Genome-wide meta-analysis identifies ancestry-specific loci for Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. METHODS: We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. RESULTS: In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. DISCUSSION: The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. HIGHLIGHTS: Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.

Shift work effects on incident neuropsychiatric disorders and shift work tolerance.

BACKGROUND: Shift work is associated with susceptibility to several neuropsychiatric disorders. This study aims to investigate the effect of shift work on the incidence of neuropsychiatric disorders, and highlighting how individual variability may influence the association. METHODS: UK Biobank participants with employment information were included. Cox survival was conducted in main and subgroup analyses. Correlation analyses explored the impact of shift work on brain structures, and mediation analyses were performed to elucidate the shared underlying mechanisms. Shift work tolerance was evaluated through survival analyses contrasting the risks associated with five neuropsychiatric disorders in shift versus non-shift workers across different demographic or occupational strata. RESULTS: The analysis encompassed 254,646 participants. Shift work was associated with higher risk of dementia (HR 1.29, 95 % CI 1.10-1.52), anxiety (1.08, 1.01-1.15), depression (1.29, 1.22-1.36), and sleep disorders (1.18, 1.09-1.28), but not stroke (p = 0.20). Shift work was correlated with decreasing volume of various brain regions, particularly in thalamus, lateral orbitofrontal, and middle temporal. Mediation analysis revealed that increased immune response and glucose levels are common pathways linking shift work to these disorders. We observed diversity in shift work tolerance across different individual characteristics, among which socioeconomic status and length of working hours were the most essential. LIMITATIONS: Self-reported employment information may cause misclassification and recall bias. And since we focused on the middle-aged population, the conclusions may not be representative of younger or older populations. CONCLUSIONS: Our findings indicated the need to monitor shift worker health and provide personalized management to help adapt to shift work.

Depression in Alzheimer's Disease: Epidemiology, Mechanisms, and Treatment.

Depression and Alzheimer's disease (AD) are substantial public health concerns. In the past decades, a link between the 2 disease entities has received extensive acknowledgment, yet the complex nature of this relationship demands further clarification. Some evidence indicates that midlife depression may be an AD risk factor, while a chronic course of depression in late life may be a precursor to or symptom of dementia. Recently, multiple pathophysiological mechanisms have been proposed to underlie the bidirectional relationship between depression and AD, including genetic predisposition, immune dysregulation, accumulation of AD-related biomarkers (e.g., amyloid-ß and tau), and alterations in brain structure. Accordingly, numerous therapeutic approaches, such as pharmacology treatments, psychotherapy, and lifestyle interventions, have been suggested as potential means of interfering with these pathways. However, the current literature on this topic remains fragmented and lacks a comprehensive review characterizing the association between depression and AD. In this review, we aim to address these gaps by providing an overview of the co-occurrence and temporal relationship between depression and AD, as well as exploring their underlying mechanisms. We also examine the current therapeutic regimens for depression and their implications for AD management and outline key challenges facing the field.

The relationship between self-esteem and aggressive behavior among Chinese adolescents: A moderated chain mediation model.

This study aimed to examine the relationship between adolescent self-esteem and aggressive behavior. Specifically, a moderated chain mediation model was developed to investigate the mediating role of jealousy and self-control and the moderating role of gender. Data were collected from 652 Chinese adolescents who completed the Self-Esteem Scale, Self-Report Jealousy Scale, Self-Control Scale and Aggressive Behavior Questionnaire. Results showed that adolescent self-esteem may significantly negatively affect aggressive behavior by mediating with jealousy and self-control. Moreover, gender possibly moderates the serial mediating effect of jealousy and self-control between adolescent self-esteem and aggressive behavior. The results have important theoretical and practical implications in that these reveal the influencing factors of adolescent aggressive behavior and the pathways to reduce such behavior.

Occupational characteristics and incident anxiety and depression: A prospective cohort study of 206,790 participants.

