Integrated proteomic and genomic analysis to identify predictive biomarkers for valproate response in bipolar disorder: a 6-month follow-up study.

BACKGROUND: Several genetic studies have been undertaken to elucidate the intricate interplay between genetics and drug responses in bipolar disorder (BD). However, there has been notably limited research on biomarkers specifically linked to valproate, with only a few studies investigating integrated proteomic and genomic factors in response to valproate treatment. Therefore, this study aimed to identify biological markers for the therapeutic response to valproate treatment in BD. Patients with BD in remission were assessed only at baseline, whereas those experiencing acute mood episodes were evaluated at three points (baseline, 8 ± 2 weeks, and 6 ± 1 months). The response to valproate treatment was measured using the Alda scale, with individuals scoring an Alda A score ≥ 5 categorized into the acute-valproate responder (acute-VPAR) group. We analyzed 158 peptides (92 proteins) from peripheral blood samples using multiple reaction monitoring mass spectrometry, and proteomic result-guided candidate gene association analyses, with 1,627 single nucleotide variants (SNVs), were performed using the Korean chip. RESULTS: The markers of 37 peptides (27 protein) showed temporal upregulation, indicating possible association with response to valproate treatment. A total of 58 SNVs in 22 genes and 37 SNVs in 16 genes showed nominally significant associations with the Alda A continuous score and the acute-VPAR group, respectively. No SNVs reached the genome-wide significance threshold; however, three SNVs (rs115788299, rs11563197, and rs117669164) in the secreted phosphoprotein 2 gene reached a gene-based false discovery rate-corrected significance threshold with response to valproate treatment. Significant markers were associated with the pathophysiological processes of bipolar disorders, including the immune response, acute phase reaction, and coagulation cascade. These results suggest that valproate effectively suppresses mechanisms associated with disease progression. CONCLUSIONS: The markers identified in this study could be valuable indicators of the underlying mechanisms associated with response to valproate treatment.

The Impact of Morningness-Eveningness on Depression through a Serial Mediation Model of Resilience and Anxiety.

OBJECTIVE: Resilience has been recently considered one of the possible mechanisms for the association between morningness-eveningness and depression. Meanwhile, anxiety is closely associated with mood disorder, but its association with morningness-eveningness is unclear. Therefore, this study aimed to explore the mediating effects of resilience and anxiety on morningness-eveningness and depression as the possible mechanisms. METHODS: This study included patient group and nonpatient group. Patient group consists of 743 patients with mood disorders [Major Depressive Disorder (MDD), 233; Bipolar Disorder Ⅰ (BDⅠ), 113; Bipolar Disorder Ⅱ (BDⅡ), 397] whereas nonpatient group consists of 818 individuals without mood disorder. The Composite Scale of Morningness, Connor-Davidson Resilience Scale, Self-Rating Depression Scale, and Beck Anxiety Inventory were used to evaluate morningness-eveningness, resilience, anxiety, and depression, respectively. RESULTS: Our model provided a good fit for the data. The association between morningness-eveningness and depression symptoms was partially serially mediated by resilience and anxiety in both the patient and nonpatient groups. The patient group exhibited significantly stronger morningness-eveningness toward resilience and anxiety than the nonpatient group. In the indirect effect of morningness-eveningness on depression, group differences exist only through each mediation of resilience and anxiety, not through serial mediation. CONCLUSION: Our results expand on the mechanism underlying the association between morningness-eveningness and depression. They highlight the importance of morningness-eveningness modification to increase resilience and the need to consider anxiety jointly in this process.

Exploring intra-diagnosis heterogeneity and inter-diagnosis commonality in genetic architectures of bipolar disorders: association of polygenic risks of major psychiatric illnesses and lifetime phenotype dimensions.

