Risk Of Major Depressive Disorder Research Articles

Periaqueductal gray is required for controlling chronic stress-induced depression-like behavior

BackgroundEnduring exposure to psychological stress is associated with an elevated risk of major depressive disorder (MDD). There is an enormous need to investigate the unexplored mechanisms of MDD. We examined whether pain-free stress alters synaptic transmission, causing depression-like behaviors in the ventrolateral periaqueductal gray (vlPAG), a brain stem nucleus that controls stress-related depression-like behavior. MethodsIn the current study, we studied neuronal changes in the vlPAG and behavioral transforms using electrophysiological recordings, behavioral tests, and pharmacological approaches. ResultsWe found that chronic restraint stress (CRS) diminished glutamatergic transmission in the vlPAG, leading to maladaptive behavioral despair and anhedonia in mice demonstrated by the forced swimming test (FST), tail suspension test (TST) and female urine sniffing test (FUST). Moreover, CRS increased behavioral hypersensitivity shown by the von Frey test. Bath perfusion with the rapid-acting antidepressant (2R,6R)-hydroxynorketamine (HNK) increased both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in vlPAG neurons in the CRS and control groups. Functionally, (2R,6R)-HNK directly enhanced the action potential firing rate in vlPAG neurons. Behaviorally, intravlPAG microinjection of (2R,6R)-HNK alleviated chronic restraint stress-induced depression-like behaviors and behavioral hypersensitivity. ConclusionsThese results demonstrate that psychological stress-elicited depression-like behavior is related to a remarkable decrease in glutamatergic transmission in the vlPAG. The maladaptive behaviors are attributed to hypoactivity of glutamatergic neurons in the vlPAG, and direct enhancement of glutamatergic neuronal activity in the vlPAG rescues depression-like behaviors. The present results prove that vlPAG is critical for controlling stress-induced depression-like behaviors through alteration of glutamatergic transmission.

Perinatal depression is associated with a higher polygenic risk for major depressive disorder than non-perinatal depression.

Distinctions between major depressive disorder (MDD) and perinatal depression (PND) reflect varying views of PND, from a unique etiological subtype of MDD to an MDD episode that happens to coincide with childbirth. This case-control study investigated genetic differences between PND and MDD outside the perinatal period (non-perinatal depression or NPD). We conducted a genome-wide association studyusing PND cases (Edinburgh Postnatal Depression Scale score ≥ 13) from the Australian Genetics of Depression Study2018 data (n = 3804) and screened controls (n = 6134). Results of gene-set enrichment analysis were compared with those of women with non-PND. For six psychiatric disorders/traits, genetic correlations with PND were evaluated, and logistic regression analysis reported polygenic score (PGS) association with both PND and NPD. Genes differentially expressed in ovarian tissue were significantly enriched (stdBeta = 0.07, p = 3.3e-04), but were not found to be associated with NPD. The genetic correlation between PND and MDD was 0.93 (SE = 0.07; p = 3.5e-38). Compared with controls, PGS for MDD are higher for PND cases (odds ratio [OR] = 1.8, confidence interval [CI] = [1.7-1.8], p = 9.5e-140) than for NPD cases (OR = 1.6, CI = [1.5-1.7], p = 1.2e-49). Highest risk is for those reporting both antenatal and postnatal depression, irrespective of prior MDD history. PND has a high genetic overlap with MDD, but points of distinction focus on differential expression in ovarian tissue and higher MDD PGS, particularly for women experiencing both antenatal and postpartum PND.

Gene-gene interaction and new onset of major depressive disorder: Findings from a Chinese freshmen nested case-control study

