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Introduction: Major depressive disorder (MDD) is one of the most prevalent and disabling mental disorders, although its underlying genetic mechanism remains unknown. Insulin receptor substrate-1 (IRS-1) is one of the critical downstream molecules in the insulin resistance signaling pathway, linking depression and diabetes. Therefore, we hypothesized that IRS-1 would be a susceptible gene for MDD, and we aimed to examine the genetic association between IRS-1 and MDD. Methods: This case-control study included 583 patients with MDD and 564 controls, and the genotypic and allelic distributions of the IRS-1 gene's four single nucleotide polymorphisms (SNPs) were detected by TaqMan SNP genotyping technology. Of the 583 patients, 191 underwent a further detailed interview about symptom severity and family history of mental illness. The chi-square or t test was used to analyze the data, and analyses were performed using SPSS19.0 software. Results: A haplotype in the 5ʹ-upstream region of IRS-1 consisting of rs13411764 and rs3820926 was a risk factor of MDD. Patients with a family history of mental illness were more likely to have a GG genotype in rs13411764 and a G-T haplotype containing rs13411714-rs3820926. Discussion: The findings imply that the haplotype consisting of rs13411764 and rs3820926 in the upstream of IRS-1 is a risk factor for MDD. This haplotype could affect IRS-1 expression levels, and it is mostly inherited from parents. Thus, the presence of variants in the upstream region of IRS-1 is a risk factor of MDD, and this study could serve as a convincing reference for further studies. [ABSTRACT FROM AUTHOR]

Dopamine receptor D2 (DRD2) and catechol- O -methyltransferase (COMT) are important in dopamine system which is proved to be associated with food-anticipatory behavior, food restriction, reward and motivation. This has made them good candidates for anorexia nervosa (AN). The aim of this work is to explore the roles of DRD2 (rs1800497) and COMT (rs4680, rs4633, rs4818) gene polymorphisms in the susceptibility of AN within the Chinese Han population. We recruited 260AN patients with DSM-IV diagnosis criteria, and 247 unrelated, normal weight controls. DRD2 (rs1800497) and COMT (rs4680, rs4633, rs4818) were genotyped in all subjects. We found rs1800497 and rs4633 were associated with the susceptibility of AN within the Chinese Han sample, and allele C of rs1800497 was a protective factor. There was a gene–gene interaction between rs1800497 of DRD2 gene and rs4633 of COMT gene. We concluded that rs1800497 and rs4633 play important roles in the AN susceptibility with respect to the Chinese Han population. The gene–gene interaction between DRD2 and COMT contributes to the risk of AN. [ABSTRACT FROM AUTHOR]

Background: 15q11–13 region is one of the most complex chromosomal regions in the human genome. UBE3A is an important candidate gene of autism spectrum disorder (ASD), which located at the 15q11–13 region and encodes ubiquitin-protein ligase E3A. Previous studies about UBE3A gene and ASD have shown inconsistent results and few studies were performed in Chinese population. This study aimed to detect the genetic mutations of UBE3A gene in Chinese Han population with ASD and analyze genetic association between these variants and ASD. Methods: The samples consisted of 192 patients with autism according to the DSM-IV diagnostic criteria and 192 healthy controls. We searched for mutations at coding sequence (CDS) regions and their adjacent non-coding regions of UBE3A gene using the high resolution melting (HRM) and Sanger sequencing methods. We further increased sample size to validate the detected variants using HRM and conducted association analysis between case and control groups. Results: A known single nucleotide polymorphism (T > C, rs150331504) located at the CDS4 and a known 5 bp insertion/deletion variation (AACTC+/−, rs71127053) located at the intron region of the upstream 288 bp of the CDS2 of UBE3A gene were detected using Sanger sequencing method. The ASD samples of case group were 391 for rs71127053, 384 for rs150331504 and 384 healthy controls, which were used to make an association analysis. The results of association analysis suggested that there were no significant difference about the allele and genotype frequencies of rs71127053 and rs150331504 between case and control groups after extending the sample size. Besides, rs150331504 is a synonymous mutation and we compared the secondary structure and minimum free energy (MFE) of mRNA harboring the allele T or C of rs150331504 using RNAfold software. We found that the centroid secondary structure apparently differs along with the polymorphisms of rs150331504 T > C, the results suggested that this variant might change the secondary structure of mRNA of UBE3A gene. We did not detect mutations in other coding regions of UBE3A gene. Conclusions: These findings showed that UBE3A gene might not be a major disease gene in Chinese ASD cases. [ABSTRACT FROM AUTHOR]

