Personality traits as mediators in the association between SIRT1 rs12415800 polymorphism and depressive symptoms among Chinese college students.

Background: Previous research has linked polymorphisms in the SIRT1 gene to depressive symptoms, particularly in Chinese individuals. However, it is not clear how personality traits may contribute to this association. Methods: To explore the potential mediating effect of personality traits, we utilized a mediation model to examine the relationship between the SIRT1 rs12415800 polymorphism and depressive symptoms in 787 Chinese college students. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale, while personality traits were measured using the Big Five Inventory (BFI). Results: Our analysis indicated a significant association between the SIRT1 rs12415800 polymorphism and depressive symptoms, with this relationship partially mediated by the personality traits of neuroticism and conscientiousness. Specifically, individuals who were heterozygous for the rs12415800 polymorphism and had higher levels of conscientiousness were less likely to experience depressive symptoms. Conversely, those who were homozygous for the rs12415800 polymorphism and had higher levels of neuroticism were more likely to experience depressive symptoms. Conclusion: Our results suggest that personality traits, particularly neuroticism and conscientiousness, may play a critical role in the association between the SIRT1 rs12415800 polymorphism and depressive symptoms among Chinese college students. These findings highlight the importance of considering both genetic factors and personality traits when exploring the etiology of depressive symptoms in this population.

College students' screening early warning factors in identification of suicide risk.

This study aimed to explore the main influencing factors of suicide risk among Chinese students and establish an early warning model to provide interventions for high-risk students. We conducted surveys of students in their first and third years from a cohort study at Jining Medical College. Logistic regression models were used to screen the early warning factors, and four machine learning models were used to establish early warning models. There were 8 factors related to suicide risk that were eventually obtained through screening, including age, having a rough father, and CES-D, OHQ, ASLEC-4, BFI-Neuroticism, BFI-Openness, and MMC-AF-C scores. A random forest model with SMOTE was adopted, and it verified that these 8 early warning signs, for suicide risk can effectively predict suicide risk within 2 years with an AUC score of 0.947. Among the factors, we constructed a model that indicated that different personality traits affected suicide risk by different paths. Moreover, the factors obtained by screening can be used to identify college students in the same year with a high risk of suicide, with an AUC score that reached 0.953. Based on this study, we suggested some interventions to prevent students going high suicide risk.

Upregulation of DGCR8, a Candidate Predisposing to Schizophrenia in Han Chinese, Contributes to Phenotypic Deficits and Neuronal Migration Delay.

DiGeorge Syndrome Critical Region Gene 8 (DGCR8) is a key component of the microprocessor complex governing the maturation of most microRNAs, some of which participate in schizophrenia and neural development. Previous studies have found that the 22q11.2 locus, containing DGCR8, confers a risk of schizophrenia. However, the role of DGCR8 in schizophrenia and the early stage of neural development has remained unknown. In the present study, we try to identify the role of DGCR8 in schizophrenia from human samples and animal models. We found that the G allele and GG genotype of rs3757 in DGCR8 conferred a higher risk of schizophrenia, which likely resulted from higher expression of DGCR8 according to our test of dual-luciferase reporter system. Employed overexpression model in utero and adult mice, we also revealed that the aberrant increase of Dgcr8 delayed neuronal migration during embryological development and consequently triggered abnormal behaviors in adult mice. Together, these results demonstrate that DGCR8 may play a role in the etiology of schizophrenia through regulating neural development.

A novel heterozygous missense variant of the ARID4A gene identified in Han Chinese families with schizophrenia-diagnosed siblings that interferes with DNA-binding activity.

ARID4A plays an important role in regulating gene expression and cell proliferation. ARID4A belongs to the AT-rich interaction domain (ARID)-containing family, and a PWWP domain immediately precedes its ARID region. The molecular mechanism and structural basis of ARID4A are largely unknown. Whole-exome sequencing (WES) revealed that a novel heterozygous missense variant, ARID4A c.1231 C > G (p.His411Asp), was associated with schizophrenia (SCZ) in this study. We determined the crystal structure of the PWWP-ARID tandem at 2.05 Å, revealing an unexpected mode in which ARID4A assembles with its PWWP and ARID from a structural and functional supramodule. Our results further showed that compared with the wild type, the p.His411Asp ARID mutant protein adopts a less compact conformation and exhibits a weaker dsDNA-binding ability. The p.His411Asp mutation decreased the number of cells that were arrested in the G0-G1 phase and caused more cells to progress to the G2-M phase. In addition, the missense mutation promoted the proliferation of HEK293T cells. In conclusion, our data provide evidence that ARID4A p.His411Asp could cause a conformational change in the ARID4A ARID domain, influence the DNA binding function, and subsequently disturb the cell cycle arrest in the G1 phase. ARID4A is likely a susceptibility gene for SCZ; thus, these findings provide new insight into the role of ARID4A in psychiatric disorders.

