Shunying Yu

Association study of tryptophan hydroxylase-2 gene in schizophrenia and its clinical features in Chinese Han population.

Schizophrenia is a chronic and severe mental illness which is characterized by the development of various detrimental clinical features, and its etiology still remains unknown. Based on the evidence from neurobiological and pharmacological research, dysfunctions in central serotonergic transmission may be involved in the development of schizophrenia. Tryptophan hydroxylase 2 (TPH2), a newly identified isoform of tryptophan hydroxylase (the rate limiting enzyme in the biosynthesis of serotonin), regulates the brain-specific serotonin synthesis. To further clarify the role of TPH2 in this disease, we performed a case-control study to examine the association of the TPH2 gene with schizophrenia and its clinical features. We genotyped three putative functional polymorphisms (rs4570625, rs7305115, and rs4290270) within the gene and carried out a case-control study consisting of 304 schizophrenia patients and 362 healthy subjects. The severity of psychotic symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). The frequencies of genotypes and alleles of rs4570625, rs7305115, and rs4290270 did not differ significantly between schizophrenic patients and controls. However, the PANSS positive symptom subcore was significantly associated with rs4570625 (Pu2009=u20090.022). These results suggest that rs4570625 of TPH2 may play an important role in the development of positive symptoms in Han Chinese schizophrenic patients.

Blood-Based Gene Expression Profiles Models for Classification of Subsyndromal Symptomatic Depression and Major Depressive Disorder

Subsyndromal symptomatic depression (SSD) is a subtype of subthreshold depressive and also lead to significant psychosocial functional impairment as same as major depressive disorder (MDD). Several studies have suggested that SSD is a transitory phenomena in the depression spectrum and is thus considered a subtype of depression. However, the pathophysioloy of depression remain largely obscure and studies on SSD are limited. The present study compared the expression profile and made the classification with the leukocytes by using whole-genome cRNA microarrays among drug-free first-episode subjects with SSD, MDD, and matched controls (8 subjects in each group). Support vector machines (SVMs) were utilized for training and testing on candidate signature expression profiles from signature selection step. Firstly, we identified 63 differentially expressed SSD signatures in contrast to control (P<u200a=u200a5.0E-4) and 30 differentially expressed MDD signatures in contrast to control, respectively. Then, 123 gene signatures were identified with significantly differential expression level between SSD and MDD. Secondly, in order to conduct priority selection for biomarkers for SSD and MDD together, we selected top gene signatures from each group of pair-wise comparison results, and merged the signatures together to generate better profiles used for clearly classify SSD and MDD sets in the same time. In details, we tried different combination of signatures from the three pair-wise compartmental results and finally determined 48 gene expression signatures with 100% accuracy. Our finding suggested that SSD and MDD did not exhibit the same expressed genome signature with peripheral blood leukocyte, and blood cell–derived RNA of these 48 gene models may have significant value for performing diagnostic functions and classifying SSD, MDD, and healthy controls.

Association of BDNF gene polymorphism with bipolar disorders in Han Chinese population.

Recent data suggest that brain‐derived neurotrophic factor (BDNF) plays an essential role in neuronal plasticity and etiology of bipolar disorders (BPD). However, results from different studies have been inconsistent. In present study, 342 patients who met DSM‐IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) criteria for bipolar disorders type I (BPD‐I) or type II (BPD‐II) and 386 matched health controls were enrolled, and TaqMan® SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) were applied to detect the functional polymorphism rs6265 (Val66Met) of BDNF gene. Treatment response to lithium and valproate was retrospectively determined. The association between Val66Met polymorphism and BPD, treatment response to mood stabilizers, was estimated. The genotype and allele distribution of Val66Met polymorphism between BPD patients and control subjects showed significant difference (genotype: χ2 = 6.18, df = 2, P = 0.046; allele: χ2 = 5.01, df = 1, P = 0.025) with Met allele as risk factor for disease susceptibility (OR = 0.79, 95%CI as 0.64–0.97). The post hoc analysis interestingly showed that Met allele had opposite effect on the treatment response for BPD‐I and BPD‐II separately. For BPD‐I patients, the response score in Val/Val group was significantly lower than that in Met allele carriers (t = −2.27, df = 144, P = 0.025); for BPD‐II patients, the response score in Val/Val group was significantly higher than that in Met allele carriers (t = 2.33, df = 26, P = 0.028). Although these results should be interpreted with caution because of the limited sample for Val/Val genotype in BPD‐II patients (N = 5), these findings strengthen the hypothesis that BDNF pathway gets involved in the etiology and pharmacology of BPD and suggest the differences between BPD‐I and BPD‐II.