BACKGROUND: Bipolar disorder (BD) shows heterogeneous illness presentation both cross-sectionally and longitudinally. This phenotypic heterogeneity might reflect underlying genetic heterogeneity. At the same time, overlapping characteristics between BD and other psychiatric illnesses are observed at clinical and biomarker levels, which implies a shared biological mechanism between them. Incorporating these two issues in a single study design, this study investigated whether phenotypically heterogeneous subtypes of BD have a distinct polygenic basis shared with other psychiatric illnesses. METHODS: Six lifetime phenotype dimensions of BD identified in our previous study were used as target phenotypes. Associations between these phenotype dimensions and polygenic risk scores (PRSs) of major psychiatric illnesses from East Asian (EA) and other available populations were analyzed. RESULTS: Each phenotype dimension showed a different association pattern with PRSs of mental illnesses. PRS for EA schizophrenia showed a significant negative association with the cyclicity dimension (p = 0.044) but a significant positive association with the psychotic/irritable mania dimension (p = 0.001). PRS of EA major depressive disorder demonstrated a significant negative association with the elation dimension (p = 0.003) but a significant positive association with the comorbidity dimension (p = 0.028). CONCLUSION: This study demonstrates that well-defined phenotype dimensions of lifetime-basis in BD have distinct genetic risks shared with other major mental illnesses. This finding supports genetic heterogeneity in BD and suggests a pleiotropy among BD subtypes and other psychiatric disorders beyond BD. Further genomic analyses adopting deep phenotyping across mental illnesses in ancestrally diverse populations are warranted to clarify intra-diagnosis heterogeneity and inter-diagnoses commonality issues in psychiatry.

Identifying predictive factors for mood recurrence in early-onset major mood disorders: A 4-year, multicenter, prospective cohort study.

We investigate the predictive factors of the mood recurrence in patients with early-onset major mood disorders from a prospective observational cohort study from July 2015 to December 2019. A total of 495 patients were classified into three groups according to recurrence during the cohort observation period: recurrence group with (hypo)manic or mixed features (MMR), recurrence group with only depressive features (ODR), and no recurrence group (NR). As a result, the baseline diagnosis of bipolar disorder type 1 (BDI) and bipolar disorder type 2 (BDII), along with a familial history of BD, are strong predictors of the MMR. The discrepancies in wake-up times between weekdays and weekends, along with disrupted circadian rhythms, are identified as a notable predictor of ODR. Our findings confirm that we need to be aware of different predictors for each form of mood recurrences in patients with early-onset mood disorders. In clinical practice, we expect that information obtained from the initial assessment of patients with mood disorders, such as mood disorder type, family history of BD, regularity of wake-up time, and disruption of circadian rhythms, can help predict the risk of recurrence for each patient, allowing for early detection and timely intervention.

Interpersonal sensitivity and childhood trauma in patients with major depressive disorder, bipolar I, and II disorder.

Childhood trauma and interpersonal sensitivity impact the development of mood disorders. In this study, we investigate the association between childhood trauma and interpersonal sensitivity in patients with mood disorders. A total 775 patients (major depressive disorder [MDD, n = 241], bipolar I disorder [BD I, n = 119], and bipolar II disorder [BD II, n = 415]) and 734 controls. For evaluation, we used the Childhood Trauma Questionnaire-Short Form (CTQ) and Interpersonal Sensitivity Measure (IPSM). We examined between-group differences for each subscale in the CTQ and IPSM. Patients with BD II had significantly higher IPSM total scores than patients with MDD, BD I, or controls. The CTQ total score was related to the IPSM total score in all participants and subgroups. Among the CTQ subscales, emotional abuse showed the highest correlation with the IPSM total score, while separation anxiety and fragile inner self showed higher positive correlations with CTQ than the other subscales of IPSM in all patient groups and the control group, respectively. The findings reveal that childhood trauma and interpersonal sensitivity are positively correlated among patients with MDD, BD I, and BD II, and that interpersonal sensitivity is higher in patients with BD II than those with BD I or MDD. Childhood trauma is associated with interpersonal sensitivity, and each trauma type has a different impact on mood disorders. We expect that this study will encourage future research on interpersonal sensitivity and childhood trauma in mood disorders to improve treatment approaches.

Network structure of symptomatology of adult attention-deficit hyperactivity disorder in patients with mood disorders.