Abstract: This case–control study enrolled 578 obsessive–compulsive disorder (OCD) patients and 649 controls and genotyped rs10491734, rs2228622, rs301430 and rs301443 to replicate association of the SLC1A1 gene with OCD in ethnic Han Chinese. The G-A-C-G and G-G-T-C haplotypes were found to be significantly associated with OCD in overall samples, male samples and female samples. [Copyright &y& Elsevier]

Abstracts Although many major breakthrough had identificated potential susceptibility genes for schizophrenia, the aetiology of schizophrenia is still unknown. In the present study, we focused on the N -methyl-Daspartate receptors related genes nitric oxide synthase 1 adaptor gene ( NOS1AP ), disrupted in schizophrenia 1 gene ( DISC1 ), d -amino acid oxidase activator gene ( DAOA ), and glycogen synthase kinase 3-beta gene ( GSK3B ). A family-based genetic association study (459 Han Chinese subjects in 153 nuclear families) using 3 single nucleotide polymorphisms in NOS1AP , 2 in DISC1 , 1 in DAOA and 1 in GSK3B was conducted. We found rs12742393 have just positive trend with schizophrenia (SCZ) (p = 0.07) after FDR correction. NOS1AP mRNA and serum levels were significantly elevated in SCZ patients (p < 0.001; p < 0.001) compared with healthy control. However, expression Quantitative Trait Loci (eQTL) analysis have demonstrated that rs12742393 genotype were not significantly associated with the NOS1AP mRNA expression. GMDR identified a significant seven-locus interaction model involving ( NOS1AP -rs348624, rs12742393, rs1415263, DISC1 -rs821633, rs1000731, DAOA -rs2391191and GSK3B - rs6438552) with a good testing accuracy (0.72). Our finding suggested statistically significant role of interaction of NOS1AP , DISC1 , DAOA , and GSK3B polymorphisms ( NOS1AP -rs348624, rs12742393, rs1415263, DISC1 -rs821633, rs1000731, DAOA -rs2391191and GSK3B -rs6438552) in EOS susceptibility. [ABSTRACT FROM AUTHOR]

GABA system genes have been implicated in neurotrophy and neurogenesis, which play pivotal roles in an individual's variation in vulnerability to amphetamine addiction or amphetamine-induced psychosis (AIP). We hypothesized that common genetic variants in the GABA system genes may be associated with amphetamine-induced psychotic disorder. In our study, thirty-six single nucleotide polymorphisms (SNPs) within the GABA system genes were genotyped in 400 amphetamine-induced psychotic disorder patients and 400 amphetamine use disorders patients (AUP) (not including those categorized as psychosis) in the Han Chinese population. In this study, 51.88% of the Han Chinese amphetamine-type substance use disorder patients met the criteria of amphetamine-induced psychotic disorder, and 79.5% amphetamine-induced psychotic disorder patients had auditory hallucinations, while 46.5% had delusions of reference. The allele frequency of rs1129647 showed nominal association with AIP in the Han Chinese population ( P = 0.03). Compared with AUP group patients, T allele frequency of AIP group patients was significantly increased. The adjustment for age and gender factors in the AIP and AUP patients was executed using unconditional logistic regression under five inheritance models. The genotype frequency of rs1129647 showed nominal association with AIP in the log-additive model ( P = 0.04). The genotype frequency of rs2290733 showed nominal association with AIP in the recessive model ( P = 0.04). Compared with female AIP patients, male patients were more likely to have the CC genotype of rs17545383 ( P = 0.04). Moreover, we determined that more male patients carried the T allele of rs2290733 in the AIP group ( P = 0.004). Unfortunately, the significant differences did not survive Benjamini-Hochberg false discovery rate correction (adjusted P > 0.05). No association between the SNPs of the GABA system genes and amphetamine-induced psychotic disorder risk was identified. No haplotype of the GABA system genes affected amphetamine-induced psychotic disorder risk. This report describes the first association study between the GABA system genes and amphetamine-induced psychotic disorder in the Han Chinese population. Our data may provide a reference for future research. [ABSTRACT FROM AUTHOR]