BackgroundThe gene-gene interaction is known to be the genetic cause of major depressive disorder (MDD). Several genes have been found to be related to MDD. The objectives of this study were to verify the susceptibility genes of MDD in a sample of university students in China, and to investigate possible gene-gene interactions in relation to the risk of MDD. Methods7,627 Chinese Han freshmen were enrolled at baseline survey in 2018. After a 2-year follow-up, 170 new onset MDD cases and 680 controls with DNA samples reserved were sequenced and genotyped for 4 selected Single Nucleotide Polymorphisms (SNPs) in a nested case-control study (ratio of 1:4). Chi-square test was used to identify the relationships between SNPs and risk of MDD. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-gene interactions. ResultsThe 2-year incidence of MDD in Chinese college students was 3.75% (95% CI: 3.24%, 4.34%). There was no statistical difference in MDD incidences between males (3.74%, 95% CI: 3.12%, 4.49%) and females (3.77%, 95% CI: 2.97%, 4.78%) (p>0.05). TMEM161B (rs768705) was positively associated with new onset MDD (χ2 = 0.75, p = 0.023). The AG genotype of rs768705 was significant (OR=1.640, 95%CI:1.414–2.358). The gene-gene interaction between TMEM161B (rs768705) and LHPP (rs35936514) was statistically significant in this nested case-control study (p = 0.011). The CV consistency was 9/10 and the testing accuracy was 0.5274. LimitationsThe results could not be inferred to other ethnics. ConclusionsThis study provided evidence that combined rs768705 (TMEM161B) and rs35936514 (LHPP) may modulate the risk of MDD.

Longitudinal associations between adolescents’ individualised risk for depression and inflammation in a UK cohort study

Inflammation is associated with poor physical and mental health including major depressive disorder (MDD). Moreover, there is evidence that childhood adversity – a risk factor for MDD – becomes biologically embedded via elevated inflammation. However, the risk of developing MDD arises from multiple sources and yet there has been little investigation of the links between individuals’ constellation of MDD risk and subsequent inflammation. We therefore examined associations between individual risk for MDD calculated in early adolescence and levels of inflammation six years later. We use data from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative UK birth cohort of 2,232 children followed to age 18 with 93% retention. Participants’ individual risk for developing future MDD was calculated at age 12 using a recently developed prediction model comprising multiple psychosocial factors. Plasma levels of three inflammation biomarkers were measured at age 18: C-reactive protein (CRP), interleukin-6 (IL-6), and a newer biomarker, soluble urokinase plasminogen activator receptor (suPAR), which is thought to reflect the level of systemic chronic inflammation. MDD risk scores calculated at age 12 were positively associated with levels of suPAR (but not CRP or IL-6) at age 18 after adjusting for key covariates (b = 1.70, 95% CI = 0.46 – 2.95, p = 0.007). Adolescents at high risk of MDD (risk scores ≥ 90th centile) had significantly higher mean levels of suPAR six years later than adolescents who had been identified as low risk (risk scores ≤ 10th centile) (b = 0.41, 95% CI = 0.18 – 0.64, p < 0.001). Findings support the notion that childhood psychosocial risk for MDD leads to increased levels of low-grade inflammation. If replicated in studies with repeated assessments of inflammation biomarkers throughout childhood and adolescence, these findings would support targeted interventions to reduce inflammation, as measured by suPAR, for adolescents at high risk of MDD to potentially prevent development of depression and physical health problems related to chronic inflammation.

Race and nonrace-specific attributions of discrimination: Implications for major depressive disorder among African American, Black Caribbean, and White adults.

The discrimination and health literature has not clearly resolved whether race-based experiences with discrimination are meaningfully distinct from other forms of unfair treatment or whether race-based experiences affect racial and ethnic minorities differently than non-Hispanic Whites. This study compared the effects of racial and nonrace-specific discrimination on lifetime risk for major depressive disorder (MDD) using data from the National Survey of American Life (NSAL), a nationally representative sample of African Americans, Caribbean Blacks, and non-Hispanic Whites (N = 6,082). Discrimination was defined in two ways: (a) nonrace-specific (any experience of discrimination regardless of the attribution) and (b) racial (discrimination attributed to a race-related reason such as race or skin color), which allowed for an assessment of any unique effects of racial discrimination on MDD risk for each ethnic group. Nonrace-specific discrimination was associated with increased MDD risk among both African Americans and non-Hispanic Whites. However, race-specific discrimination was associated with increased MDD risk for African Americans and Black Caribbeans, but not non-Hispanic Whites. These findings suggest that nonrace-specific discrimination measures-used commonly in the existing literature-may obscure unique associations between racial discrimination and depression; race-related discrimination may have uniquely detrimental consequences for MDD risk among Black people (e.g., African Americans and Black Caribbeans). (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Sleep disturbance and psychiatric disorders: a bidirectional Mendelian randomisation study.