BACKGROUND: This study aimed to analyze the impact of a wide spectrum of occupational characteristics on the incidence of anxiety and depression, and to determine the features affecting adaptation to specific characteristics. METHODS: Participants in paid employment or self-employed at baseline in UKB were included, with occupational characteristics extracted from O*NET. Cox-proportional-hazard models were conducted in the main analyses and subgroup analyses. RESULTS: Direct work with the public and exposure to disease/infections were first time demonstrated to be risk factors for both anxiety and depression, along with occupations involving more physical activities and dealing with unpleasant/physically aggressive people. Protective factors for both: time spent sitting, communication, decision making, creativity and reasoning, and responsibility in work. Protective factors for anxiety only: Coordinating/leading, fluency of ideas, originality, problem sensitivity, decision latitude, and time pressure. Risk factor for depression only: Exposure to contaminants. Females were found more sensitive to dealing with unpleasant/physically aggressive people. The impact of exposure to disease/infections was more significant among those with lower education levels. Those with BMI over 24 were more sensitive to the risk factors. LIMITATIONS: The short-term effect of the above exposures remained unclear. The scores of occupational characteristics were based on self-reported questionnaires. There was the potential for undiagnosed anxiety or depression events. The participants included only those aged from 40 to 69. Participants included in this cohort were mainly White British. CONCLUSIONS: Our findings advocate closer monitoring of the mental health of workers with risk work-related factors.

Identification of novel drug targets for the risk and prognosis of COVID-19.

Background: Since the epidemic continues, there is a pressing need to improve our understanding of coronavirus disease 2019 (COVID-19). Mendelian randomization (MR) studies provide us with a method to explore the causality between circulating proteins and COVID-19 susceptibility and severity. We aim to find new perspectives on the pathological mechanism of the disease and possible drug targets for treatment based on this study. Methods: We conducted a phenome-wide MR study to prioritize circulating proteins causally associated with COVID-19 susceptibility, which was defined as "patients tested positive for COVID-19 vs. population controls", and severity, which was defined as "patients hospitalized with COVID-19 vs. population controls". And we repeated the analysis for different definition of COVID-19 susceptibility, severity and control groups. Results: Association of three circulating proteins with COVID-19 susceptibility and severity were demonstrated via our study. C-C motif chemokine 4 (OR =1.887, 95% CI: 1.608-2.165, P=8.04×10-6) and 2'-5'-oligoadenylate synthase 1 (OR =0.511, 95% CI: 0.266-0.757, P=8.51×10-8) were found respectively positively and negatively correlated with increased COVID-19 severity. Tissue factor, contrary to previous studies, was found associated with decreased COVID-19 susceptibility (OR =0.667, 95% CI: 0.484-0.850, P=1.47×10-5) and decreased COVID-19 severity (OR =0.459, 95% CI: 0.132-0.786, P=3.01×10-6). Conclusions: Genetic evidence supports C-C motif chemokine 4 as a risk factor for COVID-19 severity, and 2'-5'-oligoadenylate synthase 1 as a protective factor for COVID-19 severity. The causal association between tissue factor and COVID-19 is contrary to the previous studies, needing further analyses. Further research is warranted to assess the viability of C-C motif chemokine 4 and 2'-5'-oligoadenylate synthase 1 as well as their downstream pathways as drug targets for anti-inflammatory and anti-virus treatment in severe cases.

The roles of PAD2- and PAD4-mediated protein citrullination catalysis in cancers.

Peptidylarginine deiminases (PADs) catalyze the conversion of arginine residues to citrulline residues on target proteins in the presence of calcium ions. This elaborate type of posttranslational modification is termed citrullination. PADs may regulate gene transcriptional activity via histone citrullination. There has been an increasing appreciation for the roles of PADs in a wide variety of biological processes. In this review article, we summarize recent evidence indicating that PADs and citrullinated proteins are involved in several physiological and pathological processes related to cancer. Of particular interest is that PAD2 and PAD4 exhibit characteristic expression levels, activities and specific biological effects in diverse types of cancer. We also list several PAD inhibitors, propose the possible mechanisms underlying the biological actions of PAD-mediated protein citrullination in experimental models and discuss the potential therapeutic value of PADs and their inhibitors for disease diagnosis and treatment.