Risk Of Major Depressive Disorder Research Articles

Associations between parental socioeconomic-, family-, and sibling status and risk of eating disorders in offspring in a Danish national female cohort.

ObjectiveStudies on parental socioeconomic status (SES) and family risk factors for eating disorders (EDs) have yielded inconsistent results; however, several studies have identified high parental educational attainment as a risk factor. The aim was to evaluate associations of parental SES and family composition with anorexia nervosa (AN), bulimia nervosa (BN), and eating disorders not otherwise specified (EDNOS) in the offspring, adjusting for parental age and parental mental health.MethodsThe cohort included women born in Denmark between January 1, 1989 and December 31, 2010, derived from Danish national registers. Each person was followed from their sixth birthday until onset of the disorder of interest or to December 31, 2016. Exposure variables were: childhood SES, defined as individually evaluated parental level of income, occupation, and education; sibling status; and family composition. Outcomes were: AN, BN, EDNOS, and major depressive disorder (MDD), included as a psychiatric comparison disorder. Risks were estimated using Cox proportional hazards.ResultsHigh parental SES was associated with increased risk of especially AN, and less so BN and EDNOS, in offspring. In comparison, low SES was associated with a higher risk of MDD. No differences between maternal or paternal socioeconomic risk factors were found. Family composition and sibling status showed limited influence on ED risk.DiscussionSES shows opposite associations with AN than MDD, whereas associations with BN and EDNOS are intermediate. The socioeconomic backdrop of AN differs markedly from that reported in other psychiatric disorders. Whether that is due to genetic and/or environmental factors remains unknown.Public Significance statementParental socioeconomic background (SES) may influence eating disorders risk in offspring somewhat differently than other psychiatric disorders. In Denmark, higher parental SES was associated with increased risk of, particularly, anorexia nervosa (AN). Importantly AN does strike across the SES spectrum. We must ensure that individuals of all backgrounds have equal access to care and are equally likely to be detected and treated appropriately for eating disorders.

Polygenic scores for schizophrenia and major depression are associated with psychosocial risk factors in children: evidence of gene-environment correlation.

Whilst genetic and environmental risk factors for schizophrenia (SCZ) and major depressive disorder (MDD) have been established, it is unclear whether exposure to environmental risk factors is genetically confounded by passive, evocative or active gene-environment correlation (rGE). This study aims to investigate: (a) whether the genetic risk for SCZ/MDD in children is correlated with established environmental and psychosocial risk factors in two British community samples, the 1958 National Child Development Study (NCDS) and the Millennium Cohort Study (MCS), (b) whether these associations vary between both psychopathologies, and (c) whether findings differ across the two cohorts which were born 42 years apart. Polygenic risk scores (PRS) from existing large genome-wide associations studies (GWAS) were applied to test the correlation between the child genetic risk for SCZ/MDD and known environmental risk factors. In addition, parental and child genetic data from MCS were used to distinguish between passive and evocative rGE. The child polygenic risk for SCZ and MDD was correlated with single parenthood in MCS. Moreover, the lack of father's involvement in child care was associated with the genetic risk for SCZ in NCDS. However, we also found associations between several indicators of low socioeconomic status and heightened genetic risk for MDD in children in both cohorts. Further, the genetic risk for MDD was associated with parental lack of interest in the child's education in NCDS as well as more maternal smoking and less maternal alcohol consumption during childhood in MCS. According to sensitivity analyses in MCS (controlling for parental genotype), more than half of our significant correlations reflected passive rGE. Findings suggest that several established environmental and psychosocial risk factors for SCZ and MDD are at least partially associated with children's genetic risk for these psychiatric disorders.

Early menarche and adult major depressive disorder among Japanese women: The role of childhood traumatic experience and socioeconomic conditions in young adulthood.