Sleep disturbance is an important factor in the pathophysiology and progression of psychiatric disorders, but whether it is a cause, or a downstream effect is still not clear. To investigate causal relationships between three sleep-associated traits and seven psychiatric diseases, we used genetic variants related to insomnia, chronotype and sleep duration to perform a two-sample bidirectional Mendelian randomisation analysis. Summary-level data on psychiatric disorders were extracted from the Psychiatric Genomics Consortium. Effect estimates were obtained by using the inverse-variance-weighted (IVW), weights modified IVW, weighted-median methods, MR-Egger regression, MR pleiotropy residual sum and outlier (MR-PRESSO) test and Robust Adjusted Profile Score (RAPS). The causal odds ratio (OR) estimate of genetically determined insomnia was 1.33 (95% confidence interval (CI) 1.22-1.45; p = 5.03 × 10-11) for attention-deficit/hyperactivity disorder (ADHD), 1.31 (95% CI 1.25-1.37; p = 6.88 × 10-31) for major depressive disorder (MDD) and 1.32 (95% CI 1.23-1.40; p = 1.42 × 10-16) for post-traumatic stress disorder (PTSD). There were suggestive inverse associations of morningness chronotype with risk of MDD and schizophrenia (SCZ). Genetically predicted sleep duration was also nominally associated with the risk of bipolar disorder (BD). Conversely, PTSD and MDD were associated with an increased risk of insomnia (OR = 1.06, 95% CI 1.03-1.10, p = 7.85 × 10-4 for PTSD; OR = 1.37, 95% CI 1.14-1.64; p = 0.001 for MDD). A suggestive inverse association of ADHD and MDD with sleep duration was also observed. Our findings provide evidence of potential causal relationships between sleep disturbance and psychiatric disorders. This suggests that abnormal sleep patterns may serve as markers for psychiatric disorders and offer opportunities for prevention and management in psychiatric disorders.

Understanding Sleepiness and Fatigue in Cabin Crew Using COVID-19 to Dissociate Causative Factors.

OBJECTIVES: Airline cabin crew experience high levels of fatigue and sleepiness. Whether these are solely related to their work schedules/jetlag or are in part related to individual factors is unknown. The COVID-19 pandemic has significantly disrupted the aviation industry and many cabin crew have been grounded. This provides a unique opportunity to assess the causes of fatigue and sleepiness in this population.METHODS: An online anonymous survey was distributed in April-June 2020 to cabin crew who were 1) flying, 2) grounded but doing alternative work, and 3) grounded, not working, or unemployed. The survey measured fatigue, sleepiness, and mental health. It also screened their risk for insomnia, depression, and shift work disorder and assessed drug and caffeine use.RESULTS: Collected were 409 valid responses: 45 currently flying; 35 grounded but doing alternate work; and 329 not working. On average, all three groups experienced normal levels of fatigue and sleepiness. The risk for major depressive disorder was 27.4%, with 59.5% of individuals reporting abnormal levels of anxiety. Caffeine intake and the use of drugs and alcohol to facilitate sleep were common, although not different between those currently flying vs. grounded.CONCLUSIONS: With reduced workloads or not flying, cabin crew reported lowered fatigue and sleepiness compared to prepandemic findings, along with reduced risk for major depressive disorder. However, a high occurrence of negative emotional states were reported, potentially related to the uncertainty surrounding the pandemic. This study suggests fatigue and sleepiness is primarily related to airline operational rather than personal variables.Wen CC-Y, Nicholas CL, Howard ME, Trinder J, Jordan AS. Understanding sleepiness and fatigue in cabin crew using COVID-19 to dissociate causative factors. Aerosp Med Hum Perform. 2022; 93(1):50-53.

The Mental Health of Long-Term Evacuees outside Fukushima Prefecture after the Great East Japan Earthquake.

Ten years after the Great East Japan Earthquake, thousands of residents of Fukushima Prefecture were still living as evacuees. Among them, unignorable numbers of people were living outside of the prefecture. A survey was conducted with evacuees to Ibaraki, the neighboring prefecture of Fukushima, to investigate their medium- to long-term mental care needs. A questionnaire was sent to 1,470 households that had been living in Fukushima on March 11, 2011, and who were evacuated to Ibaraki by October 2016. Binary logistic regression analyses were performed to identify risk factors for major depressive disorder, post-traumatic stress disorder (PTSD), and suicidal ideation. Of the participants, 16.5% had a high risk for major depressive disorder, 39.0% exhibited a high risk for PTSD, and 19.7% indicated suicidal ideation. "Own injuries and illnesses" and "Worries about the hometown" were risk factors for major depressive disorder, PTSD, and suicidal ideation. "Not receiving compensation for damages" was a risk factor common to major depressive disorder and suicidal ideation. There is a high possibility that many people who have evacuated to other prefectures might still be suffering from psychological symptoms after the disaster. Worries about their hometowns were highly related to their mental disorders.

