Adipose METTL14-Elicited N6 -Methyladenosine Promotes Obesity, Insulin Resistance, and NAFLD Through Suppressing ß Adrenergic Signaling and Lipolysis.

White adipose tissue (WAT) lipolysis releases free fatty acids as a key energy substance to support metabolism in fasting, cold exposure, and exercise. Atgl, in concert with Cgi-58, catalyzes the first lipolytic reaction. The sympathetic nervous system (SNS) stimulates lipolysis via neurotransmitter norepinephrine that activates adipocyte ß adrenergic receptors (Adrb1-3). In obesity, adipose Adrb signaling and lipolysis are impaired, contributing to pathogenic WAT expansion; however, the underling mechanism remains poorly understood. Recent studies highlight importance of N6 -methyladenosine (m6A)-based RNA modification in health and disease. METTL14 heterodimerizes with METTL3 to form an RNA methyltransferase complex that installs m6A in transcripts. Here, this work shows that adipose Mettl3 and Mettl14 are influenced by fasting, refeeding, and insulin, and are upregulated in high fat diet (HFD) induced obesity. Adipose Adrb2, Adrb3, Atgl, and Cgi-58 transcript m6A contents are elevated in obesity. Mettl14 ablation decreases these transcripts' m6A contents and increases their translations and protein levels in adipocytes, thereby increasing Adrb signaling and lipolysis. Mice with adipocyte-specific deletion of Mettl14 are resistant to HFD-induced obesity, insulin resistance, glucose intolerance, and nonalcoholic fatty liver disease (NAFLD). These results unravel a METTL14/m6A/translation pathway governing Adrb signaling and lipolysis. METTL14/m6A-based epitranscriptomic reprogramming impairs adipose Adrb signaling and lipolysis, promoting obesity, NAFLD, and metabolic disease.

TULP4, a novel E3 ligase gene, participates in neuronal migration as a candidate in schizophrenia.

BACKGROUND: TUB-like protein 4 (TULP4) is one of the distant members of tubby family proteins, whose function remains largely unknown. In the present study, we intend to identify the role of TULP4 in schizophrenia from human samples and animal models. METHODS: Whole-exome sequencing was used to detect the four schizophrenia families collected. In different cell lines, the effects of identified variants in TULP4 gene on its expression and localization were analyzed. Knockdown models in utero and adult mice were employed to investigate the role of Tulp4 on neuronal migration and schizophrenia-related behavior. Subsequently, co-IP assays were used to search for proteins that interact with TULP4 and the effects of mutants on the molecular function of TULP4. RESULTS: For the first time, we identified five rare variants in TULP4 from schizophrenia families, of which three significantly reduced TULP4 protein expression. Knockdown the expression of Tulp4 delayed neuronal migration during embryological development and consequently triggered abnormal behaviors in adult mice, including impaired sensorimotor gating and cognitive dysfunction. Furthermore, we confirmed that TULP4 is involved in the formation of a novel E3 ligase through interaction with CUL5-ELOB/C-RNF7 and the three deleterious variants affected the binding amount of TULP4 and CUL5 to a certain extent. CONCLUSIONS: Together, we believe TULP4 plays an important role in neurodevelopment and subsequent schizophrenic-related phenotypes through its E3 ubiquitin ligase function.

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.

Reduction of mRNA m6A associates with glucose metabolism via YTHDC1 in human and mice.

AIMS: N6-methyladenosine (m6A) in mRNA is involved in glucose metabolism. Our goal is to investigate the relationship of glucose metabolism, m6A and YTH domain-containing protein 1 (YTHDC1), a binding protein to m6A, in the development of type 2 diabetes (T2D). METHODS: HPLC-MS/MS and qRT-PCR were used to quantify m6A and YTHDC1 levels in white blood cells from patients with T2D and healthy individuals. MIP-CreERT and tamoxifen treatment were used to create ß-cell Ythdc1 knockout mice (ßKO). m6A sequencing and RNA sequencing were performed in wildtype/ßKO islets and MIN6 cells to identify the differential genes. RESULTS: In T2D patients, both of m6A and YTHDC1 levels were reduced and associated with fasting glucose. Deletion of Ythdc1 resulted in glucose intolerance and diabetes due to decreased insulin secretion, even though ß-cell mass in ßKO mice was comparable to wildtype mice. Moreover, Ythdc1 was shown to bind to SRSF3 (serine/arginine-rich splicing factor 3) and CPSF6 (cleavage and polyadenylation specific factor 6) in ß-cells. CONCLUSIONS: Our data suggested that YTHDC1 may regulate mRNA splicing and export by interacting with SRSF3 and CPSF6 to modulate glucose metabolism via regulating insulin secretion, implying YTHDC1 might be a novel potential target for lowing glucose.

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.

NGFR Gene and Single Nucleotide Polymorphisms, rs2072446 and rs11466162, Playing Roles in Psychiatric Disorders.

Psychiatric disorders are a class of complex disorders characterized by brain dysfunction with varying degrees of impairment in cognition, emotion, consciousness and behavior, which has become a serious public health issue. The NGFR gene encodes the p75 neurotrophin receptor, which regulates neuronal growth, survival and plasticity, and was reported to be associated with depression, schizophrenia and antidepressant efficacy in human patient and animal studies. In this study, we investigated its association with schizophrenia and major depression and its role in the behavioral phenotype of adult mice. Four NGFR SNPs were detected based on a study among 1010 schizophrenia patients, 610 patients with major depressive disorders (MDD) and 1034 normal controls, respectively. We then knocked down the expression of NGFR protein in the hippocampal dentate gyrus of the mouse brain by injection of shRNA lentivirus to further investigate its behavioral effect in mice. We found significant associations of s2072446 and rs11466162 for schizophrenia. Ngfr knockdown mice showed social and behavioral abnormalities, suggesting that it is linked to the etiology of neuropsychiatric disorders. We found significant associations between NGFR and schizophrenia and that Ngfr may contribute to the social behavior of adult mice in the functional study, which provided meaningful clues to the pathogenesis of psychiatric disorders.