The aim of this study is to examine the long-term impact of early menarche with adult depression, and to assess whether this association was explained by childhood traumatic experience and socioeconomic condition in early adulthood. The data were derived from World Mental Health Survey Japan Second, a cross-sectional survey conducted among Japanese community residents between 2013 and 2015. We used the data of female respondents aged 20-75 years (N = 1171). Hazard ratio (HR) of the onset of major depression up to 40 years was calculated for an early-menarche group and a non-early-menarche group, respectively. Kaplan-Meier curve and log-rank statistics were used to examine the difference in failure. Cox proportional hazard models were administered for the association of major depression with early-menarche and early-life psychosocial factors. Risk for major depressive disorders were three to four times higher in an early-menarche group, and the differences in survival functions were significant (p < 0.001). HR of early menarche was 2.79 (95% CI = 1.29-6.02), and was slightly changed when childhood traumatic experience and socioeconomic conditions in young adulthood were added in the model (HR = 2.88, 95% CI = 1.30-6.38; HR = 3.19, 95% CI = 1.41-7.21). Early menarche was significantly associated with increased risk for depression by the age of 40 years. Childhood trauma and socioeconomic hardship in early adulthood did not account for the association. Both physical and psychosocial risk factors in early life need to be addressed for preventing women's depression.

Trends of Prevalence Estimates and Risk Factors of Depressive Symptoms among Healthcare Workers Over one Year of the COVID-19 Pandemic.

COVID-19 pandemic has an overwhelming psychologic burden on healthcare workers (HCWs). This study aims to investigate the changes in the prevalence, estimates, severity, and risk factors of depressive symptoms among HCWs within the first year of the COVID-19 pandemic. An observational e-survey collected data on HCWs' socio-demographic characteristics, occupational situation, and depressive symptoms as measured by Patient Health Questionnaire-9 (PHQ-9). The e-survey was distributed one month after the onset of the COVID-19 pandemic (onset group) and again after one year (one-year group). A total of 422 HCWs were included (Mean (SD) age, 35.3 (9.9) years; 71.3% males), with 211 (50%) participants in each group. In the total cohort, the mean PHQ-9 score was 8.5, and 36.7% reported clinically significant levels of depressive symptoms with a PHQ-9 score of ≥10. Compared to the onset group, the one-year group reported a higher risk of major depressive disorder (41.7% vs. 31.8%; OR 1.538; 95%CI 1.032-2.291; p=0.034), a higher mean PHQ-9 score (9.5 (6.8) vs. 7.4 (5.3), p<0.001), and more severe depressive symptoms (p<0.005). Participants who were younger, unmarried, underwent testing for COVID-19, reported lower monthly income, did not receive special COVID-19 education, or had lower satisfaction with institutional preparedness had significantly higher depression scores and symptoms in both onset and one-year groups (p<0.05 for each category). Female gender and direct contact with COVID-19 patients or samples were significant risk factors within the onset group. Occupation as a physician, history of COVID-19 testing or infection, and perception of significant changes in work schedule or intensity were significantly associated with higher depression scores and symptoms among the one-year group. This study sheds light on an unspoken but significant rise in prevalence estimates and severity of depressive symptoms among HCWs over a year of the COVID-19 pandemic and shows the vulnerable subgroups for whom a psychological intervention might be warranted.

Associations of a family history of lupus with the risks of lupus and major psychiatric disorders in first-degree relatives.

Genetic factors link psychiatric disorders, particularly major depressive disorder (MDD), bipolar disorder, and obsessive-compulsive disorder (OCD), with systemic lupus erythematosus (SLE). Additionally, maternal SLE is a risk factor for long-term developmental problems, particularly learning disabilities, attention disorders, autism spectrum disorder (ASD) and speech disorders, in children. We aimed to determine whether first-degree relatives (FDRs) of patients with SLE have increased risks of SLE and major psychiatric disorders. Using the Taiwan National Health Insurance Research Database, we recruited 40 462 FDRs of patients with SLE as well as 161 848 matched controls. The risks of major psychiatric disorders, including schizophrenia, bipolar disorder, OCD, MDD, ASD and attention-deficit/hyperactivity disorder (ADHD), were assessed. The FDRs of patients with SLE had higher risks of SLE (reported as the adjusted relative risk and 95% confidence interval: 14.54; 12.19-17.34), MDD (1.23; 1.12-1.34), ADHD (1.60; 1.55-1.65), OCD (1.41; 1.14-1.74) and bipolar disorder (1.18; 1.01-1.38) compared with controls. Specifically, male FDRs of patients with SLE had higher risks of SLE and bipolar disorder, whereas female FDRs of patients with SLE had higher risks of MDD and OCD. Differences in the familial relationship (i.e. parents, children, siblings and twins) were consistently associated with higher risks of these disorders compared with controls. The FDRs of patients with SLE had higher risks of SLE, MDD, ADHD, OCD and bipolar disorder than the controls.