Background Anxiety disorders are a category of mental disorders characterized by feelings of anxiety and fear, which include generalized anxiety disorder (GAD). Obsessive-Compulsive Disorder (OCD) used to be categorized as anxiety disorder in DSM-IV. However OCD was no longer included in anxiety disorders and came into its own category titled as Obsessive-Compulsive and Related Disorders (OCRD) in DSM-5. It will be interesting to explore is there any different biological characteristics between OCD and anxiety disorders. Brain-derived neurotrophic factor (BDNF) was a potential candidate gene in both OCD and GAD. The results of genetic association studies between BDNF and OCD have been inconsistent. BDNF plasma/serum levels in OCD have been found lower than those in healthy controls. However the heritable reason of the lowered BDNF levels was not well elucidated. The amount of studies about BDNF and GAD were relatively small. The aims of this study were to determine whether single nucleotide polymorphism Val66Met of BDNF was associated with OCD and GAD, to examine BDNF plasma levels in OCD and GAD, and to explore whether Val66Met variation influences BDNF plasma levels. Methods We genotyped Val66Met variation in 148 OCD patients, 108 GAD patients and 99 healthy controls. Within the same sample, BDNF plasma levels were determined in 113 OCD patients, 102 GAD patients and 63 healthy controls. Results Val66Met variation was not associated with OCD or GAD. BDNF plasma levels in OCD and GAD patients were significant lower than those in healthy controls. Val66Met variation had no influence on BDNF plasma levels. No difference was found between OCD and GAD. Results do not change no matter taking OCD and GAD as one group or separated two. Limitations First, the sample size for genotyping was relatively small, which leaded to a low statistical power of the genetic part in this study. Second, we genotyped just one SNP in BDNF gene. Third, parts of the participants did not be assayed for BDNF plasma levels. Conclusions Our findings support the hypothesis that BDNF is involved in the pathophysiology of mental disorders, not only OCD but also GAD. OCD and GAD patients both show lower BDNF plasma levels compared to healthy controls. The BDNF plasma levels are not associated with Val66Met variation. [ABSTRACT FROM AUTHOR]

Background Subsyndromal symptomatic depression (SSD) is a common disease with significant social dysfunction. However, SSD is still not well understood and the pathophysiology of it remains unclear. Methods We classified 48 candidate genes for SSD according to our previous study into clusters and pathways using DAVID Bioinformatics Functional Annotation Tool. We further replicated the result by using real-time Quantitative PCR (qPCR) studies to examine the expression of identified genes (i.e., STAT5b , PKCB1 , ABL1 and NRAS) in another group of Han Chinese patients with SSD (n = 50). We further validated the result by examining PRKCB1 expression collected from MDD patients (n = 20). To test whether a deficit in PRKCB1 expression leads to dysregulation in PRKCB1 dependent transcript networks, we tested mRNA expression levels for the remaining 44 genes out of 48 genes in SSD patients. Finally, the power of discovery was improved by incorporating information from Quantitative Trait (eQTL) analysis. Results The results showed that the PRCKB1 gene expression in peripheral blood mononuclear cells (PBMC) was 33.3% down-regulated in SSD patients (n = 48, t = 3.202, p = 0.002), and a more dramatic (n = 17, 49%) down-regulation in MDD patients than control (n = 49, t = 2.114, p = 0.001). We also identified 37 genes that displayed a strong correlation with PRKCB1 mRNA expression levels in SSD patients. The expression of PRKCB1 was regulated by multiple single nucleotide polymorphisms (SNPs) both at the transcript level and exon level. Conclusions In conclusion, we first found a significant decrease of PRCKB1 mRNA expression in SSD, suggesting PRKCB1 might be the candidate gene and biomarker for SSD. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor A ( VEGFA ) has been implicated in neurotrophy and neurogenesis, which play a pivotal role in brain development and may be involved in the pathophysiology of schizophrenia (SCZ). We hypothesized that common genetic variants in the VEGFA gene may be associated with SCZ. In our study, seven tag single nucleotide polymorphisms (SNPs) within VEGFA were genotyped in 1034 SCZ patients and 952 healthy controls in the Han Chinese population. No significant differences of allele and genotype distributions of the 7 tag SNPs were identified between SCZ patients and healthy controls. The AA genotype of rs699947 nominally decreased the risk of SCZ in recessive inheritance model ( p = 0.03, OR = 0.65, 95%CI = 0.44–0.95, adjusted p = 0.18). No significant associations were found between different haplotypes and the risk of SCZ ( p > 0.05). Our findings suggested that the selected tag SNPs of VEGFA may not confer a susceptibility of SCZ in the Han Chinese population. [ABSTRACT FROM AUTHOR]