LncRNA SOX1-OT V1 acts as a decoy of HDAC10 to promote SOX1-dependent hESC neuronal differentiation.

Long noncoding RNAs (lncRNAs) are abundantly expressed in the nervous system, but their regulatory roles in neuronal differentiation are poorly understood. Using a human embryonic stem cell (hESC)-based 2D neural differentiation approach and a 3D cerebral organoid system, we show that SOX1-OT variant 1 (SOX1-OT V1), a SOX1 overlapping noncoding RNA, plays essential roles in both dorsal cortical neuron differentiation and ventral GABAergic neuron differentiation by facilitating SOX1 expression. SOX1-OT V1 physically interacts with HDAC10 through its 5' region, acts as a decoy to block HDAC10 binding to the SOX1 promoter, and thus maintains histone acetylation levels at the SOX1 promoter. SOX1 in turn activates ASCL1 expression and promotes neuronal differentiation. Taken together, we identify a SOX1-OT V1/HDAC10-SOX1-ASCL1 axis, which promotes neurogenesis, highlighting a role for lncRNAs in hESC neuronal differentiation.

Effect of exercise and diet intervention in NAFLD and NASH via GAB2 methylation.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a disorder that extends from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is effectively alleviated by lifestyle intervention. Nevertheless, DNA methylation mechanism underling the effect of environmental factors on NAFLD and NASH is still obscure. The aim of this study was to investigate the effect of exercise and diet intervention in NAFLD and NASH via DNA methylation of GAB2. METHODS: Methylation of genomic DNA in human NAFLD was quantified using Infinium Methylation EPIC BeadChip assay after exercise (Ex), low carbohydrate diet (LCD) and exercise plus low carbohydrate diet (ELCD) intervention. The output Idat files were processed using ChAMP package. False discovery rate on genome-wide analysis of DNA methylation (q < 0.05), and cytosine-guanine dinucleotides (CpGs) which are located in promoters were used for subsequent analysis (|Δß|≥ 0.1). K-means clustering was used to cluster differentially methylated genes according to 3D genome information from Human embryonic stem cell. To quantify DNA methylation and mRNA expression of GRB2 associated binding protein 2 (GAB2) in NASH mice after Ex, low fat diet (LFD) and exercise plus low fat diet (ELFD), MassARRAY EpiTYPER and quantitative reverse transcription polymerase chain reaction were used. RESULTS: Both LCD and ELCD intervention on human NAFLD can induce same DNA methylation alterations at critical genes in blood, e.g., GAB2, which was also validated in liver and adipose of NASH mice after LFD and ELFD intervention. Moreover, methylation of CpG units (i.e., CpG_10.11.12) inversely correlated with mRNA expression GAB2 in adipose tissue of NASH mice after ELFD intervention. CONCLUSIONS: We highlighted the susceptibility of DNA methylation in GAB2 to ELFD intervention, through which exercise and diet can protect against the progression of NAFLD and NASH on the genome level, and demonstrated that the DNA methylation variation in blood could mirror epigenetic signatures in target tissues of important biological function, i.e., liver and adipose tissue. Trial registration International Standard Randomized Controlled Trial Number Register (ISRCTN 42622771).

A study of negative life events driven depressive symptoms and academic engagement in Chinese college students.

Negative life events (NLEs) are an important predictor of depressive symptoms (DS). College students experiencing NLEs are at risk of developing DS that could further weaken their academic engagement (AE), while social supports may assuage such negative effect. The aim of this study was to examine the relationship between negative life events, depressive symptoms, and academic engagement, and how the NLE-DS-AE relationship is affected by the level of social support among Chinese college students. To test this hypothesis, we applied data from the Decoding Happiness Gene Cohort Study (DHGCS). Baseline depressive symptoms and academic engagement were measured at the beginning of the first academic year. Approximately 12 months later, negative life events and social support over the past year were assessed retrospectively along with current depressive symptoms and academic engagement. A total of 3629 college students (Age = 18.67 ± 0.82) were included in the study. The prevalence of depressive symptoms was 26.7% and 36.7% in college students at the beginning of the first and second academic year, respectively. Depressive symptoms predicted subsequent academic engagement rather than the reverse based on cross-lagged analyses. Using structural equation modeling analyses, findings revealed a partial mediation effect of social support between negative life events and the development of depressive symptoms, and a partial mediation effect between negative life events and academic engagement. The findings presented negative life events jeopardize the academic engagement via depressive symptoms, while social supports are able to cancel such negative effect among college students under the Chinese cultural context.

RGCC balances self-renewal and neuronal differentiation of neural stem cells in the developing mammalian neocortex.