Anxiety and depression prevalence and determinants in health sciences students during Covid-19 pandemic: a quantitative study in Nampula, Mozambique

Introduction: anxiety and depression are the most prevalent mental disorders in the world, close to 50% of the international disease burden due to psychiatric disorders and substance use. Research with university students show psychiatric disorders ‘rates around 15 to 25%. Student’ environment interferes in higher education and life conditions bias training context, often adverse and a mental health stressor. Population’ depressive disorders prevalence is around 7%, but these disorders’ incidence increased due to the SARS-CoV-2 pandemic, impairing individual’s functional and psychosocial lives, and increasing the risk of major depressive disorder if not recognized and treated. Objective: estimate anxiety and depression prevalence rates in Faculty of Health Sciences’ students, at Lúrio University in Nampula, Mozambique, and associated determinants, during the Covid-19 pandemic. Methods: descriptive, quantitative cross-sectional study, applying a digital survey about psychologic stress determinant factors, based on Hospital Anxiety and Depression Scale. The Faculty of Health Sciences students’ random sample in Nampula answered the survey during August to October 2020, in a declared Public Calamity period due to Covid-19 pandemic. Results were analysed with Statistic Package for Social Science with a confidence interval of 95% and an error margin of 5%, using Q2 test to determine statistically significant associations. Results: 276 students answered the survey, 50% of each gender, aged from 17 to 51 years, 60% coming from Nampula province, showing high rates of anxiety, depression and co morbidity, respectively 42.3, 34.3 and 25.9%, with a statistically significant association with bad relationships with friends, not enough sleep, trauma, lost and family antecedents. Conclusion: we confirmed the high prevalence of mental disorders in the Mozambican population, aggravated by governmental restrictive measures due to SARS-CoV-2 pandemic, implementing distance digital learning. Faculty of Health Sciences’ students have high anxiety and depression prevalence rates, mental disorders limiting academic performance and decreasing life quality. These results are important to allow the University to launch preventative activities and to promote therapeutic options, to grant the teaching – learning system success.

Recent advances in understanding depressive disorder: Possible relevance to brain stimulation therapies.

Recent research has provided novel insights into the major depressive disorder (MDD) and identified certain biomarkers of this disease. There are four main mechanisms playing a key role in the related pathophysiology, namely (1) monoamine systems dysfunction, (2) stress response, (3) neuroinflammation, and (4) neurotrophic factors alteration. Robust evidence on the decreased homovanillic acid in the cerebrospinal fluid (CSF) of patients with MDD supports a rationale for therapeutic stimulation of the medial forebrain bundle activating the dopamine reward system. Both activation and suppression of the hypothalamic-pituitary-adrenal (HPA) axis in MDD and related conditions indicate usefulness of its evaluation for the disease subtyping. Elevated proinflammatory cytokines (specifically, interleukin-6) in CSF imply the role of neuroinflammation resulting in activation of the tryptophan-kynurenine pathway. Finally, neuroplasticity and trophic effects of the brain-derived neurotrophic factor (BDNF) may be related to both structural abnormalities of the brain in MDD and the underlying mechanisms of various therapies. In addition, the gut-brain interaction is pivotal, since lack of beneficial microbes confer the risk of MDD through negative effects on the dopamine system, HPA axis, and vagal nerve. All these factors may be highly relevant to treatment of MDD with contemporary brain stimulation therapies.

The Latent Structure of Negative Symptoms in the General Population in Adolescence and Emerging Adulthood.