Accumulating evidence has implied that serotonin system dysfunction may be involved in the etiology of anorexia nervosa (AN). Serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism is the genetic variant coding for the serotonin transporter and has a modulatory effect on its expression. This study aimed to investigate the possible association between the 5-HTTLPR and the susceptibility and severity of AN in Han Chinese using a case-control (255 patients and 351 controls) and family based study (198 trios). Eating disorder examination was used to measure the severity of AN behavioral symptoms. For the case-control study, the 5-HTTLPR showed significant association with AN in our sample (genotypic P = 0.03). The frequency of S allele was significantly higher in patients than that in controls (OR = 1.38, 95%CI: 1.06–1.79, P = 0.017). For the family-based study, the S allele of 5-HTTLPR was preferentially transmitted rather than non-transmitted from the parents to affected offspring (P = 0.013). The results of ANCOVA test revealed no significant association between the 5-HTTLPR polymorphism and severity of AN. Our findings suggested that 5-HTTLPR is able to confer susceptibility to AN in Han Chinese. [ABSTRACT FROM AUTHOR]

Background: A growing body of evidence highlights the existence of shared genetic susceptibility to both major depressive disorder (MDD) and bipolar disorder (BD), suggesting some potential genetic overlap between the disorders. Genome-wide association studies have identified consistent association of single nucleotide polymorphisms of the α-1 C subunit of the L-type voltage-gated calcium channel gene (CACNA1C) with MDD and BD, suggesting CACNA1C as a promising candidate gene for susceptibility to mood disorders. In the present study, we tested the association of CACNA1C with MDD and BD in Han Chinese. Methods: We genotyped three potentially functional polymorphisms in 635 MDD patients, 286 BD patients and 730 normal, control patients. Results: The genotype frequencies of SNP rs1051375 showed statistically significant differences between the BD and control groups (P=0.005). At the allele level, the difference of G allele frequency of rs1051375 between BD patients and control subjects was also significant (P=0.011; OR=1.30, 95% CI: 1.06–1.58). We found that GG genotype of rs1051375 carriers had a lower age at onset than those with the AG or AA genotype, and the mean±standard deviation ages at onset of GG, AG and AA carriers were 24.04±4.22, 25.76±4.75 and 25.78±4.33 years, respectively. Neither genotype nor allele frequencies of the three polymorphisms were found to be significantly different between the MDD patients and control subjects. Limitations: The relative small sample size in BD group should be considered a limitation of this study. Conclusions: Our initial findings support a potential association of CACNA1C as a genetic risk factor for BD susceptibility. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Abstract: Schizophrenia is one of highly heritable psychiatric disorders. Patients with early onset schizophrenia tend to have a greater genetic loading and may be an attractive subpopulation for genetics studies. A single nucleotide polymorphism (SNP) rs139887 in sex-determining region Y-box 10 (SOX10), a candidate gene for schizophrenia, was suggested to be associated with schizophrenia although inconsistent results had been reported. The aim of this study was to evaluate the association between SOX10 rs139887 polymorphism and schizophrenia using an early onset sample in the Chinese Han population. A total of 321 schizophrenic patients with onset before age 18 and 400 healthy controls were recruited for association study. In addition, two populations involved in three studies were selected for meta-analysis to determine the effect of rs139887 on schizophrenia. Our association study results showed that the allele and genotype frequencies were significantly different between schizophrenic patients and controls (P =0.013 and P =0.034, respectively). Interestingly, a significant association in allele and genotype frequencies were found in male patients (P =0.017 and P =0.045, respectively), but not female patients. Moreover, the C/C genotype had a significant association with an earlier age of onset in male schizophrenic patients (Kaplan–Meier log-rank test P =0.029), but not in female patients (Kaplan–Meier log-rank test P =0.876). The meta-analysis result showed the same C allele was significantly associated with schizophrenia (P =0.007). In conclusion, the SOX10 rs139887 polymorphism was related to the development of schizophrenia in a gender-specific manner, and may be a significant genetic marker for managing subgroups and etiological clues in schizophrenia. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Objective: Consistent 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. Methods: Case–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. Results: The 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). Conclusion: Our findings indicate that DNMT3B may be a candidate gene for susceptibility to early onset schizophrenia. [Copyright &y& Elsevier]