During neocortical development, neural stem cells (NSCs) divide symmetrically to self-renew at the early stage and then divide asymmetrically to generate post-mitotic neurons. The molecular mechanisms regulating the balance between NSC self-renewal and neurogenesis are not fully understood. Using mouse in utero electroporation (IUE) technique and in vitro human NSC differentiation models including cerebral organoids (hCOs), we show here that regulator of cell cycle (RGCC) modulates NSC self-renewal and neuronal differentiation by affecting cell cycle regulation and spindle orientation. RGCC deficiency hampers normal cell cycle process and dysregulates the mitotic spindle, thus driving more cells to divide asymmetrically. These modulations diminish the NSC population and cause NSC pre-differentiation that eventually leads to brain developmental malformation in hCOs. We further show that RGCC might regulate NSC spindle orientation by affecting the organization of centrosome and microtubules. Our results demonstrate that RGCC is essential to maintain the NSC pool during cortical development and suggest that RGCC defects could have etiological roles in human brain malformations.

PAUPAR and PAX6 sequentially regulate human embryonic stem cell cortical differentiation.

Long noncoding RNAs (lncRNAs) play a wide range of roles in the epigenetic regulation of crucial biological processes, but the functions of lncRNAs in cortical development are poorly understood. Using human embryonic stem cell (hESC)-based 2D neural differentiation approach and 3D cerebral organoid system, we identified that the lncRNA PAUPAR, which is adjacent to PAX6, plays essential roles in cortical differentiation by interacting with PAX6 to regulate the expression of a large number of neural genes. Mechanistic studies showed that PAUPAR confers PAX6 proper binding sites on the target neural genes by directly binding the genomic regions of these genes. Moreover, PAX6 recruits the histone methyltransferase NSD1 through its C-terminal PST enrichment domain, then regulate H3K36 methylation and the expression of target genes. Collectively, our data reveal that the PAUPAR/PAX6/NSD1 complex plays a critical role in the epigenetic regulation of hESC cortical differentiation and highlight the importance of PAUPAR as an intrinsic regulator of cortical differentiation.

No Association Between SLC6A4 Gene Polymorphisms With Treatment Remission to Venlafaxine in Han Chinese Depressive Patients.

OBJECTIVE: Major depressive disorder (MDD) is a heterogeneous psychiatric disorder and considered to be one of the most common mental diseases worldwide. The antidepressant venlafaxine, as a serotonin noradrenaline reuptake inhibitor, is applied to MDD relief. Solute carrier family 6 member 4 (SLC6A4) has been reported to promote the reuptake of serotonin and to be closely correlated to depression. The present study examined whether rs6354 and rs1487971 in SLC6A4 are associated with remission after venlafaxine treatment in MDD patients. METHODS: This study consisted of 195 Han Chinese patients with MDD, who accepted a 6-week treatment with venlafaxine. Two SLC6A4 single-nucleotide polymorphisms (SNPs) were selected from database of SNP and genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometer in MassARRAY Analyzer 4 platforms. The 17-item Hamilton Depression Scale was used to access the severity of major depression. Allele and genotype frequencies between patients in remission and nonremission were calculated with online software SHEsis. RESULTS: No significant differences in allele or genotype frequencies were observed in rs6354 and rs1487971. There were no significant associations between 2 SNPs and venlafaxine treatment outcome. CONCLUSIONS: It suggested that rs6354 or rs1487971 within SLC6A4 appears not to be involved in the venlafaxine treatment outcome in Han Chinese patients with MDD.

Impact of OXTR Polymorphisms on Subjective Well-Being: The Intermediary Role of Attributional Style.

Polymorphisms in the oxytocin receptor (OXTR) gene are related to individual differences in negative emotions, such as depressive symptoms and anxiety. However, it remains unclear what the potential roles of OXTR polymorphisms are in subjective well-being (SWB), which is negatively correlated with depressive symptoms. We examined attributional styles as mediator between SWB and five polymorphisms of the oxytocin receptor gene (OXTR rs53576, rs2254298, rs1042778, rs2268494, and rs2268490) among 627 full-time college freshmen (M age = 20.90, SD = 0.82 for male; M age = 20.81, SD = 0.92 for female) using structural equation modeling. The results showed that individuals with the OXTR rs2254298 AA genotype and rs53576 AA/GA genotype reported higher scores on SWB, which suggested that individuals with this genotype experienced more happiness. Moreover, external attributional style partially mediated the association between OXTR rs2254298 polymorphism and SWB (ß = 0.019, 95%CI [0.001, 0.036], p = 0.035). In conclusion, our findings demonstrated that the genetic variations of OXTR played a role in the individual differences of SWB, and external attribution style could mediate the association.

Interaction of CEND1 gene and life events in susceptibility to depressive symptoms in Chinese Han college students.