Negative symptoms predict adverse outcomes within psychotic disorders, in individuals at high-risk for psychosis, and in young people in the community. There is considerable interest in the dimensional structure of negative symptoms in clinical samples, and accumulating evidence suggests a 5-factor structure. Little is known about the underlying structure of negative symptoms in young people despite the importance of this developmental stage for mental health. We used confirmatory factor analysis to test the structure of parent-reported negative symptoms at mean ages 16.32 (SD 0.68, N = 4974), 17.06 (SD 0.88, N = 1469) and 22.30 (SD 0.93, N = 5179) in a community sample. Given previously reported associations between total negative symptoms and genome-wide polygenic scores (GPS) for major depressive disorder (MDD) and schizophrenia in adolescence, we assessed associations between individual subdomains and these GPSs. A 5-factor model of flat affect, alogia, avolition, anhedonia, and asociality provided the best fit at each age and was invariant over time. The results of our linear regression analyses showed associations between MDD GPS with avolition, flat affect, anhedonia, and asociality, and between schizophrenia GPS with avolition and flat affect. We showed that a 5-factor structure of negative symptoms is present from ages 16 to 22 in the community. Avolition was most consistently associated with polygenic liability to MDD and schizophrenia, and alogia was least associated. These findings highlight the value of dissecting negative symptoms into psychometrically derived subdomains and may offer insights into early manifestation of genetic risk for MDD and schizophrenia.

Erectile Dysfunction is a Modifiable Risk Factor for Major Depressive Disorder: Analysis of a Federated Research Network

BackgroundErectile dysfunction is one of many conditions associated with depression, but few studies exist to establish the risk of major depressive disorder (MDD) in the large population of men with erectile dysfunction, and it is unclear whether erectile dysfunction (ED) treatment is associated with decreased rates of MDD. AimWe determined the risk of major depressive disorder in men with erectile dysfunction and evaluated whether treatment of ED with phosphodiesterase-5 inhibitor or penile prosthesis is associated with a lower risk of developing major depressive disorder. MethodsWe reviewed a large, retrospective, cohort that utilized electronic health record data collected by the TriNetX Research Network, a global federated database that provides healthcare data for analysis. We performed multiple comparisons: men with ED against men without ED; men with ED treated with phosphodiesterase-5 inhibitors against untreated ED patients, and of men with ED who received penile prosthesis against those who did not. We assessed major depressive disorder (ICD-10-CM F32-F33) as a primary outcome and used propensity score matching to control for ethnicity, race, type 2 diabetes mellitus (E11), essential hypertension (I10), acute myocardial infarction (I21), chronic ischemic heart disease (I25), cerebral infarction (I63), overweight and obesity (E66), personal history of nicotine (Z87.891), hypogonadism (E29.1), and alcohol related disorders (F10). OutcomesWe assessed new diagnosis of major depressive disorder (F32-F33) within a 3-year time window following index event of ED diagnosis, visit to healthcare organization, or ED treatment with phosphodiesterase-5 inhibitor or penile prosthesis as the primary outcome. ResultsED was associated with major depressive disorder both before and after (OR 2.00, 95% CI 1.94–2.06) controlling for confounding variables through propensity score matching. Men who received ED therapies had lower rates of depression compared to those who did not, whether they were treated with phosphodiesterase-5 inhibitor (0.80, 0.77–0.83) or penile prosthesis (0.73, 0.60–0.89). Strengths and LimitationsStrengths include a large sample size and robust statistical techniques. Limitations include lack of detailed information regarding clinical severity and socioeconomic factors. Clinical ImplicationsOur findings indicate that clinicians should consider evaluating depressive symptoms among men with erectile dysfunction and counsel them regarding the risk of developing major depressive disorder. ConclusionsErectile dysfunction is associated with major depressive disorder, but treatment is associated with decreased rates of MDD.S Nackeeran, A Havanur, J Ory, et al. Erectile Dysfunction is a Modifiable Risk Factor for Major Depressive Disorder: Analysis of a Federated Research Network. J Sex Med 2021;18:2005–2011.