Patients with mood disorders commonly manifest comorbid psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). However, few studies have evaluated ADHD symptoms in this population. The current study aimed to explore the network structure of ADHD symptomology and identify central symptoms in patients with mood disorders. The Korean version of the Adult ADHD Self-Report Scale was used to assess the overall ADHD symptoms in 1,086 individuals diagnosed with mood disorders (major depressive disorder [n = 373], bipolar I disorder [n = 314], and bipolar II disorder [n = 399]). We used exploratory graph analysis to detect the number of communities, and the network structure was analyzed using regularized partial correlation models. We identified the central ADHD symptom using centrality indices. Network comparison tests were conducted with different subgroups of patients with mood disorders, including three mood diagnosis groups, between the patients who met the diagnostic criteria for ADHD [ADHD-suspected, n = 259] in their self-report and the others [ADHD-non-suspected, n = 827], and groups with high [n = 503] versus low [n = 252] levels of depressive state. The network analysis detected four communities: disorganization, agitation/restlessness, hyperactivity/impulsivity, and inattention. The centrality indices indicated that "feeling restless" was the core ADHD symptom. The result was replicated in the subgroup analyses within our clinically diverse population of mood disorders, encompassing three presentations: Patients with suspected ADHD, patients without suspected ADHD, and patients with a high depressive state. Our findings reveal that "feeling restless" is the central ADHD symptom. The treatment intervention for "feeling restless" may thus play a pivotal role in tackling ADHD symptoms in adult patients with mood disorders.

Association between Plasma Metabolic Profiles of the Antidepressant Escitalopram and Clinical Response in Subjects with Depression.

Liquid chromatography/electrospray ionization-mass spectrometry revealed plasma metabolic profiles for the antidepressant drug escitalopram (ECTP) and associated clinical responses in subjects with major depressive disorder (MDD). Metabolic profiles contribute to variations in responses to drug treatment of depression. To assess clinical responses and treatment outcomes, we quantified the levels of metabolites, including those of the parent drug, in plasma samples collected at different time points (days 0, 7, 14, and 42) during treatment of seven patients with MDD. Results showed that mean plasma levels of key metabolites and ECTP at day 7 were significantly associated with the clinical response at 42 days after treatment. Statistical analyses, including principal component analysis, of key metabolites and ECTP samples at different time points clearly distinguished the clinical responders from non-responder subjects. Although further validation with a larger cohort is necessary, our results indicate that early improvement and plasma levels of key metabolites and ECTP are predictive of therapeutic treatment outcomes and thus can be used to guide the use of ECTP.

Validation of the Short Form of the Mood Instability Questionnaire-Trait (MIQ-T-SF) in the Korean General Population.

OBJECTIVE: Mood instability (MI) is a clinically significant trait associated with psychiatric disorders. However, there are no concise measurements to evaluate MI. The initial Mood Instability Questionnaire-Trait (MIQ-T) was developed to fill this gap. The current study aimed to create a short form of MIQ-T (MIQ-T-SF) that measures MI with high validity and reliability in the Korean general population. METHODS: Of the 59 items in the MIQ-T, 17 items were chosen for the MIQ-T-SF following the factor analysis process. In total, 540 participants completed the MIQ-T-SF. Cronbach's alpha and McDonald's omega were used to evaluate reliability. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to determine construct validity. Concurrent validity was confirmed via comparisons with Personality Assessment Inventory-Borderline Features Scale. Measurement invariance across gender and age groups was confirmed before analyzing differences in scores using Kruskal-Wallis test. RESULTS: The MIQ-T-SF displayed expected correlations and high internal consistency (α=0.71-0.90, Ωt=0.72-0.92). Using EFA and CFA, a five-factor structure was confirmed. Measurement invariance was supported, and gender differences were observed. CONCLUSION: The MIQ-T-SF is an accurate and reliable method to detect MI in the Korean general population. The study's results offer new perspectives for future studies on MI.

Effect of Home-based Self-administered Transcranial Direct Stimulation in Patients with Mild to Moderate Major Depressive Disorder: A Single-arm, Multicentral Trial.

