in a rat mod
el of scopolamine-induced delirium and its underlying mechanism. RESULTS: A delirium rat model was established by intraperitoneal injection of scopolamine and behavioral changes evaluated through open field and elevated plus maze experiments. Concentrations of monoamines in the hippocampus and amygdalae were detected by high performance liquid chromatography. The effect of WAY-100635 on the recovery of rats from delirium was assessed by stereotactic injection of WAY-100635 and its mechanism of action determined by measuring mRNA and protein expression via real time PCR and western blotting methods. The total distance and the number of crossing and rearing in the elevated plus maze test and the time spent in the light compartment in the dark/light test of scopolamine-treated rats were significantly increased while the percentage of time spent in the open arms was decreased, showing the validity of the established delirium rat model. The measurement of the concentrations of noradrenaline, 3,4-dihydroxyphenylacetic acid, the homovanillic acid, 5-hydroxy-3-indoleacetic acid and serotonin concentrations in the cerebrospinal fluid (CSF) of scopolamine-induced delirium rats were significantly increased. The intra-hippocampus and intra-BLA injections of WAY-100635 improved the delirium-like behavior of rats by significantly reducing the expression of NLRP3 inflammasome and the release of IL1-β and IL8 into CSF. CONCLUSIONS: Taken together, these findings indicate that WAY-100635 may exert a therapeutic effect on post-operative delirium by controlling neurotransmission as well as suppressing neuroinflammation in the central nervous system.
Blaya C, etal., Neurosci Lett. 2010 Nov 12;485(1):11-5. Epub 2010 Sep 15.
OBJECTIVE: The aim of this study is to evaluate the association between HTR1A, HTR2A and the 5-HTTLPR in panic disorder (PD) patients and controls. In addition, this study also aims to evaluate the interaction between these genes and two environmental factors pr
eviously associated with PD: childhood trauma and parental bonding. METHODS: This is a case-control candidate gene association study (107 PD patients and 125 controls). Genes were analyzed using a gene-based test in PLINK followed by single marker association tests and haplotype test only for genes that reached experiment-wide significance in the gene-based test in order to minimize multiple testing. Logistic regression was used to test the relationships between genotype in the additive model, trauma, optimal paternal parenting and optimal maternal parenting and their interactions. RESULTS: Only HTR1A was associated with PD in gene-based test after correction for multiple tests (p(corrected)=0.027) and one HTR1A haplotype comprising four SNPs was associated with PD (p(corrected)=0.032). In the interaction analysis, no significant gene-environment interaction was found with the genes evaluated. CONCLUSION: This study reinforces the association between HTR1A and PD. No major evidence of gene-environment interaction in PD with parenting or trauma was found. Further studies are necessary in order to confirm these findings.
Zuo L, etal., Am J Med Genet B Neuropsychiatr Genet. 2015 Oct;168(7):544-56. doi: 10.1002/ajmg.b.32329. Epub 2015 Jun 16.
We comprehensively examined the rare variants in the IPO11-HTR1A region to explore their roles in neuropsychiatric disorders. Five hundred seventy-three to 1,181 rare SNPs in subjects of European descent and 1,234-2,529 SNPs in subjects of African descent (0 <
minor allele frequency (MAF) < 0.05) were analyzed in a total of 49,268 subjects in 21 independent cohorts with 11 different neuropsychiatric disorders. Associations between rare variant constellations and diseases and associations between individual rare variants and diseases were tested. RNA expression changes of this region were also explored. We identified a rare variant constellation across the entire IPO11-HTR1A region that was associated with attention deficit hyperactivity disorder (ADHD) in Caucasians (T5: P = 7.9 x 10(-31) ; Fp: P = 1.3 x 10(-32) ), but not with any other disorder examined; association signals mainly came from IPO11 (T5: P = 3.6 x 10(-10) ; Fp: P = 3.2 x 1 0(-10) ) and the intergenic region between IPO11 and HTR1A (T5: P = 4.1 x 10(-30) ; Fp: P = 5.4 x 10(-32) ). One association between ADHD and an intergenic rare variant, i.e., rs10042956, exhibited region- and cohort-wide significance (P = 5.2 x 10(-6) ) and survived correction for false discovery rate (q = 0.006). Cis-eQTL analysis showed that, 29 among the 41 SNPs within or around IPO11 had replicable significant regulatory effects on IPO11 exon expression (1.5 x 10(-17) HTR1A was a significant risk gene region for ADHD in Caucasians.
