Association of intestinal anti-inflammatory drug target genes with psychiatric Disorders: A Mendelian randomization study.

INTRODUCTION: Psychiatric disorders present a substantial global public health burden with limited drug options. The gut-brain axis connects inflammatory bowel diseases and psychiatric disorders, which often have comorbidities. While some evidence hints at anti-inflammatory drugs aiding in treating psychiatric conditions, the specific effects of intestinal anti-inflammatory drugs remain unclear. OBJECTIVES: This study investigates the causal effect of intestinal anti-inflammatory drug targets on psychiatric disorders. We hypothesize that these drug targets may offer new insights into the treatment and prevention of such disorders. Additionally, we explore gut microbiota's mediating role between drug target genes and psychiatric disorders. METHODS: We performed two-sample Mendelian randomization (MR) using summary data from existing expression quantitative trait loci (eQTL) and protein QTL in the brain, along with public genome-wide association studies of disease. We also explored gut microbiota's mediating effect. The statistics encompassed six psychiatric disorders involving 9,725-500,199 individuals. Colocalization analysis enhanced the MR evidence. RESULTS: We uncovered a causal link between TPMT (a target of olsalazine) expression in the amygdala and bipolar disorder (BD) risk (odds ratio [OR] = 1.08; P = 4.29 × 10-4). This association was observed even when the sigmoid colon and whole blood eQTL were considered as exposures. Colocalization analysis revealed a shared genetic variant (rs11751561) between TPMT expression and BD, with a posterior probability of 61.6 %. Interestingly, this causal effect was influenced by a decrease in the gut microbiota abundance of the genus Roseburia (effect proportion = 10.05 %). Moreover, elevated ACAT1 expression was associated with higher obsessive-compulsive disorder risk (OR = 1.62; P = 3.64 × 10-4; posterior probability = 3.1 %). CONCLUSION: These findings provide novel targets for the treatment of psychiatric disorders, underscore the potential of repurposing olsalazine, and emphasize the importance of TPMT and ACAT1 in future drug development.

Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysis.

BACKGROUND: Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. METHODS: We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. FINDINGS: After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. INTERPRETATION: Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. FUNDING: National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.

The Association of Redox Regulatory Drug Target Genes with Psychiatric Disorders: A Mendelian Randomization Study.

Redox regulatory drug (RRD) targets may be considered potential novel drug targets of psychosis due to the fact that the brain is highly susceptible to oxidative stress imbalance. The aim of the present study is to identify potential associations between RRD targets' perturbation and the risk of psychoses; to achieve this, Mendelian randomization analyses were conducted. The expression quantitative trait loci (eQTL) and protein QTL data were used to derive the genetic instrumental variables. We obtained the latest summary data of genome-wide association studies on seven psychoses as outcomes, including schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD), attention-deficit/hyperactivity disorder, autism, obsessive-compulsive disorder and anorexia nervosa. In total, 95 unique targets were included in the eQTL panel, and 48 targets in the pQTL one. Genetic variations in the vitamin C target (OGFOD2, OR = 0.784, p = 2.14 × 10-7) and melatonin target (RORB, OR = 1.263, p = 8.80 × 10-9) were significantly related to the risk of SCZ. Genetic variation in the vitamin E (PRKCB, OR = 0.248, p = 1.24 × 10-5) target was related to an increased risk of BD. Genetic variation in the vitamin C target (P4HTM: cerebellum, OR = 1.071, p = 4.64 × 10-7; cerebellar hemisphere, OR = 1.092, p = 1.98 × 10-6) was related to an increased risk of MDD. Cognitive function mediated the effects on causal associations. In conclusion, this study provides supportive evidence for a causal association between RRD targets and risk of SCZ, BD or MDD, which were partially mediated by cognition.

Genome-wide association study implicates lipid pathway dysfunction in antipsychotic-induced weight gain: multi-ancestry validation.

Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic medication and may contribute to diabetes and coronary heart disease. To expand the unclear genetic mechanism underlying AIWG, we conducted a two-stage genome-wide association study in Han Chinese patients with schizophrenia. The study included a discovery cohort of 1936 patients and a validation cohort of 534 patients, with an additional 630 multi-ancestry patients from the CATIE study for external validation. We applied Mendelian randomization (MR) analysis to investigate the relationship between AIWG and antipsychotic-induced lipid changes. Our results identified two novel genome-wide significant loci associated with AIWG: rs10422861 in PEPD (P = 1.373 × 10-9) and rs3824417 in PTPRD (P = 3.348 × 10-9) in Chinese Han samples. The association of rs10422861 was validated in the European samples. Fine-mapping and functional annotation revealed that PEPD and PTPRD are potentially causal genes for AIWG, with their proteins being prospective therapeutic targets. Colocalization analysis suggested that AIWG and type 2 diabetes (T2D) shared a causal variant in PEPD. Polygenic risk scores (PRSs) for AIWG and T2D significantly predicted AIWG in multi-ancestry samples. Furthermore, MR revealed a risky causal effect of genetically predicted changes in low-density lipoprotein cholesterol (P = 7.58 × 10-4) and triglycerides (P = 2.06 × 10-3) caused by acute-phase of antipsychotic treatment on AIWG, which had not been previously reported. Our model, incorporating antipsychotic-induced lipid changes, PRSs, and clinical predictors, significantly predicted BMI percentage change after 6-month antipsychotic treatment (AUC = 0.79, R2 = 0.332). Our results highlight that the mechanism of AIWG involves lipid pathway dysfunction and may share a genetic basis with T2D through PEPD. Overall, this study provides new insights into the pathogenesis of AIWG and contributes to personalized treatment of schizophrenia.

Application of the partial least square regression method in determining the natural background of soil heavy metals: A case study in the Songhua River basin, China.

The "background" is an essential index for identifying anthropogenic inputs and potential ecological risks of soil heavy metals. However, the lithology of bedrock can cause significant spatial variation in the natural background of soil elements, posing considerable difficulties in estimating background values. In this study, an attempt was made to calculate the natural background through regression analysis of soil chemical composition, and reasonably evaluate the impact of lithology. A total of 1771 surface soil samples were collected from the Songhua River Basin, China, for chemical composition analysis, and the partial least square regression (PLSR) method was employed to establish the relationship between heavy metals (As, Hg, Cr, Cd, Pb, Cu, Zn, and Ni) and soil chemical composition/environmental parameters (SiO2, Al2O3, TFe2O3, MgO, CaO, K2O, Na2O, La, Y, Zr, V, Sc, Sr, Li and pH). The result shows that As, Cr, Pb, Cu, Zn, and Ni have significant linear relationships with soil chemical composition. Each of these six heavy metals obtained 1771 regression background values; some were higher than the uniform background value obtained from the boxplot, while others were lower. The regression background values recognized not only subtle anthropogenic inputs and potential ecological risks in low-background regions but also spurious contamination in high-background areas. All these indicate that the PLSR method can effectively improve the determination accuracy of the natural background of soil heavy metals. More attention should be paid to the serious anthropogenic inputs appearing in some places of the study area.

Association between transition patterns of sleep problems and suicidal ideation in Chinese female nurses: A prospective study.

OBJECTIVE: Suicidal ideation and sleep problems are both common in nurses. However, few longitudinal studies are available to examine the temporal association between sleep and suicidal ideation in nurses. METHOD: Data from the Health Longitudinal Survey of Nurses in Shandong Province was analyzed, involving 623 female nurses who had completed data of concern in 2018 (T1) and 2019 (T2). Sleep problem was assessed by the Pittsburgh Sleep Quality Index, in which the transition patterns for global and specific sleep component and the cumulative number of sleep component problems were defined. Suicidal ideation was measured by the ninth item of the Patient Health Questionnaire. Binary logistic regression was used to explore the association between sleep and suicidal ideation. RESULTS: Chronic and deteriorated global sleep problems is associated with a greater risk of suicidal ideation. For the specific component of sleep, sleep disturbance and short sleep duration are associated with a higher risk of suicidal ideation. The higher number of cumulative sleep component problems is associated with a higher risk of suicidal ideation. CONCLUSION: Findings indicate sleep disturbance and short sleep duration may be pathways to suicidal ideation. Initiatives that target at sleep problems may be important to reduce suicidal ideation in nurses.