Prevalence and Unmet Need for Mental Healthcare of Major Depressive Disorder in Community-Dwelling Chinese People Living With Vision Disability.

ObjectiveMental health services have been recognized as an essential part of the comprehensive eye care services, but data regarding the mental health of people living with vision disability (PLwVD) remain very limited. This study examined the epidemiology of major depressive disorder (MDD) among Chinese PLwVD, as well as their perceived needs for and utilization of mental health services.MethodsBy using stratified cluster sampling method, a total of 1,753 PLwVD were successfully recruited from 73 urban communities and 169 rural villages in Wuhan, China, and interviewed with the Mini-international Neuropsychiatric Interview 5.0. Standardized questions were used to measure perceived mental healthcare needs and use of mental health services of PLwVD with MDD.ResultsThe one-month prevalence of MDD was 24.4%. Among the PLwVD with MDD, 26.0% perceived needs for mental healthcare and only 1.2% sought treatment from mental health specialists for their emotional problems. Factors associated with MDD were middle age [vs. young adulthood, odds ratio (OR) = 1.96, P < 0.001], older adulthood (vs. young adulthood, OR = 1.79, P = 0.004), being never-married (vs. married, remarried, and cohabiting, OR = 1.96, P < 0.001), being separated, divorced, and widowed (vs. married, remarried, and cohabiting, OR = 12.30, P < 0.001), a low level of objective social support (vs. high, OR = 1.83, P < 0.001), currently drinking (OR = 1.81, P < 0.001), having childhood-onset eye conditions (OR = 1.89, P = 0.005), and having difficulties in performing daily activities (OR = 2.78, P < 0.001).ConclusionsChinese PLwVD are at high risk for MDD and have a high level of unmet need for mental healthcare. Public strategies are warranted to improve the mental health literacy of PLwVD and make the mental health services available, accessible, and affordable for PLwVD.

Association Between MTHFR rs17367504 Polymorphism and Major Depressive Disorder in Taiwan: Evidence for Effect Modification by Exercise Habits

Background/AimRecent studies reported that folate supplementation has beneficial effects on major depression. The Methylenetetrahydrofolate reductase (MTHFR) enzyme is crucial in folate metabolism. This population-based study examined the association between MTHFR rs17367504 polymorphism and major depressive disorder based on exercise habits.MethodsTaiwan Biobank (TWB) provided demographic and genotype data between 2008 and 2015. The biobank participants were Taiwanese aged 30 to 70. Data on major depressive disorder (MDD) were obtained from the National Health Insurance Research Database (NHIRD).ResultsA total of 636 individuals were identified with MDD, whereas 17,298 individuals were considered controls. The associations of MTHFR rs17367504 and exercise with MDD risk were estimated using logistic regression models. The distribution of MTHFR rs17367504 genotype frequencies differed significantly between the MDD and control groups. We found that, compared with the AA genotype, the GG genotype was associated with a significantly increased risk of MDD [adjusted odds ratio (aOR), 1.76; 95% confidence interval (CI), 1.05–2.94; p = 0.033]. We found an interaction (p = 0.04) between rs17367504 and exercise, a well-known protective factor for MDD. A substantial increase in the risk of MDD was found among those with GG genotypes who did not exercise (aOR, 2.93; 95% CI, 1.66–5.17; p < 0.001).ConclusionsOur findings indicate that MDD is related to MTHFR rs17367504 and exercise, though the mechanisms remain to be determined.