Lack of effect of brain derived neurotrophic factor (BDNF) Val66Met polymorphism on early onset schizophrenia in Chinese Han population.

Schizophrenia is a chronic psychiatric disorder with high heritability. Schizophrenic patients with early-age onset tend to have a greater genetic component and may be an attractive subpopulation for genetic studies. Brain-derived neurotrophic factor (BDNF) is considered a candidate gene for schizophrenia. A single nucleotide polymorphism (BDNF Val66Met) was reported to be associated with schizophrenia, although discrepancy remains. The aim of this study was to evaluate the association between BDNF Val66Met polymorphism and schizophrenia using an early onset sample in the Chinese Han population. Our sample consisted of 353 schizophrenic patients with onset before age 18 and 394 healthy controls. All subjects were of an ethnically homogenous Han Chinese origin. No significant differences of genotype or allele distribution were identified between the patients and controls. However, the Met allele was significantly associated with an earlier age of onset in male schizophrenic patients (Kaplan-Meier log-rank test P=0.005), but not in females (P=0.289). The BDNF Val66Met polymorphism has an important effect on the age of onset of schizophrenia in a gender-specific manner. This may represent a significant genetic clue for the etiology of schizophrenia and thus, further studies are required to uncover the exact role of BDNF in the development of schizophrenia.

DNA methyltransferase 3B gene increases risk of early onset schizophrenia.

OBJECTIVEnConsistent evidence indicated that aberrant DNA methylation may be involved in the development of schizophrenia. DNA methyltransferase 3B (DNMT3B) is the key methyltransferase in DNA methylation regulations. In this study, we investigated the association between DNMT3B polymorphisms and the susceptibility of early onset schizophrenia in Chinese Han population.nnnMETHODSnCase-control (patients=381 and controls=472) and family based (trios=103) study was performed through genotyping two tag single nucleotide polymorphisms (rs2424908 and rs6119954) covering the whole DNMT3B gene. Single nucleotide polymorphism association and haplotype analysis were performed.nnnRESULTSnThe frequency of G allele of rs6119954 was significantly higher in patients than that in controls (P=0.017). Genotype distribution of rs6119954 was significantly different between patients and controls (P=0.046). A haplotype-wise analysis revealed a higher frequency of the T-G (rs2424908-rs6119954) haplotype in patients than that in controls (P=0.033). In the transmission disequilibrium test analysis, G allele of rs6119954 was preferentially transmitted in the trios (P=0.030).nnnCONCLUSIONnOur findings indicate that DNMT3B may be a candidate gene for susceptibility to early onset schizophrenia.

Venlafaxine inhibits the upregulation of plasma tumor necrosis factor-alpha (TNF-α) in the Chinese patients with major depressive disorder: A prospective longitudinal study

Although tumor necrosis factor-alpha (TNF-α) has been recognized to be involved in the pathogenesis of major depressive disorder (MDD) for a long time, only few studies so far investigated the effects of antidepressant, venlafaxine on TNF-α and the results are inconsistent. Moreover, the association between plasma TNF-α levels and suicide accompanied with MDD is entirely unknown. To elucidate these relationships, in the present study, 64 first-episode drug-naïve MDD patients and 64 matched healthy controls were recruited. Total 61 MDD patients received 8-week venlafaxine treatment and they were divided into responders and non-responders according to the reduction rate of HRSD-17. Prior to venlafaxine treatment, both responders and non-responders shared a similar plasma TNF-α (p=0.33), which was significantly decreased following venlafaxine treatment (p<0.001, p=0.03, respectively). Compared to non-responders, the responder group had a greater reduction in TNF-α (p=0.01), which was associated with the greater reduction rate of HRSD-17 (B=1.02, p=0.01). In addition, the plasma TNF-α levels were equally higher in both suicidal and non-suicidal MDD patients (p=0.84) compared to the healthy controls on admission (p=0.001, p=0.03, respectively). Together, our data suggest that MDD per se rather than suicide is associated with the elevated plasma TNF-α, which can be inhibited with venlfaxine monotherapy. The extent of TNF-α reduction may be associated with the efficiency of venlafaxine.