Objective: Although the effects and safety of transcranial direct current stimulation (tDCS) treatment in depressive patients are largely investigated, whether the self-administration of tDCS treatment at patient's home is comparable to clinic-based treatment is still unknown. Methods: In this single-arm, multi-center clinical trial, 61 patients with mild to moderate major depressive disorder were enrolled. tDCS treatment was delivered at the patient's home once a day, 5 to 7 times a week for 6 weeks, and each session lasted for 30 minutes. The primary outcome was a total Beck-Depression Inventory-II score, and no concurrent antidepressants were used. Results: The remission rates in both Full-Analysis (FA) (n = 61) and Per-Protocol (PP) (n = 43) groups were statistically significant (FA: 57.4% [0.44-0.70], PP: 62.8% [0.47-0.77]; percent [95% confidence interval]). The degree of depression- related symptoms was also significantly improved in 2, 4, and 6 weeks after the treatment when compared with baseline. There was no significant association between treatment compliance and remission rate in both FA and PP groups. Conclusion: These results suggest that acute treatment of patient-administered tDCS might be effective in improving the subjective feeling of depressive symptoms in mild to moderate major depressive disorder patients.

Korean Validation of the Short Version of the TEMPS-A (Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire) in Patients with Mood Disorders.

BACKGROUND AND OBJECTIVES: The Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A) is designed to assess affective temperaments. The short version of the TEMPS-A (TEMPS-A-SV) has been translated into various languages for use in research and clinical settings. However, no research has been conducted to validate the Korean version of the TEMPS-A-SV in patients with mood disorders. The goal of this study is to evaluate the reliability and validity of the TEMPS-A-SV in Korean mood disorder patients. MATERIALS AND METHODS: In this cross-sectional retrospective study, a total of 715 patients (267 patients with major depressive disorder, 94 patients with bipolar disorder I, and 354 patients with bipolar disorder II) completed the Korean TEMPS-A-SV. Cronbach's alpha and McDonald's omega were used to assess the reliability. Exploratory factor analysis (EFA) was also performed. Spearman's correlation coefficient was used to examine associations between the five temperaments. The difference in five temperament scores between the gender or diagnosis groups was analyzed, and the correlation between five temperament scores and age was tested. RESULTS: The Korean TEMPS-A-SV displayed good internal consistency (α = 0.65-0.88, ω = 0.66-0.9) and significant correlations between the subscales except one (the correlation between hyperthymic and anxious). Using EFA, a two-factor structure was produced: Factor I (cyclothymic, depressive, irritable, and anxious) and Factor II (hyperthymic). The cyclothymic temperament score differed by gender and the anxious temperament score was significantly correlated with age. All the temperaments, except for irritable temperament, showed significant differences between diagnosis groups. CONCLUSIONS: Overall, the results show that the TEMPS-A-SV is a reliable and valid measurement that can be used for estimating Koreans' affective temperaments. However, more research is required on affective temperaments and associated characteristics in people with mood disorders.

Prediction of impending mood episode recurrence using real-time digital phenotypes in major depression and bipolar disorders in South Korea: a prospective nationwide cohort study.

BACKGROUND: Mood disorders require consistent management of symptoms to prevent recurrences of mood episodes. Circadian rhythm (CR) disruption is a key symptom of mood disorders to be proactively managed to prevent mood episode recurrences. This study aims to predict impending mood episodes recurrences using digital phenotypes related to CR obtained from wearable devices and smartphones. METHODS: The study is a multicenter, nationwide, prospective, observational study with major depressive disorder, bipolar disorder I, and bipolar II disorder. A total of 495 patients were recruited from eight hospitals in South Korea. Patients were followed up for an average of 279.7 days (a total sample of 75 506 days) with wearable devices and smartphones and with clinical interviews conducted every 3 months. Algorithms predicting impending mood episodes were developed with machine learning. Algorithm-predicted mood episodes were then compared to those identified through face-to-face clinical interviews incorporating ecological momentary assessments of daily mood and energy. RESULTS: Two hundred seventy mood episodes recurred in 135 subjects during the follow-up period. The prediction accuracies for impending major depressive episodes, manic episodes, and hypomanic episodes for the next 3 days were 90.1, 92.6, and 93.0%, with the area under the curve values of 0.937, 0.957, and 0.963, respectively. CONCLUSIONS: We predicted the onset of mood episode recurrences exclusively using digital phenotypes. Specifically, phenotypes indicating CR misalignment contributed the most to the prediction of episodes recurrences. Our findings suggest that monitoring of CR using digital devices can be useful in preventing and treating mood disorders.