Acute Macular Neuroretinopathy after SARS-CoV-2 Infection: An Analysis of Clinical and Multimodal Imaging Characteristics.

BACKGROUND: This study aimed to analyze clinical and multimodal imaging characteristics of acute macular neuroretinopathy (AMN) post-recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Retrospective observational study. Medical records and multimodal imaging of 12 AMN eyes of eight patients (six female and two male) with recent SARS-CoV-2 infection were retrospectively analyzed. RESULTS: Four patients (50%) presented with bilateral AMN. Fundus ophthalmoscopy revealed a reddish-brown lesion around the macula, and two eyes had cotton-wool spots at the posterior pole. Three eyes showed mild hypo-autofluorescence. All FFA images (7 eyes) showed no abnormal signs. On OCT scans, all eyes showed outer nuclear layer (ONL) thinning, 8 eyes (66.7%) showed ONL hyperreflectivity, 5 eyes (41.7%) showed outer plexiform layer (OPL) hyperreflectivity, 8 eyes (66.7%) showed interdigitation zone (IZ) disruption, 11 eyes (91.6%) showed ellipsoid zone (EZ) disruption, 2 eyes (16.7%) showed cotton-wool spots and inner plexiform layer (IPL) hyperreflectivity, 1 eye (8.3%) had intraretinal cyst and 1 eye (8.3%) had inner nuclear layer (INL) thinning. Persistent scotoma, ONL hyperreflectivity and IZ/EZ disruption as well as recovery of OPL hyperreflectivity were reported after follow-up in three cases. CONCLUSIONS: AMN post-SARS-CoV-2 mostly affected young females and could present unilaterally or bilaterally. Dark lesions on IR reflectance and outer retinal hyperreflectivity on OCT are useful in diagnosing AMN. OPL/ONL hyperreflectivity on OCT could disappear after follow-up, but ONL thinning and IZ/EZ could persist.

Multigenetic Pharmacogenomics-Guided Treatment vs Treatment As Usual Among Hospitalized Men With Schizophrenia: A Randomized Clinical Trial.

Importance: Limited evidence supports multigenetic pharmacogenomics-guided treatment (MPGT) in schizophrenia. Objective: To evaluate the clinical effectiveness of MPGT in schizophrenia in a randomized clinical trial (RCT). Design, Setting, and Participants: This RCT was conducted from March 2020 to March 2022. Male Chinese Han inpatients aged 18 to 60 years diagnosed with schizophrenia with a Positive and Negative Symptom Scale (PANSS) score of 60 or more from 2 selected study hospitals were included. Patients and raters were masked to MPGT or treatment as usual (TAU) randomization. Interventions: Participants were randomly assigned in a 1:1 ratio to receive either MPGT or TAU for 12 weeks. Main Outcomes and Measures: The primary efficacy outcome was the percentage change in PANSS total scores (range, 30 to 210) from baseline to week 6 analyzed by a modified intention-to-treat mixed model for repeated measures. The secondary outcome included response and symptomatic remission rates. Results: A total of 210 participants (mean [SD] age, 29.2 [8.8] years) were enrolled and analyzed, with 113 assigned to MPGT and 97 to TAU. Compared with those randomized to TAU, participants randomized to MPGT demonstrated a significantly higher percentage change in PANSS score (74.2% vs 64.9%; adjusted mean difference, 9.2 percentage points; 95% CI, 4.4-14.1 percentage points; P < .001) and a higher response rate (93 of 113 [82.3%] vs 63 of 97 [64.9%]; adjusted odds ratio, 2.48; 95% CI, 1.28-4.80; P = .01) at the end of week 6. Conclusions and Relevance: In this RCT of MPGT, MPGT was more effective than TAU in treating patients with schizophrenia. These findings suggest that multigenetic pharmacogenomic testing could serve as an effective tool to guide the treatment of schizophrenia. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000029671.