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.

The association between rs1260326 with the risk of NAFLD and the mediation effect of triglyceride on NAFLD in the elderly Chinese Han population.

BACKGROUND: Accumulated studies have pointed out the striking association between variants in or near APOC3, GCKR, PNPLA3, and nonalcoholic fatty liver disease (NAFLD) at various ages from multiple ethnic groups. This association remained unclear in the Chinese Han elderly population, and whether this relationship correlated to any clinical parameters was also unclear. OBJECTIVES: This study aims to decipher the complex relevance between gene polymorphisms, clinical parameters, and NAFLD by association study and mediation analysis. METHODS: Eight SNPs (rs2854116, rs2854117, rs780093, rs780094, rs1260362, rs738409, rs2294918, and rs2281135) within APOC3, GCKR, and PNPLA3 were genotyped using the MassARRAY® platform in a large Chinese Han sample comprising of 733 elderly NAFLD patients and 824 age- and ethnic-matched controls. Association and mediation analysis were employed by R. RESULTS: The genotypic frequencies of rs1260326 and rs780094 were significantly different between NAFLD and control (rs1260326: P=0.004, Pcorr=0.020, OR [95%CI]= 0.69 [0.54-0.89]; rs780094: P=0.005, Pcorr=0.025, OR [95%CI]= 0.70 [0.55-0.90]). Particularly, an increased triglyceride level was observed in carriers of rs1260326 T allele (1.94±1.19 mmol/L) compared with non-carriers (1.73±1.05 mmol/L).no significant results were observed in rs780094. Notably, triglyceride levels had considerably indirect impacts on association between NAFLD and rs1260326 (ß =0.01, 95% CI: 0.01-0.02), indicating that 12.7% of the association of NAFLD with rs1260326 was mediated by triglyceride levels. CONCLUSIONS: Our results identified a prominent relationship between GCKR rs1260326 and NAFLD, and highlighted the mediated effect of triglyceride levels on the that association in the Chinese Han elderly.

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.

Structure and Membrane Targeting of the PDZD7 Harmonin Homology Domain (HHD) Associated With Hearing Loss.

Usher syndrome (USH) is the leading cause of hereditary hearing-vision loss in humans. PDZ domain-containing 7 (PDZD7) has been reported to be a modifier of and contributor to USH. PDZD7 co-localizes with USH2 proteins in the inner ear hair cells and is essential for ankle-link formation and stereocilia development. PDZD7 contains three PDZ domains and a low-complexity region between the last two PDZ domains, which has been overlooked in the previous studies. Here we characterized a well-folded harmonin homology domain (HHD) from the middle region and solved the PDZD7 HHD structure at the resolution of 1.49 Å. PDZD7 HHD adopts the same five-helix fold as other HHDs found in Harmonin and Whirlin; however, in PDZD7 HHD, a unique α1N helix occupies the canonical binding pocket, suggesting a distinct binding mode. Moreover, we found that the PDZD7 HHD domain can bind lipid and mediate the localization of PDZD7 to the plasma membrane in HEK293T cells. Intriguingly, a hearing-loss mutation at the N-terminal extension region of the HHD can disrupt the lipid-binding ability of PDZD7 HHD, suggesting that HHD-mediated membrane targeting is required for the hearing process. This structural and biochemical characterization of the PDZD7 HHD region provides mechanistic explanations for human deafness-causing mutations in PDZD7. Furthermore, this structure will also facilitate biochemical and functional studies of other HHDs.

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.

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.

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.

Association and functional study between ADIPOQ and metabolic syndrome in elderly Chinese Han population.

OBJECTIVE: Metabolic syndrome (MetS) is a cluster of health problems that places individuals at higher risk of developing cardiovascular disease, diabetes and stroke. The prevalence of MetS is increasing worldwide. It is also well accepted that genetic and environmental factors play significant roles in the occurrence/development of MetS, but studies exploring genetic factors are still lacking. Here, we aimed to investigate the association of ADIPOQ gene variants with MetS in an elderly Chinese Han population. RESULTS: We found that the allelic frequencies of rs6773957 and rs3774261 were significantly different between MetS and the control (p = 0.031; p = 0.049). Furthermore, a reduction in luciferase activity was observed when HEK293T cells were transfected with rs6773957 mutant fragments compared with wild type. CONCLUSION: Our results suggest that rs6773957 and rs3774261 of ADIPOQ were associated with MetS in the elderly Chinese Han population. The functional assays performed indicate that the rs6773957 variant might be pathogenic and may provide evidence for mechanistic studies of MetS in the future. METHODS: Four single nucleotide polymorphisms (SNPs) were selected and genotyped (rs6773957, rs182052, rs3774261 and rs17366568) in 1337 subjects, including 569 healthy controls and 768 MetS cases. The clinical characteristics of all the subjects were obtained and analyzed. Additionally, a functional study of rs6773957 in regulating the expression of ADIPOQ was performed in this study.

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.