No genetic association between dopamine D1 receptor gene and [early onset] schizophrenia

Decreased dopaminergic activity in the prefrontal cortex (PFC) has been consistently reported in schizophrenia patients. The dopamine D1 receptor (DRD1) plays an important role in mediating dopaminergic transmission in the PFC. Controversy about this topic still exists despite ample evidence suggesting that the DRD1 gene is associated with performance on neuropsychological tests probing the function of the PFC in schizophrenia, as well as positive and negative symptoms and therapeutic response to antipsychotics. To determine whether this gene is involved in the etiology of schizophrenia, we undertook a case-control study to look for an association. We genotyped five single nucleotide polymorphisms (SNPs) rs4532, rs5326, rs2168631, rs6882300 and rs267418 within the DRD1 involving 373 schizophrenia patients with early age of onset and 379 healthy subjects. No significant differences of genotype, allele or haplotype distribution were identified between patients and controls. Our results do not preclude a possible role of DRD1 in the etiology of schizophrenia. As an important dopaminergic gene, DRD1 may contribute to schizophrenia by interacting with other genes. Further relevant studies are warranted.

Pathways to Age of Onset of Heroin Use: A Structural Model Approach Exploring the Relationship of the COMT Gene, Impulsivity and Childhood Trauma

Background The interaction of the association of dopamine genes, impulsivity and childhood trauma with substance abuse remains unclear. Objectives To clarify the impacts and the interactions of the Catechol -O-methyltransferase (COMT) gene, impulsivity and childhood trauma on the age of onset of heroin use among heroin dependent patients in China. Methods 202 male and 248 female inpatients who meet DSM-IV criteria of heroin dependence were enrolled. Impulsivity and childhood trauma were measured using BIS-11 (Barratt Impulsiveness Scale-11) and ETISR-SF (Early Trauma Inventory Self Report-Short Form). The single nucleotide polymorphism (SNP) rs737866 on the COMT gene-which has previously been associated with heroin abuse, was genotyped using a DNA sequence detection system. Structural equations model was used to assess the interaction paths between these factors and the age of onset of heroin use. Principal Findings Chi-square test indicated the individuals with TT allele have earlier age of onset of heroin use than those with CT or CC allele. In the correlation analysis, the severity of childhood trauma was positively correlated to impulsive score, but both of them were negatively related to the age of onset of heroin use. In structure equation model, both the COMT gene and childhood trauma had impacts on the age of onset of heroin use directly or via impulsive personality. Conclusions Our findings indicated that the COMT gene, impulsive personality traits and childhood trauma experience were interacted to impact the age of onset of heroin use, which play a critical role in the development of heroin dependence. The impact of environmental factor was greater than the COMT gene in the development of heroin dependence.

Association Between SLC1A1 Gene and Early-Onset OCD in the Han Chinese Population: A Case-Control Study

Obsessive–compulsive disorder (OCD) is a common and severe mental illness, and its etiology still remains unknown. The glutamate transporter gene solute carrier family 1, member 1 was previously tested as a promising candidate for OCD by several research groups. However, subsequent studies were not consistent. OCD is a heterogeneous disease. Early-onset OCD is a demographically and clinically distinct subtype of OCD and may be a more homogeneous subtype. Gender-matched 244 early-onset OCD patients, 244 late-onset OCD patients, and 244 healthy controls were genotyped with four SNPs (rs10491734, rs2228622, rs301430, and rs301443) through TaqMan SNP genotyping assays. There were statistical differences in allele and genotype frequencies of rs10491734 in early-onset OCD patients compared to late-onset OCD or control subjects. The haplotype analysis showed that the four-locus haplotype (A-A-C-C and A-G-C-C) were associated with early onset obsessive–compulsive disorder after Bonferroni correction. The present study provided suggestive evidence that the rs10491734 was significantly associated with early-onset OCD in the Han Chinese population. However, these findings need further replication.

Influence of maternal MTHFR A1298C polymorphism on the risk in offspring of schizophrenia

Several lines of evidence have suggested that two functional methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, C677T and A1298C, may be implicated in the etiology of schizophrenia. We examined these MTHFR polymorphisms in 111 families, composed of a patient and their parents, as well as 143 mothers of patients with schizophrenia and 235 age-matched mothers who had healthy children. The maternal MTHFR 1298C allele was associated with a significantly increased risk of schizophrenia (OR=1.63, 95%CI: 1.11-2.39, P=0.01). The haplotype analysis showed a weak association for the 1298C-677C haplotype (OR=1.54, 95%CI=1.03-2.29, P=0.04). Analysis of Transmission Disequilibrium Test (TDT) showed no preferential transmission of 1298C and 677T alleles from parents to probands (P=0.64 and P=0.71, respectively). Our results suggest that deficient MTHFR enzyme activity in pregnant women, related to the A1298C variant, is associated with a higher risk of having offspring affected with schizophrenia. Given the low sample size in this study, the present results seem tentative and need further studies to replicate.