Neural and peripheral markers of reward during positive social evaluation are associated with less clinician-rated depression symptom severity in adolescence

Although blunted sensitivity to reward is thought to play a key role in promoting risk for depression, most research on this topic has utilized monetary reward paradigms and focused on currently depressed adults. To address this issue, we analyzed neural reward and β-endorphin data from the Psychobiology of Stress and Adolescent Depression (PSY SAD) Study, which recruited a well-characterized sample of adolescent girls at high vs. low risk for major depressive disorder (MDD) (N = 52, Mage = 14.90, SD = 1.35) based on their mothers’ lifetime history of MDD. As hypothesized, greater striatal activity while receiving positive (vs. neutral) social evaluation was associated with lower depression symptom severity as independently assessed by the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS). This association was present for girls at high but not low risk for MDD, suggesting that this neural response may represent a pre-clinical marker of risk for depression. Consistent with these results, higher post-social evaluation levels of a peripheral marker of reward sensitivity, β-endorphin, were related to lower clinician-rated depression symptom severity. Together, these results indicate that neural and peripheral markers of responsivity to social reward are both related to depression severity, which may have implications for understanding the pathophysiology of depression.

Integrative PheWAS analysis in risk categorization of major depressive disorder and identifying their associations with genetic variants using a latent topic model approach.

Major depressive disorder (MDD) is the most prevalent mental disorder that constitutes a major public health problem. A tool for predicting the risk of MDD could assist with the early identification of MDD patients and targeted interventions to reduce the risk. We aimed to derive a risk prediction tool that can categorize the risk of MDD as well as discover biologically meaningful genetic variants. Data analyzed were from the fourth and fifth data collections of a longitudinal community-based cohort from Southwest Montreal, Canada, between 2015 and 2018. To account for high dimensional features, we adopted a latent topic model approach to infer a set of topical distributions over those studied predictors that characterize the underlying meta-phenotypes of the MDD cohort. MDD probability derived from 30 MDD meta-phenotypes demonstrated superior prediction accuracy to differentiate MDD cases and controls. Six latent MDD meta-phenotypes we inferred via a latent topic model were highly interpretable. We then explored potential genetic variants that were statistically associated with these MDD meta-phenotypes. The genetic heritability of MDD meta-phenotypes was 0.126 (SE = 0.316), compared to 0.000001 (SE = 0.297) for MDD diagnosis defined by the structured interviews. We discovered a list of significant MDD - related genes and pathways that were missed by MDD diagnosis. Our risk prediction model confers not only accurate MDD risk categorization but also meaningful associations with genetic predispositions that are linked to MDD subtypes. Our findings shed light on future research focusing on these identified genes and pathways for MDD subtypes.

Association between Attention Deficit Hyperactivity Disorder Medication and Depression: A 10-year Follow-up Self-controlled Case Study.

ObjectiveThere is clinical concern that the stimulant methylphenidate (MPH) might increase the risk of depression, particularly in children. This study aimed to investigate the association between MPH use and the risk of depression.MethodsA population-based electronic medical records database was used. We obtained claims data for prescription of ADHD medication, diagnosis of depression, and prescription of antidepressant medication between January 2007 and December 2016 for 43,259 individuals aged 6 to 19 who were diagnosed with ADHD between July 1, 2007 and December 31, 2007. The final analysis was based on 2,330 eligible participants. A self-controlled case series design was used to identify risk factors for major depressive disorder (MDD).ResultsAn elevated MDD risk was found during the 90 days before MPH exposure, with an incidence rate ratio (IRR) of 12.12 (95% confidence interval [95% CI] 10.06−14.61, p < 0.0001). During methylphenidate treatment, the IRR was 18.06 with a 95% CI of 16.67 to 19.56 (p < 0.0001), but it returned to baseline levels after day 31 of MPH treatment discontinuation. The IRR for patients aged 6 to 9 years was 13.11 (95% CI 9.58−17.95) during the 90 days before MPH exposure, and 17.7 (95% CI 15.6−20.08) during MPH treatment, but returned to baseline levels after discontinuation of MPH treatment.ConclusionWe confirmed the temporal relationship between depression and methylphenidate use in young people with ADHD. Though the absolute risk is low, the risk of depression should be carefully considered, particularly in the period directly following the start of methylphenidate treatment.