Predictive role of pulvinar in social functional outcome of schizophrenia.

Identifying objective biological subtypes that predict long-term functional outcomes is crucial for understanding neurobiological mechanisms and identifying potential targets. Using resting-state functional magnetic resonance imaging data from 178 patients and 70 controls, we explored social function patterns using latent profile analysis. Long-term outcomes were compared among the biological subtypes using K-means clustering. Partial least squares regression (PLSR) was used to identify gene expression profiles associated with alterations in activity by leveraging transcriptional data from the Allen Human Brain Atlas. In patients with more functional impairment, left medial pulvinar (PM) exhibited significantly lower regional homogeneity of brain activity (ReHo, [95% CI (0.06-0.27), P = 0.002), a finding validated in the independent cohort. Functional connectivity between PM and secondary visual cortex displayed a suggestive decrease. Patients belonging to "higher pulvinar ReHo - better information processing" demonstrated better long-term outcomes and acute treatment response [95% CI (11.2-34.4), P < 0.001]. The PLSR component of imaging-transcriptomic associations partly explained the ReHo differences among patients with varying levels of functional impairment. It revealed enrichment of genes in the synaptic signaling pathway. Pathological changes in the pulvinar may affect social functioning. Higher pulvinar ReHo and better information processing, two objective biomarkers, have a predictive value for better long-term functional outcomes.

Genome-wide association study identified six loci associated with adverse drug reactions to aripiprazole in schizophrenia patients.

Aripiprazole is recommended for routine use in schizophrenia patients. However, the biological mechanism for the adverse drug reactions (ADRs) among schizophrenia patients with the antipsychotic drug aripiprazole is far from clear. To explore the potential genetic factors that may cause movement-related adverse antipsychotic effects in patients, we conducted an association analysis between movement-related ADRs and SNPs in schizophrenia patients receiving aripiprazole monotherapy. In this study, multiple ADRs of 384 patients were quantified within 6-week treatment, and the scores of movement-related ADRs at baseline and follow-up time points during treatment were obtained. The highest score record was used as the quantitative index in analysis, and genetic analysis at the genome-wide level was conducted. The SNP rs4149181 in SLC22A8 [P = 2.28 × 10-8] showed genome-wide significance, and rs2284223 in ADCYAP1R1 [P = 9.76 × 10-8], rs73258503 in KCNIP4 [P = 1.39 × 10-7], rs678428 in SMAD9 [P = 4.70 × 10-7], rs6421034 in NAP1L4 [P = 6.80 × 10-7], and rs1394796 in ERBB4 [P = 8.60 × 10-7] were found to be significantly associated with movement-related ADRs. The combined prediction model of these six loci showed acceptable performance in predicting adverse events [area under the curve (AUC): 0.84]. Combined with the function and network of the above genes and other candidate loci (KCNA1, CACNG1, etc.), we hypothesize that SLC22A8 and KCNIP4-Kv channel perform their respective functions as transporter or channel and participate in the in vivo metabolism or effects of aripiprazole. The above results imply the important function of ion transporters and channels in movement-related adverse antipsychotic effects in aripiprazole monotherapy schizophrenia patients.

Dissecting the causal association between social or physical inactivity and depression: a bidirectional two-sample Mendelian Randomization study.