Comparing Copy Number Variations in a Danish Case Cohort of Individuals With Psychiatric Disorders

Although the association between several recurrent genomic copy number variants (CNVs) and mental disorders has been studied for more than a decade, unbiased, population-based estimates of the prevalence, disease risks and trajectories, fertility, and mortality to contrast chromosomal abnormalities and advance precision health care are lacking. To generate unbiased, population-based estimates of prevalence, disease risks and trajectories, fertility, and mortality of CNVs implicated in neuropsychiatric disorders. In a population-based case-cohort study, using the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) 2012 database, individuals born between May 1, 1981, and December 31, 2005, and followed up until December 31, 2012, were analyzed. All individuals (n = 57 377) with attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), schizophrenia (SCZ), autism spectrum disorder (ASD), or bipolar disorder (BPD) were included, as well as 30 000 individuals randomly drawn from the database. Data analysis was conducted from July 1, 2017, to September 7, 2021. Copy number variants at 6 genomic loci (1q21.1, 15q11.2, 15q13.3, 16p11.2, 17p12, and 17q12). Population-unbiased hazard ratio (HR) and survival estimates of CNV associations with the 5 ascertained psychiatric disorders, epilepsy, intellectual disability, selected somatic disorders, fertility, and mortality. Participants' age ranged from 1 to 32 years (mean, 12.0 [IQR, 6.9] years) during follow-up, and 38 662 were male (52.3%). Copy number variants broadly associated with an increased risk of autism spectrum disorder and ADHD, whereas risk estimates of SCZ for most CNVs were lower than previously reported. Comparison with previous studies suggests that the lower risk estimates are associated with a higher CNV prevalence in the general population than in control samples of most case-control studies. Significant risk of major depressive disorder (HR, 5.8; 95% CI, 1.5-22.2) and sex-specific risk of bipolar disorder (HR, 17; 95% CI, 1.5-189.3, in men only) were noted for the 1q21.1 deletion. Although CNVs at 1q21.1 and 15q13.3 were associated with increased risk across most diagnoses, the 17p12 deletion consistently conferred less risk of psychiatric disorders (HR 0.4-0.8), although none of the estimates differed significantly from the general population. Trajectory analyses noted that, although diagnostic risk profiles differed across loci, they were similar for deletions and duplications within each locus. Sex-stratified analyses suggest that pathogenicity of many CNVs may be modulated by sex. The findings of this study suggest that the iPSYCH population case cohort reveals broad disease risk for some of the studied CNVs and narrower risk for others, in addition to sex differential liability. This finding on genomic risk variants at the level of a population may be important for health care planning and clinical decision making, and thus the advancement of precision health care.

Associations of parental mental disorders and age with childhood mental disorders: a population-based cohort study with four million offspring.

This Taiwan study examined the associations of parental age and mental disorders with the offspring risks of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), major depressive disorder (MDD), and bipolar disorder (BD). Children born between January 1991 and December 2004 in Taiwan were enrolled as the birth cohort (n = 4,138,151) and followed up until December 2011. A logistic regression analysis was performed to identify the odds ratio (OR). The advanced age effects were significant in ADHD (range of OR: 1.04 to 1.49) and ASD (range of OR: 1.35 to 2.27). Teenage mothers, teenage fathers, and fathers ≥ 50years had higher offspring risks of MDD (range of OR: 1.24 to 1.46); and teenage mothers and fathers ≥ 50years had increased offspring risks of BD (range of OR: 1.23 to 1.87). Both paternal and maternal mental disorders were associated with higher risks of within-disorder transmission for ADHD, ASD, MDD, and BD (range of OR: 2.64 to 30.41). Besides, parents with one of these four mental disorders (ADHD, ASD, MDD, and BD) might have higher risk of cross-disorder transmission to at least one of the other three mental disorders in the offspring (range of OR: 1.35 to 7.15). Parental age and mental disorders had complex and nuanced patterns in association with offspring mental disorders.

Abstract 12478: Investigating the Shared Genetic Architecture Between Coronary Artery Disease and Major Depressive Disorder