Relationship between childhood trauma and resilience in patients with mood disorders.

BACKGROUND: Childhood trauma has lasting negative impacts on individuals' psychological functioning. However, there is limited empirical evidence on the association between childhood trauma and resilience and none examining such relationship among diverse clinical populations. This study aimed to investigate the relationship in patients with major depressive disorder, bipolar I disorder, bipolar II disorder, and a comparison group. METHODS: In total, 787 psychiatric patients and 734 people from the general population participated in the study. The Childhood Trauma Questionnaire-Short Form and Connor-Davidson Resilience Scale were used to assess childhood trauma and resilience, respectively. RESULTS: Individuals with childhood trauma showed lower levels of resilience in all subjects; among them, those who experienced emotional abuse and emotional neglect exhibited even stronger associations than other types of childhood trauma. There was a significant difference in the negative relationship between childhood trauma and resilience by group, where the association was more prominent in the comparison group than in MDD and BD II patient groups. LIMITATIONS: The generalizability of our results may be limited due to unproportionate patient sample size. Also, we could not examine the causal relationship between childhood trauma and resilience. CONCLUSION: Childhood trauma and resilience had a significantly negative association. Our results suggest that people who have experienced emotional abuse and emotional neglect should be closely assisted to develop resilience. Interventions that promote resilience should be provided to individuals predisposed to psychological risks as a result of childhood trauma.

Understanding of Depressive Symptomatology across Major Depressive Disorder and Bipolar Disorder: A Network Analysis.

Background and Objectives: Depressive symptoms are prominent in both major depressive disorder (MDD) and bipolar disorder (BD). However, comparative research on the network structure of depressive symptoms in these two diagnostic groups has been limited. This study aims to compare the network structure of depressive symptoms in MDD and BD, providing a deeper understanding of the depressive symptomatology of each disorder. Materials and Methods: The Zung Self-Rating Depressive Scale, a 20-item questionnaire, was administered to assess the depressive symptoms in individuals with MDD (n = 322) and BD (n = 516). A network analysis was conducted using exploratory graph analysis (EGA), and the network structure was analyzed using regularized partial correlation models. To validate the dimensionality of the Zung SDS, principal component analysis (PCA) was adopted. Centrality measures of the depressive symptoms within each group were assessed, followed by a network comparison test between the two groups. Results: In both diagnostic groups, the network analysis revealed four distinct categories, aligning closely with the PCA results. "Depressed affect" emerged as the most central symptom in both MDD and BD. Furthermore, non-core symptoms, "Personal devaluation" in MDD and "Confusion" in BD, displayed strong centrality. The network comparison test did not reveal significant differences in the network structure between MDD and BD. Conclusions: The absence of significant differences in the network structures between MDD and BD suggests that the underlying mechanisms of depressive symptoms may be similar across these disorders. The identified central symptoms, including "Depressed affect", in both disorders and the distinct non-core symptoms in each highlight the complexity of the depressive symptomatology. Future research should focus on validating these symptoms as therapeutic targets and incorporate various methodologies, including non-metric dimension reduction techniques or canonical analysis.

Borderline Personality Pathology in Major Depressive Disorder, Bipolar I and II Disorder, and Its Relationship With Childhood Trauma.