A growing body of research suggests that social or physical activity can affect the risk of Major depressive disorder (MDD). However, the bidirectional relationship between them remains to be clarified further, especially between inactivity and MDD. Here, we performed a two-sample Mendelian Randomization analysis using genetic variants associated with social/physical activities and MDD, and assessed the mediating effect of obesity-related measures and brain imaging phenotypes. The dataset on MDD, social activities, and physical activities included 500,199; 461,369; 460,376 individuals, respectively. Information regarding body mass index (BMI), body fat percentage (BFP), IDPs for 454,633; 461,460; 8,428 participants, respectively. We identified bidirectional causal relationships between sport clubs or gyms, strenuous sports, heavy do-it-youself, other exercises and MDD. We also observed that leisure/social inactivity (odds ratio [OR] = 1.64; P = 5.14 × 10-5) or physical inactivity (OR = 3.67; P = 1.99 × 10-5) caused an increased risk of MDD, which were partially mediated by BMI or BFP and masked by the weighted-mean orientation dispersion index of left acoustic radiation or volume of right caudate. Furthermore, we discovered that MDD increased the risk of leisure/social inactivity (OR = 1.03; P = 9.89 × 10-4) or physical inactivity (OR = 1.01; P = 7.96 × 10-4). In conclusions, we found that social/physical activities reduced the risk of MDD, while MDD in turn hindered social/physical activities. Inactivity may increase the risk of MDD, which was mediated or masked by brain imaging phenotypes. These results help to understand the manifestations of MDD and provide evidence and direction for the advancement of intervention and prevention.

Role of the EM clustering method in determining the geochemical background of As and Cr in soils: a case study in the north of Changchun, China.

Determining the geochemical background for heavy metals is vital in soil management activities. Although many statistical methods for geochemical background determination have been proposed, the multi-population problem of geochemical data, primarily regional ones, derived mainly from mixing multiple populations belonging to various geological sources or processes, needs to be better addressed. In this study, the Expectation-Maximization (EM) algorithm was employed to separate multiple populations in a 1:250,000 scale regional geochemical data set of soils in a lithologically complex region in the north of Changchun, China. The data set included 3746 surface soil samples analyzed for SiO2, K2O, Al2O3, CaO, La, Rb, Y, Ti, Ce, V, Cr, and As. The potential high-risk areas of As and Cr were determined before and after the separation of multiple populations. The comparison results show that the EM clustering method can efficiently separate multiple populations and determine soil geochemical background more reasonably, thus eliminating false contamination that is easily misidentified and better revealing concealed contamination that is challenging to detect.

Comparison of the probability of four anticonvulsant mood stabilizers to facilitate polycystic ovary syndrome in women with epilepsies or bipolar disorder-A systematic review and meta-analysis.

Background: Patients treated with anticonvulsant mood stabilizers have a higher incidence of polycystic ovary syndrome (PCOS). However, there is no comparison between different anticonvulsant mood stabilizers. The purpose of this study was to systematically evaluate the prevalence of PCOS in women taking anticonvulsant mood stabilizers and compare the probability of PCOS caused by different anticonvulsant mood stabilizers. Methods: Five databases, namely PubMed, Embase, Web of Science, Cochrane Library, and Clinical Trials, were searched for literature on anticonvulsant mood stabilizers and PCOS published up to October 28, 2022. This meta-analysis was performed using Revman 5.4, Stata 14.0, and R4.1.0, and effect size pooling was performed in fixed- or random-effects models based on the results of I2 and Q-test, and the surface under the cumulative ranking curve (SUCRA) was used for analysis to assess the cumulative probability of drug-induced PCOS. Publication bias was assessed by funnel plot Egger's test and meta regression. Results: Twenty studies with a total of 1,524 patients were included in a single-arm analysis, which showed a combined effect size (95% CI) of 0.21 (0.15-0.28) for PCOS in patients taking anticonvulsant mood stabilizers. Nine controlled studies, including 500 patients taking medication and 457 healthy controls, were included in a meta-analysis, which showed OR = 3.23 and 95% CI = 2.19-4.76 for PCOS in women taking anticonvulsant mood stabilizers. Sixteen studies with a total of 1416 patients were included in a network meta-analysis involving four drugs, valproate (VPA), carbamazepine (CBZ), oxcarbazepine (OXC), and lamotrigine (LTG), and the results of the network meta-analysis showed that VPA (OR = 6.86, 95% CI = 2.92-24.07), CBZ (OR = 3.28, 95% CI = 0.99-12.64), OXC (OR = 4.30, 95% CI = 0.40-49.49), and LTG (OR = 1.99, 95% CI = 0.16-10.30), with cumulative probabilities ranked as VPA (90.1%), OXC (63.9%), CBZ (50.1%), and LTG (44.0%). Conclusion: The incidence of PCOS was higher in female patients treated with anticonvulsant mood stabilizers than in the healthy population, with VPA having the highest likelihood of causing PCOS. The most recommended medication when considering PCOS factors is LTG. Systematic review registration: identifier: CRD42022380927.