Personality mediates the association between juvenile conduct problems and adulthood mood disorders

This study aimed to examine the association between conduct problems and mood disorders, and to evaluate the mediating roles of personality traits in it. Adult participants (N = 309), for which patients with major depressive disorder (MDD) or bipolar disorder (BD), and controls without major psychiatric history were recruited. Juvenile conduct problem was defined by the items in Composite International Diagnosis Interview. We assessed personality traits of extraversion and neuroticism. Multiple mediation model was performed to investigate the intervening effect of personality traits between juvenile conduct problems and adulthood mood disorders. Participants had on average 2.7 symptoms of conduct problems, and 43.4% had conduct problems. Having more symptoms of conduct problems was associated with a higher likelihood of BD (OR = 1.20). Higher neuroticism was associated with elevated risks of both MDD and BD. There was no direct effect of binary conduct problems on the risk of BD, and showed significant total indirect effect mediated by neuroticism for BD (OR = 1.49; bias-corrected and accelerated 95% CI = 1.10–2.05), but not through extraversion. Conduct problems defined as a continuous variable had a direct effect on the risk of adult MDD (OR = 1.36; bias-corrected and accelerated 95% CI = 1.05–1.76), while had an indirect effect on the risk of BD via the mediation of neuroticism (OR = 1.08; bias-corrected and accelerated 95% CI = 1.02–1.14). Neuroticism mediates between the association of juvenile conduct problems and adult BD. This finding raises our attention to assess personality traits in individuals with juvenile conduct problems for timely intervention strategies of reducing the vulnerability for developing mood disorders.

Screening Depressive Symptoms and Incident Major Depressive Disorder Among Chinese Community Residents Using a Mobile App-Based Integrated Mental Health Care Model: Cohort Study.

BackgroundDepression is associated with significant morbidity and human capital costs globally. Early screening for depressive symptoms and timely depressive disorder case identification and intervention may improve health outcomes and cost-effectiveness among affected individuals. China’s public and academic communities have reached a consensus on the need to improve access to early screening, diagnosis, and treatment of depression.ObjectiveThis study aims to estimate the screening prevalence and associated factors of subthreshold depressive symptoms among Chinese residents enrolled in the cohort study using a mobile app–based integrated mental health care model and investigate the 12-month incidence rate and related factors of major depressive disorder (MDD) among those with subthreshold depressive symptoms.MethodsData were drawn from the Depression Cohort in China (DCC) study. A total of 4243 community residents aged 18 to 64 years living in Nanshan district, Shenzhen city, in Guangdong province, China, were encouraged to participate in the DCC study when visiting the participating primary health care centers, and 4066 (95.83%) residents who met the DCC study criteria were screened for subthreshold depressive symptoms using the Patient Health Questionnaire-9 at baseline. Of the 4066 screened residents, 3168 (77.91%) with subthreshold depressive symptoms were referred to hospitals to receive a psychiatric diagnosis of MDD within 12 months. Sleep duration, anxiety symptoms, well-being, insomnia symptoms, and resilience were also investigated. The diagnosis of MDD was provided by trained psychiatrists using the Mini-International Neuropsychiatric Interview. Univariate and multivariate logistic regression models were performed to explore the potential factors related to subthreshold depressive symptoms at baseline, and Cox proportional hazards models were performed to explore the potential factors related to incident MDD.ResultsAnxiety symptoms (adjusted odds ratio [AOR] 1.63, 95% CI 1.42-1.87) and insomnia symptoms (AOR 1.13, 95% CI 1.05-1.22) were associated with an increased risk of subthreshold depressive symptoms, whereas well-being (AOR 0.93, 95% CI 0.87-0.99) was negatively associated with depressive symptoms. During the follow-up period, the 12-month incidence rate of MDD among participants with subthreshold depressive symptoms was 5.97% (189/3168). After incorporating all significant variables from the univariate analyses, the multivariate Cox proportional hazards model reported that a history of comorbidities (adjusted hazard ratio [AHR] 1.49, 95% CI 1.04-2.14) and anxiety symptoms (AHR 1.13, 95% CI 1.09-1.17) were independently associated with an increased risk of incident MDD. The 5-item World Health Organization Well-Being Index was associated with a decreased risk of incident MDD (AHR 0.90, 95% CI 0.86-0.94).ConclusionsElevated anxiety symptoms and unfavorable general well-being were significantly associated with subthreshold depressive symptoms and incident MDD among Chinese residents in Shenzhen. Early screening for subthreshold depressive symptoms and related factors may be helpful for identifying populations at high risk of incident MDD.