BACKGROUND: . The development of depressive symptoms (DSs) is a complex process caused by both genetic and environmental factors. CEND1 gene coordinates cell division, differentiation and maturation of neural precursor cells, which affects brain structure and function. Our study investigated whether CEND1 was a genetic factor for DSs, particularly under negative life events. METHODS: . 272 freshmen with DSs and 467 healthy controls were recruited via the Center for Epidemiologic Studies Depression Scale (CES-D). The adolescent Self-rating Life Event Checklist (ASLEC) was adopted to assess stressful life events during the past 12 months. Two SNPs (rs7946354, rs6597982) within the CEND1 gene were genotyped using Agena MassARRAY iPLEX technology. We combined generalized multifactor dimensionality reduction (GMDR) with RStudio programming to assess the direct association and gene-environment interaction (G × E). RESULTS: . Rs7946354 was associated with DSs in an overdominant model (GT vs. GG+TT). In addition, both rs7946354 and rs6597982 had considerable impacts on negative life events. GMDR showed a statistical G × E that the AG genotype of rs6597982 and GT genotype of rs7946354 contribute to the maximum risk of DSs under high negative life events. LIMITATIONS: . Only two single nucleotide polymorphisms (SNPs) were examined. Verification studies with bigger sample size and more varied demographic background information could be adopted to further support the generalization of these findings. CONCLUSIONS: .CEND1 can potentially cause high sensitivity to life events and affect DSs especially in the presence of negative life events, which contribute to the field of depression prevention and treatment.

Influence and interaction of genetic, cognitive, neuroendocrine and personalistic markers to antidepressant response in Chinese patients with major depression.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Application of Fused Organoid Models to Study Human Brain Development and Neural Disorders.

Human brain organoids cultured from human pluripotent stem cells provide a promising platform to recapitulate histological features of the human brain and model neural disorders. However, unlike animal models, brain organoids lack a reproducible topographic organization, which limits their application in modeling intricate biology, such as the interaction between different brain regions. To overcome these drawbacks, brain organoids have been pre-patterned into specific brain regions and fused to form an assembloid that represents reproducible models recapitulating more complex biological processes of human brain development and neurological diseases. This approach has been applied to model interneuron migration, neuronal projections, tumor invasion, oligodendrogenesis, forebrain axis establishment, and brain vascularization. In this review article, we will summarize the usage of this technology to understand the fundamental biology underpinning human brain development and disorders.

Role of rs454214 in Personality mediated Depression and Subjective Well-being.

Happiness and depression are interlinked and both heritable, while personality, as an important predictor of them, shares the genetic basis with them. We conjecture that genetic factors of depression can affect both depressive symptoms (DS) and subjective well-being (SWB), while personality traits play important roles in mediating this process. In this study, 878 Han Chinese college freshmen and 384 Han Chinese patients with the major depressive disorder (MDD) were included. SNPs were genotyped using AGENA MassARRAY iPLEX technology and we investigated an important MDD variant rs454214. Correlation, association and mediation analysis were employed, aiming to decipher the complex relationship between SWB, DS, personality traits and the genetic variant. Association study indicated that rs454214 was not only associated with both SWB and DS (P < 0.05), but also possibly linked to MDD. Mediational analysis showed that rs454214 had no direct effect on SWB and DS, but had a significant indirect effect through personality traits, i.e., Extraversion, Neuroticism, Agreeableness and Openness to Experience or SWB, Extraversion, Neuroticism and Agreeableness for DS. This study found a shared genetic basis for happiness and depression; the causal process could be better explained if personality traits are taken as mediating factors.

A novel NR3C2 polymorphism and the increased thyroid-stimulating hormone concentration are associated with venlafaxine treatment outcome in Chinese Han MDD patients.

OBJECTIVE: We aimed to study the association among venlafaxine antidepressive outcome, NR3C2 gene polymorphisms and the change of two neuroendocrine hormones during treatment. METHODS: 195 Chinese Han major depressive disorder (MDD) patients were recruited and received a 6-week venlafaxine treatment in this study. Adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH) levels were measured at the beginning and at the end of treatment. Six single-nucleotide polymorphisms (SNPs) (NR3C2: rs1512325, rs1512342, rs2070951; NR3C1: rs6191, rs6196, rs10482614) were selected for high-throughput SNP genotyping. Allele and genotype frequencies of them were compared between remission and non-remission groups. RESULTS: We found that genotype frequency of the rs1512325 located in the NR3C2 gene was significantly different between remission and non-remission groups respectively (p < 0.05). Meanwhile, the frequency of the rs1512325 C-allele was significantly lower (p < 0.05) in remission group. The TSH concentration significantly increased after venlafaxine treatment in remission group (p < 0.05). CONCLUSION: The rs1512325 in NR3C2 gene and TSH concentration may be related to venlafaxine treatment outcome in Chinese Han MDD patients.