Therapeutic outcomes wide association scan of different antipsychotics in patients with schizophrenia: Randomized clinical trials and multi-ancestry validation.

AIM: This study identified discrepant therapeutic outcomes of antipsychotics. METHODS: A total of 5191 patients with schizophrenia were enrolled, 3030 as discovery cohort, 1395 as validation cohort, and 766 as multi-ancestry validation cohort. Therapeutic Outcomes Wide Association Scan was conducted. Types of antipsychotics (one antipsychotic vs other antipsychotics) were dependent variables, therapeutic outcomes including efficacy and safety were independent variables. RESULTS: In discovery cohort, olanzapine related to higher risk of weight gain (AIWG, OR: 2.21-2.86), liver dysfunction (OR: 1.75-2.33), sedation (OR: 1.76-2.86), increased lipid level (OR: 2.04-2.12), and lower risk of extrapyramidal syndrome (EPS, OR: 0.14-0.46); risperidone related to higher risk of hyperprolactinemia (OR: 12.45-20.53); quetiapine related to higher risk of sedation (OR = 1.73), palpitation (OR = 2.87), increased lipid level (OR = 1.69), lower risk of hyperprolactinemia (OR: 0.09-0.11), and EPS (OR: 0.15-0.44); aripiprazole related to lower risk of hyperprolactinemia (OR: 0.09-0.14), AIWG (OR = 0.44), sedation (OR: 0.33-0.47), and QTc prolongation (ß = -2.17); ziprasidone related to higher risk of increased QT interval (ß range: 3.11-3.22), nausea (OR: 3.22-3.91), lower risk of AIWG (OR: 0.27-0.46), liver dysfunction (OR: 0.41-0.38), and increased lipid level (OR: 0.41-0.55); haloperidol related to higher risk of EPS (OR: 2.64-6.29), hyperprolactinemia (OR: 5.45-9.44), and increased salivation (OR: 3.50-3.68). Perphenazine related to higher risk of EPS (OR: 1.89-2.54). Higher risk of liver dysfunction in olanzapine and lower risk of hyperprolactinemia in aripiprazole were confirmed in validation cohort, and higher risk of AIWG in olanzapine and hyperprolactinemia in risperidone were confirmed in multi-ancestry validation cohort. CONCLUSION: Future precision medicine should focus on personalized side-effects.

The positive association between antipsychotic-induced weight gain and therapeutic response: New biotypes of schizophrenia.

Co-occurrence of antipsychotic-induced weight gain (AIWG) and therapeutic response (TR) did exist in clinic but was rarely studied. This study aims to identify potential TR/ AIWG biotypes and explore the clinical, genetic and neuroimaging features. This study enrolled 3030 patients to identify potential TR/AIWG biotypes and explore the clinical, genetic and neuroimaging features. We found three biotypes: TR+nonAIWG (46.91%), TR+AIWG (18.82%), and nonTR+nonAIWG (34.27%). TR+AIWG showed lower weight and lipid level at baseline, but higher changing rate, and higher genetic risk of obesity than TR+nonAIWG and nonTR+nonAIWG. GWAS identified ADIPOQ gene related to TR+AIWG biotypes and top-ranked loci enriched in one-carbon metabolic process, which related to both schizophrenia and metabolic dysfunction. Genetically predicted TR+AIWG was associated with higher odds of diabetes (OR=1.05). The left supplementary motor area was significantly negatively correlated with PRS of obesity. The distinguishing ability with multi-omics data to identify TR+AIWG reached 0.787. In a word, the "thin" patients with a higher risk of obesity are the target population of early intervention.