Despite there is a wide range of antidepressants available, with various mechanisms of actions, the efficacy of current therapeutic options is yet satisfactory. Previous shreds of evidence have indicated that genetics, cognitive, neuroendocrine, as well as personality factors, are all intrinsically linked and contribute to the diversity of treatment outcomes. We, therefore, sought to investigate this hypothesis in this study. Based on 610 samples treated with a selection of serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), noradrenergic and specific serotonergic antidepressant (NaSSA) or tricyclic antidepressant (TCA), we compared the therapeutic effects of these four classes of drugs by survival analyses. Pharmacogenomic and survival analyses were carried out to explore the hereditary factors for curative effect and the accumulation of genetic factors was further discussed through pathway analysis and the global test. We built a machine learning-based prediction model that integrates genetic and non-genetic factors (including cognition, endocrinology, personality intelligence) to distinguish drug efficacy in single class drug situations. The values of the non-genetic makers after 6 weeks' treatment were collected to evaluate the efficacy of the model. Our results from the 6-week antidepressant therapeutic study indicated that SSRI and SNRI are better treatments than those of TCA and NaSSA in the Chinese population. Among all possible paired single-agent survival analyses, citalopram and venlafaxine were more effective than mirtazapine. Allele C carriers at rs6354 (SLC6A4) and allele G carriers at rs12150214 (SLC6A4) were significantly prone to poorer treatment response to fluoxetine. Besides, the combination of three loci (rs929377-rs6191-rs32897) located in HPA pathway was significantly associated with the treatment outcome of fluoxetine. In female MDD patients, the minor allele of rs6323 and rs1137070 on the MAOA gene likely lead to a worse response to venlafaxine. Furthermore, genetic variants linked to drug efficacy tended to concentrate on the neurotrophin pathway in depressed patients comorbid with anxiety. From multivariate models, more severe cognitive deficits, psychopathic personality and lower levels of operational intelligence, and higher levels of cortisol predicted worse response status with SSRI or SNRI after 6-week treatment. Notably, genetic factors in the multi-dimensional prediction model for both classes of drugs include loci in HTR2A and CRHBP genes. SSRI and SNRI are more suitable for the treatment of Chinese people with depression. SLC6A4 genetic variants, as well as HPA pathway, play an important role in the fluoxetine antidepressant therapeutic response while the polymorphism of MAOA gene involved in the pharmacological action of venlafaxine among female MDD patients. The presence of anxiety in MDD patients was related to the neurotrophin pathway. Genetic, cognitive, neuroendocrine, and personality intelligence factors combined have an ensemble impact on the medication effect of patients with major depression, leading to more precise and personalized medicine for specific groups of people. • SSRI and SNRI are better treatments in the Chinese population • SLC6A4 gene and HPA pathway play an important role in the fluoxetine antidepressant therapeutic response • The polymorphism of MAOA gene involved in the pharmacological action of venlafaxine among female patients • anxiety in MDD patients was related to the neurotrophin pathway • Genetic, cognition and concomitant symptom are critical factors in the selection of antidepressants for specific patients [ABSTRACT FROM AUTHOR]