Morphological Biomarkers in the Amygdala and Hippocampus of Children and Adults at High Familial Risk for Depression.

Major Depressive Disorder (MDD) is highly familial, and the hippocampus and amygdala are important in the pathophysiology of MDD. Whether morphological markers of risk for familial depression are present in the hippocampus or amygdala is unknown. We imaged the brains of 148 individuals, aged 6 to 54 years, who were members of a three-generation family cohort study and who were at either high or low familial risk for MDD. We compared surface morphological features of the hippocampus and amygdala across risk groups and assessed their associations with depression severity. High- compared with low-risk individuals had inward deformations of the head of both hippocampi and the medial surface of the left amygdala. The hippocampus findings persisted in analyses that included only those participants who had never had MDD, suggesting that these are true endophenotypic biomarkers for familial MDD. Posterior extension of the inward deformations was associated with more severe depressive symptoms, suggesting that a greater spatial extent of this biomarker may contribute to the transition from risk to the overt expression of symptoms. Significant associations of these biomarkers with corresponding biomarkers for cortical thickness suggest that these markers are components of a distributed cortico-limbic network of familial vulnerability to MDD.

Volumetric changes in specific neurofunctional subfields of the hippocampus in major depressive disorder.

There is evidence that hippocampal volume is abnormal in patients with major depressive disorder (MDD), but there have been no studies on volumetric changes in different subfields based on functional topography. This was investigated in the present study by comparing hippocampal neurofunctional subfield volumes between MDD patients and healthy control (HC) subjects. Patients with MDD (n = 44) and HCs (n = 27) recruited at Shanghai Traditional Chinese Medicine Integrated Hospital underwent a T1-weighted anatomical MRI scan in the sagittal orientation, and the data were used to calculate hippocampal subfield volumes. Logistic regression was used to evaluate the association between the volumes and risk of MDD. A nomogram for predicting MDD risk based on volume changes in different subfields was developed, and its predictive power was evaluated by calculating the concordance (C)-index. Compared with HCs, MDD patients showed reduced volume in hippocampal neurofunctional subfields, specifically in left (L)1, right (R)1, and R2 (related to emotion) and L2, L3, and R4 (related to cognition and perception). The logistic regression analysis revealed that the risk of MDD was 4.59-, 5.8-, 8.33-, and 6.92-fold higher with atrophies of L1, L2, L3, and R4, respectively. A nomogram for predicting MDD risk was developed based on age; sex; and hippocampal L1, L2, L3, and R4 subfield volumes and showed good accuracy, with a C-index of 0.784. Volumetric changes in the neurofunctional subfield of the hippocampus are potential imaging markers that can predict the occurrence of MDD.

Unique and joint associations of polygenic risk for major depression and opioid use disorder with endogenous opioid system function.

Major depressive disorder (MDD) and opioid use disorder (OUD) are common, potentially fatal, polygenic disorders that are moderately heritable and often co-occur. We examined the unique and shared associations of polygenic risk scores (PRS) for these disorders with µ-opioid receptor (MOR) concentration and endogenous opioid response during a stressful stimulus. Participants were 144 healthy European-ancestry (EA) subjects (88 females) who underwent MOR quantification scans with [11C]carfentanil and PET and provided DNA for genotyping. MOR non-displaceable binding potential(BPND) was measured in 5 regions of interest (ROIs) related to mood and addiction. We examined associations of PRS bothat baseline and following opioid release calculated as the ratio of baseline and stress-challenge scans, first in the entire sample and then separately by sex. MOR availability at baseline was positively associated with MDD PRS in the amygdala and ventral pallidum. MDD and OUD PRS were significantly associated with stress-induced opioid system activation in multiple ROIs, accounting for up to 14.5% and 5.4%, respectively, of the variance in regional activation. The associations were most robust among females, where combined they accounted for up to 25.0% of the variance among the ROIs. We conclude that there is a pathophysiologic link between polygenic risk for MDD and OUD and opioid system activity, as evidenced by PRS with unique and overlapping regional associations with this neurotransmitter system. This link could help to explain the high rate of comorbidity of MDD and OUD and suggests that opioid-modulating interventions could be useful in treating MDD and OUD, both individually and jointly.