OBJECTIVE: Mood disorder and borderline personality pathology (BPP) are frequently comorbid and relate to childhood trauma. We investigated the relationship between childhood trauma and BPP features in mood disorder patients versus controls. METHODS: A total of 488 mood disorder patients, particularly major depressive disorder (MDD), bipolar I disorder (BD I), and bipolar II disorder (BD II), and 734 controls were included. We examined between-group BPP-related differences and correlated between BPP and childhood trauma using the Childhood Trauma Questionnaire-Short Form (CTQ) and the Personality Assessment Inventory-Borderline Features Scale. RESULTS: BD II patients showed significantly higher BPP. Emotional abuse and neglect were prominently associated with BPP, while affective instability and negative relationships exhibited a stronger association with childhood trauma. We also found a positive relationship between childhood trauma and BPP in MDD, BD I, and BD II patients. CONCLUSION: The findings of the present study imply that BPP features are more likely to be found in patients with BD II than BD I or MDD. Mood disorder patients with severe childhood trauma may have higher BPP features. Thus, further study of the relationship between childhood trauma and BPP features could improve the therapeutic approaches and help understand patients with mood disorders.

Korean Validation of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire.

OBJECTIVE: The Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) has been validated in more than 30 languages and is noted for its broad application in research and clinical settings. This study presents the first attempt to examine the reliability and validity of the TEMPS-A in Korea. METHODS: A total of 540 non-clinical participants completed the Korean TEMPS-A, which was adapted from the original English version via a comprehensive translation procedure. Reliability was assessed using Cronbach's α, and associations between temperaments were examined using Spearman's correlation coefficient. Exploratory factor analysis (EFA) was performed, and differences in TEMPS-A scores between the gender- and age-based groups were examined using Kruskal-Wallis analysis. RESULTS: The Korean TEMPS-A exhibited excellent internal consistency (0.70-0.91) and significant correlations between subscales. EFA resulted in a two-factor structure: Factor I (depressive, cyclothymic, irritable, and anxious) and Factor II (hyperthymic). Gender and age group differences were observed. CONCLUSION: Overall, our results suggest that TEMPS-A is a reliable and valid measure of affective temperaments for the Korean population. This study opens new possibilities for further research on affective temperaments and their related traits.

Efficacy and safety of daily home-based transcranial direct current stimulation as adjunct treatment for bipolar depressive episodes: Double-blind sham-controlled randomized clinical trial.

Background: Although transcranial direct current stimulation (tDCS) is known to be a promising therapeutic modality for unipolar depression, the efficacy and safety of tDCS for bipolar depressive episodes (BD) are still unknown and clinical trials of home-based tDCS treatment are scarce. As a result, we set out to investigate the efficacy and safety of home-based tDCS for the treatment BD. Methods: Participants (n = 64), diagnosed as bipolar disorder as per the diagnostic and statistical manual of mental disorders (DSM-5), were randomly assigned to receive tDCS. Hamilton Depression Rating Scale (HDRS-17) scores were measured at the baseline, week 2, 4, and 6, and home-based tDCS (for 30 min with 2 mA) was self-administered daily. Results: Of the 64 patients (15.6% bipolar disorder I, 84.4% bipolar disorder II), 41 patients completed the entire assessment. In the intention-to-treat analysis, time-group interaction for the HDRS-17 [F (3, 146.36) = 2.060; p = 0.108] and adverse effect differences between two groups were not statistically significant, except the pain score, which was higher in the active group than the sham group (week 0-2: p < 0.01, week 2-4: p < 0.05, and week 4-6: p < 0.01). Conclusion: Even though we found no evidence for the efficacy of home-based tDCS for patients with BD, this tool was found to be a safe and tolerable treatment modality for BD. Clinical trial registration: [https://clinicaltrials.gov/show/NCT03974815], identifier [NCT03974815].

The relationship between morningness-eveningness and mood symptoms and quality of life in euthymic state of mood disorders: Results from a prospective observational cohort study.