Scalable mixed model methods for set-based association studies on large-scale categorical data analysis and its application to exome-sequencing data in UK Biobank.

The ongoing release of large-scale sequencing data in the UK Biobank allows for the identification of associations between rare variants and complex traits. SAIGE-GENE+ is a valid approach to conducting set-based association tests for quantitative and binary traits. However, for ordinal categorical phenotypes, applying SAIGE-GENE+ with treating the trait as quantitative or binarizing the trait can cause inflated type I error rates or power loss. In this study, we propose a scalable and accurate method for rare-variant association tests, POLMM-GENE, in which we used a proportional odds logistic mixed model to characterize ordinal categorical phenotypes while adjusting for sample relatedness. POLMM-GENE fully utilizes the categorical nature of phenotypes and thus can well control type I error rates while remaining powerful. In the analyses of UK Biobank 450k whole-exome-sequencing data for five ordinal categorical traits, POLMM-GENE identified 54 gene-phenotype associations.

Identifying causal associations between early sexual intercourse or number of sexual partners and major depressive disorders: A bidirectional two-sample Mendelian randomization analysis.

BACKGROUND: Early sexual intercourse and a greater number of sexual partners have been proved associated with depression. However, the causality of these associations is not clear. METHODS: To unveil the causal associations between sexual factors and major depression disorder (MDD). The bidirectional, two-sample Mendelian randomization (MR) study was conducted, which used genetic variants associated with two sexual factors (age first had sexual intercourse, n = 406,457; lifetime number of sexual partners, n = 378,882) and MDD (n = 500,199) from the largest genome-wide association studies (GWASs) conducted by the UK biobank and the Psychiatric Genomics Consortium. The two-step MR analysis was applied to assess mediation. The Genetic predictors for five risky behaviors were also obtained from the most up-to-date GWAS conducted by the UK Biobank (ever self-harmed: 117,733; ever attempted suicide: 4933; psychoactive substance abuse, alcohol use, and tobacco use: 463,010). RESULTS: MR analysis indicated a risky causal effect of age first had sexual intercourse (OR = 0.720, 95 % CI: 0.661-0.784, P = 2.45 × 10-14) and lifetime number of sexual partners (OR = 1.656, 95 % CI: 1.356-2.022, P = 7.46 × 10-7) on MDD. Mediation analysis showed the effects were mediated by tobacco use, with a proportion of 34.20 % on age first had sexual intercourse and 22.94 % on lifetime number of sexual partners separately. LIMITATIONS: The overlap of participants in different traits and unclear gender. CONCLUSIONS: Robust genetic evidence indicated that premature sexual intercourse and more sexual partners were risks for MDD. Risky behaviors, especially the tobacco use, mediated this effect.

High-risk group and functional subtypes of non-suicidal self-injury in young adults with mental disorders.

Background: Identifying high-risk groups of non-suicidal self-injury (NSSI) with multiple risk factors and different functional subtypes contribute to implementing person-centered interventions. Methods: We investigated NSSI profiles among a sample of 258 psychiatric inpatients aged 18-25 years. All participants completed well-validated measures of internal personal and external environmental characteristics. One-hundred and ninety patients reported a lifetime history of NSSI and completed an additional NSSI assessment. A k-means cluster analysis was conducted to extract characteristics of risk factors and functional subtypes. Independent sample t-test, analysis of variance and χ 2 test were used to test the difference of demographic statistical factors, risk factors and functional scores among groups with different frequency of NSSI. Results: The clustering of risk factors analyses supported 4-clusters. The proportion of repeat NSSI patients was the highest (67.1%) in the group with unfavorable personal and unfavorable environmental characteristics. Functional subtype clustering analyses supported 5-clusters. Among patients with repeated NSSI, those with depression were mainly accompanied by the "Sensation Seeking" subtype (39.7%), bipolar disorder mainly supported the "Anti-suicide" subtype (37.9%), and eating disorders were mostly "Social Influence" subtype (33.3%). There was an interaction between functional subtypes and mental disorders. Limitations: All participants were in treatment in a psychiatric service and the results may not be generalizable to a community sample. The data included retrospective self-report which may be inaccurate due to recall bias. Conclusion: It is necessary to identify high-risk groups of NSSI who with unfavorable personal and environmental characteristics and clinical interventions need to consider the heterogeneity of patients' functional subtypes of NSSI.