Genetic evidence for a potential causal relationship between insomnia symptoms and suicidal behavior: a Mendelian randomization study

Insomnia and restless leg syndrome (RLS) are associated with increased risk for suicidal behavior (SB), which is often comorbid with mood or thought disorders; however, it is unclear whether these relationships are causal. We performed a two-sample Mendelian randomization study using summary-level genetic associations with insomnia symptoms and RLS against the outcomes of risk of major depressive disorder (MDD), bipolar disorder (BP), schizophrenia (SCZ), and SB. The inverse-variance weighted method was used in the main analysis. We performed replication and sensitivity analyses to examine the robustness of the results. We identified outcome cohorts for MDD (n = 170,756 cases/329,443 controls), BP (n = 20,352/31,358), SCZ (n = 69,369/236,642), SB-Cohort-2019 (n = 6569/14,996 all with MDD, BP or SCZ; and SB within individual disease categories), and SB-Cohort-2020 (n = 29,782/519,961). Genetically proxied liability to insomnia symptoms significantly associated with increased risk of MDD (odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.2–1.26, P = 1.37 × 10–61), BP (OR = 1.15, 95% CI = 1.07–1.23, P = 5.11 × 10–5), SB-Cohort-2019 (OR = 1.17, 95% CI = 1.07–1.27, P = 2.30 × 10–4), SB-Cohort-2019 in depressed patients (OR = 1.34, 95% CI = 1.16–1.54, P = 5.97 × 10–5), and SB-Cohort-2020 (OR = 1.24, 95% CI = 1.18–1.3, P = 1.47 × 10–18). Genetically proxied liability to RLS did not significantly influence the risk of any of the outcomes (all corrected P > 0.05). Results were replicated for insomnia with MDD and SB in Mass General Brigham Biobank and were consistent in multiple lines of sensitivity analyses. In conclusion, human genetic evidence supports for the first time a potentially independent and causal effect of insomnia on SB and encourages further clinical investigation of treatment of insomnia for prevention or treatment of SB.

Complex trait methylation scores in the prediction of major depressive disorder.

SummaryBackgroundDNA methylation (DNAm) is associated with time-varying environmental factors that contribute to major depressive disorder (MDD) risk. We sought to test whether DNAm signatures of lifestyle and biochemical factors were associated with MDD to reveal dynamic biomarkers of MDD risk that may be amenable to lifestyle interventions.MethodsHere, we calculated methylation scores (MS) at multiple p-value thresholds for lifestyle (BMI, smoking, alcohol consumption, and educational attainment) and biochemical (high-density lipoprotein (HDL) and total cholesterol) factors in Generation Scotland (GS) (N=9,502) and in a replication cohort (ALSPACadults, N=565), using CpG sites reported in previous well-powered methylome-wide association studies. We also compared their predictive accuracy for MDD to a MDD MS in an independent GS sub-sample (N=4,432).FindingsEach trait MS was significantly associated with its corresponding phenotype in GS (βrange=0.089–1.457) and in ALSPAC (βrange=0.078–2.533). Each MS was also significantly associated with MDD before and after adjustment for its corresponding phenotype in GS (βrange=0.053–0.145). After accounting for relevant lifestyle factors, MS for educational attainment (β=0.094) and alcohol consumption (MSp-value<0.01–0.5; βrange=-0.069–0.083) remained significantly associated with MDD in GS. Smoking (AUC=0.569) and educational attainment (AUC=0.585) MSs could discriminate MDD from controls better than the MDD MS (AUC=0.553) in the independent GS sub-sample. Analyses implicating MDD did not replicate across ALSPAC, although the direction of effect was consistent for all traits when adjusting for the MS corresponding phenotypes.InterpretationWe showed that lifestyle and biochemical MS were associated with MDD before and after adjustment for their corresponding phenotypes (pnominal<0.05), but not when smoking, alcohol consumption, and BMI were also included as covariates. MDD results did not replicate in the smaller, female-only independent ALSPAC cohort (NALSPAC=565; NGS=9,502), potentially due to demographic differences or low statistical power, but effect sizes were consistent with the direction reported in GS. DNAm scores for modifiable MDD risk factors may contribute to disease vulnerability and, in some cases, explain additional variance to their observed phenotypes.FundingWellcome Trust.