BACKGROUND: The clinical importance of morningness-eveningness, especially in mood disorders, is prevailing. The differential relation of chronotype with diagnoses of early-onset mood disorders, mood symptoms, anxiety, and quality of life was evaluated. METHODS: Early-onset mood disorder patients [n = 419; 146 major depressive disorder (MDD); 123 bipolar I disorder (BDI); 150 bipolar II disorder (BDII)] from the Mood Disorder Cohort Research Consortium were assessed for chronotype using the composite scale for morningness (CSM) and its association with clinical variables obtained during the clinician-verified euthymic state. RESULTS: The mean total CSM of BDI was significantly higher than MDD and BDII (p < 0.001). In all types of mood disorders, higher total CSM was associated with lower Quick inventory of depressive symptomatology (p < 0.005) and higher WHO quality of life (p < 0.005). Such negative correlations between the total CSM and Montgomery-Asberg depression rating were significant in MDD and BDI (p < 0.05) and marginally significant in BDII (p = 0.077). CSM was a significant contributor to quality of life in BDI (p < 0.001) and BDII (p = 0.011), but it was not for MDD. LIMITATIONS: The defined 'euthymic state' that may not fully reflect the remission of episode; limited generalizability due to clinical characteristic of early-onset mood disorder; the disparity between diurnal preference measured by the CSM and chronotype; possible effects of the last mood episode polarity and medication; and, lack of control group. CONCLUSION: Less eveningness was associated with less severe depressive symptoms and better quality of life. This suggests that morningness may reduce residual depressive symptoms and recover function of patients.

Shared genetic architectures of subjective well-being in East Asian and European ancestry populations.

Subjective well-being (SWB) has been explored in European ancestral populations; however, whether the SWB genetic architecture is shared across populations remains unclear. We conducted a cross-population genome-wide association study for SWB using samples from Korean (n = 110,919) and European (n = 563,176) ancestries. Five ancestry-specific loci and twelve cross-ancestry significant genomic loci were identified. One novel locus (rs12298541 near HMGA2) associated with SWB was also identified through the European meta-analysis. Significant cross-ancestry genetic correlation for SWB between samples was observed. Polygenic risk analysis in an independent Korean cohort (n = 22,455) demonstrated transferability between populations. Significant correlations between SWB and major depressive disorder, and significant enrichment of central nervous system-related polymorphisms heritability in both ancestry populations were found. Hence, large-scale cross-ancestry genome-wide association studies can advance our understanding of SWB genetic architecture and mental health.

Genome-wide association study of occupational attainment as a proxy for cognitive reserve.

Occupational attainment, which represents middle-age cognitive activities, is a known proxy marker of cognitive reserve for Alzheimer's disease. Previous genome-wide association studies have identified numerous genetic variants and revealed the genetic architecture of educational attainment, another marker of cognitive reserve. However, the genetic architecture and heritability for occupational attainment remain elusive. We performed a large-scale genome-wide association study of occupational attainment with 248 847 European individuals from the UK Biobank using the proportional odds logistic mixed model method. In this analysis, we defined occupational attainment using the classified job levels formulated in the UK Standard Occupational Classification system considering the individual professional skill and academic level. We identified 30 significant loci (P < 5 × 10-8); 12 were novel variants, not associated with other traits. Among them, four lead variants were associated with genes expressed in brain tissues by expression quantitative trait loci mapping from 10 brain regions: rs13002946, rs3741368, rs11654986 and rs1627527. The single nucleotide polymorphism-based heritability was estimated to be 8.5% (standard error of the mean = 0.004) and partitioned heritability was enriched in the CNS and brain tissues. Genetic correlation analysis showed shared genetic backgrounds between occupational attainment and multiple traits, including education, intelligence, leisure activities, life satisfaction and neuropsychiatric disorders. In two-sample Mendelian randomization analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.65-0.92 in inverse variance weighted method; OR = 0.73, 95% CI = 0.57-0.92 in the weighted median method]. This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic single nucleotide polymorphisms (OR = 0.72, 95% CI = 0.57-0.91 in the inverse variance weighted method; OR = 0.72, 95% CI = 0.53-0.97 in the weighted median method). Multivariable Mendelian randomization confirmed that occupational attainment had an independent effect on the risk for Alzheimer's disease even after taking educational attainment into account (OR = 0.72, 95% CI = 0.54-0.95 in the inverse variance weighted method; OR = 0.68, 95% CI = 0.48-0.97 in the weighted median method). Overall, our analyses provide insights into the genetic architecture of occupational attainment and demonstrate that occupational attainment is a potential causal protective factor for Alzheimer's disease as a proxy marker of cognitive reserve.