Psychometric properties of the Chinese version of the Cognitive Reserve Assessment Scale in Health in patients with cancer.

BACKGROUND: Cognitive reserve is a modifiable factor that could prevent cognitive decline in patients with cancer. The Cognitive Reserve Assessment Scale in Health (CRASH) is an instrument used to assess cognitive reserve. This study aims to develop and examine the psychometric properties of the Chinese version of the CRASH for patients with cancer. METHODS: A cross-sectional survey was conducted with 167 cancer patients from four wards of two hospitals in China. Thirty-one patients were re-assessed to examine the test-retest reliability. Four translators and three reviewers developed the Chinese version of the scale. We assessed its structural validity, concurrent validity, internal consistency, test-retest reliability, measurement error, and floor/ceiling effects. RESULTS: Confirmatory factor analysis showed a good model fit with the four-factor structure of the original CRASH. The CRASH scores were statistically significantly associated with neuropsychological test scores, indicating sufficient concurrent validity. The internal consistency was acceptable, except for leisure activities, with standardized Cronbach's alphas (0.64-0.94) and standardized Omega (0.66-0.95). There was excellent test-retest reliability, with a high intraclass correlation coefficient (0.914-0.993) of total scores and scores for each domain. The measurement error was acceptable, and no floor or ceiling effects were observed. CONCLUSIONS: The Chinese version of the CRASH is a valid and reliable instrument to assess cognitive reserve in patients with cancer. Moreover, cognitive reserve measured by the CRASH was associated with low cognitive performance in cancer patients.

Yoga and Mindfulness for Social-Emotional Development and Resilience in 3-5 Year-Old Children: Non-Randomized, Controlled Intervention.

Background: Early childhood is the key life course period for development of social-emotional skills, providing the foundation for school readiness and resilience in later life. Age-appropriate yoga and mindfulness programs may contribute to the development of critical skills in children. Young children from minoritized communities that face structural racism and health disparities may benefit from programs that support social-emotional development and contribute to future academic success. Systematic reviews of yoga interventions for young children have indicated the potential for effectiveness in supporting social-emotional development, executive function, and physical activity. However, studies of yoga and mindfulness with non-White children are sparse and, overall, the evidence base to date for such programs remains limited by non-controlled studies and the variable quality of studies evaluating programs in early childhood settings. Methods: The analysis of data from a non-randomized, controlled intervention aimed to assess the effect of exposure to a yoga and mindfulness program for early childhood development of social-emotional skills in a majority Black/African American urban preschool setting in southeastern US. Children in the intervention received group yoga and mindfulness led by a certified children's yoga teacher who also had training and experience as a school teacher. Intervention participants engaged in activities for 20 minutes once per week for 32 weeks, while the control group had no yoga. The final sample included 579 in the historical control group and 122 in the intervention group. Results: Results indicated that children who participated in the yoga and mindfulness program had higher total protective factor (TPF) subscores on the Devereux Early Childhood Assessment over time than children who did not receive yoga and mindfulness programming, and that the difference was statistically significant (P<0.05). Participation in the intervention group significantly predicted increases in initiative score, self-control score, and TPF score, as well as a decrease in the behavioral concerns. Discussion: School based yoga and mindfulness programming can support social-emotional skills and resilience in young children. Additional studies with larger sample sizes and randomization are needed on use of yoga and mindfulness in young children for social-emotional development, particularly for Black/African American children and others from minoritized communities.