P323. Blunted Amygdala Activity to Positive Memories in Young Adults With High Familial Risk for Depression

Depression is associated with a tendency to recall fewer specific and fewer positive autobiographical memories (AMs), and reduced amygdala hemodynamic activity when recalling positive AMs. This amygdala response may be a causal mechanism underlying depression, yet whether it is a precursor to disease onset is unclear. This study evaluates if blunted amygdala activity during positive AM recall is detectable in healthy individuals at risk for major depressive disorder (MDD), to inform its utility as an early therapeutic target aimed at disease prevention.

Association of the Combined Effects between Insulin-Like Growth Factor-1 Gene Polymorphisms and Negative Life Events with Major Depressive Disorder among Chinese population in the Context of Oxidative Stress

Background Oxidative stress may be increased in a number of psychiatric disorders, including major depressive disorder (MDD). MDD has been shown to be related to insulin-like growth factor-1 (IGF-1) as well as to negative life events; exploring the interaction of IGF-1 polymorphisms and negative life events on the risk of MDD is needed. The aim of this study was to analyze the single and combined effects of IGF-1 polymorphisms (rs972936 and rs978458) and negative life events with MDD among Chinese population. Methods 420 MDD patients (according to DSM-V) and 420 age- and gender-matched control subjects were recruited in a case-control study. Negative life events were assessed using standard rating scales. IGF-1 rs972936 and rs978458 were identified by sequencing. The chi-square (χ2) tests were performed to explore the association of negative life events and IGF-1 polymorphisms with MDD. Results Our results found that the negative life events were associated with the risk of MDD (P < 0.001; OR = 3.28, 95% CI: 2.19-4.85). The genotypes of IGF-1 were associated with the risk of MDD (P < 0.001); carrying the IGF-1 rs972936 C allele (OR = 1.53, 95% CI: 1.26-1.85) and rs978458 T allele (OR = 1.92, 95% CI: 1.58-2.34) had a higher risk of MDD. The combined effects between IGF-1 rs978458 and negative life events were associated with the risk of MDD (P < 0.05; OR = 2.94, 95% CI: 1.23-7.03), but IGF-1 rs972936 was not associated (P > 0.05). Conclusions Based on the oxidative stress hypothesis, we confirm that carrying IGF-1 rs972936 C allele and rs978458 T allele have a higher risk of MDD and the combined effects between IGF-1 rs978458 and negative life events were associated with the risk of MDD among Chinese population.

The association between midlife living arrangement and psychiatrist-diagnosed depression in later life: who among your family members reduces the risk of depression?

This study investigates the longitudinal association between living arrangements and psychiatrists’ diagnosis of depression in the general population. In 1990, 1254 Japanese men and women aged 40–59 years were enroled and completed questionnaires on the living arrangement in the Japan Public Health Center-based Prospective Study (JPHC Study) and participated in a mental health screening (2014–2015). The study diagnosed a major depressive disorder (MDD) assessed by well-trained certified psychiatrists through medical examinations. During the follow-up, a total of 105 participants (36 men and 69 women) aged 64–84 years were diagnosed with MDD by psychiatrists. Living with a child (ren) was associated with a reduced risk of MDD for men but not for women; the respective multivariable ORs (95% CIs) were 0.42 (0.19–0.96) and 0.59 (0.32–1.09). These associations remained unchanged after adjusting for living with spouse and parent(s). In conclusion, living with a child (ren) was associated with a reduced risk of MDD in men, suggesting the role of a child (ren) in the prevention of MDD.