Coronary Artery Disease is a highly polygenic disorder and has increased comorbidity with Major Depressive Disorder (MDD). Our previous work demonstrated that the PRS for MDD was significantly associated with manifestations of CAD including ischemic heart disease (OR = 1.09, p=8.28x10-6) and coronary atherosclerosis (OR = 1.10, p=1.08x10-5) in a large hospital population. Furthermore, the association remained robust after adjusting for known CAD risk factors, suggesting that some proportion of genes that increase susceptibility to MDD act pleiotropically to increase CAD risk. Therefore, the aim of our study was to identify genes that increase risk for both CAD and MDD. We first performed an imputed TWAS using existing GWAS data on CAD from the CARDIoGRAMplusC4D consortium and UKBB and MDD from Psychiatric Genomics Consortium. TWAS uses the summary statistics from a GWAS and expression prediction models to infer the association between the genetically predicted expression of each gene and a phenotype of interest. We identified genes for which predicted expression was associated with increased risk of both MDD and CAD. We then further tested the relationship between those genes and quantitative biomarkers recorded in the Vanderbilt electronic health record (EHR). For this, we used Vanderbilt’s collection of de-identified biosamples (BioVU) which currently includes ~100k genotyped patient DNA samples linked with their EHRs. We used PredixVU, a gene-based association method to determine whether genes identified in the TWAS were associated with clinical biomarkers. We identified significant overlap in the genes associated with both MDD and CAD at an FDR of 0.01 (hypergeometric enrichment factor of 3.2; p = 0.002) and 0.05 (hypergeometric enrichment factor of 2.4; p = 8.35e-9). TMEM106B was significantly associated with both MDD and CAD after Bonferroni correction was applied. TMEM106B is involved in lysosomal activity and has been independently associated with both, CAD and MDD. The predicted expression of TMEM106B in the putamen is associated with decreased levels of hydroxyproline (OR = 0.830, P-Value = 7.5 e-5). For our future work, we aim to investigate the shared pathways of these genes across Asian, European and African ancestry using BioVU.

The importance of social activity to risk of major depression in older adults.

Several social determinants of health (SDoH) have been associated with the onset of major depressive disorder (MDD). However, prior studies largely focused on individual SDoH and thus less is known about the relative importance (RI) of SDoH variables, especially in older adults. Given that risk factors for MDD may differ across the lifespan, we aimed to identify the SDoH that was most strongly related to newly diagnosed MDD in a cohort of older adults. We used self-reported health-related survey data from 41 174 older adults (50-89 years, median age = 67 years) who participated in the Mayo Clinic Biobank, and linked ICD codes for MDD in the participants' electronic health records. Participants with a history of clinically documented or self-reported MDD prior to survey completion were excluded from analysis (N = 10 938, 27%). We used Cox proportional hazards models with a gradient boosting machine approach to quantify the RI of 30 pre-selected SDoH variables on the risk of future MDD diagnosis. Following biobank enrollment, 2073 older participants were diagnosed with MDD during the follow-up period (median duration = 6.7 years). The most influential SDoH was perceived level of social activity (RI = 0.17). Lower level of social activity was associated with a higher risk of MDD [hazard ratio = 2.27 (95% CI 2.00-2.50) for highest v. lowest level]. Across a range of SDoH variables, perceived level of social activity is most strongly related to MDD in older adults. Monitoring changes in the level of social activity may help identify older adults at an increased risk of MDD.

Shared Genetic Liability and Causal Associations Between Major Depressive Disorder and Cardiovascular Diseases.

Major depressive disorder (MDD) is phenotypically associated with cardiovascular diseases (CVD). We aim to investigate mechanisms underlying relationships between MDD and CVD in the context of shared genetic variations. Polygenic overlap analysis was used to test genetic correlation and to analyze shared genetic variations between MDD and seven cardiovascular outcomes (coronary artery disease (CAD), heart failure, atrial fibrillation, stroke, systolic blood pressure, diastolic blood pressure, and pulse pressure measurement). Mendelian randomization analysis was used to uncover causal relationships between MDD and cardiovascular traits. By cross-trait meta-analysis, we identified a set of genomic loci shared between the traits of MDD and stroke. Putative causal genes for MDD and stroke were prioritized by fine-mapping of transcriptome-wide associations. Polygenic overlap analysis pointed toward substantial genetic variation overlap between MDD and CVD. Mendelian randomization analysis indicated that genetic liability to MDD has a causal effect on CAD and stroke. Comparison of genome-wide genes shared by MDD and CVD suggests 20q12 as a pleiotropic region conferring risk for both MDD and CVD. Cross-trait meta-analyses and fine-mapping of transcriptome-wide association signals identified novel risk genes for MDD and stroke, including RPL31P12, BORSC7, PNPT11, and PGF. Many genetic variations associated with MDD and CVD outcomes are shared, thus, pointing that genetic liability to MDD may also confer risk for stroke and CAD. Presented results shed light on mechanistic connections between MDD and CVD phenotypes.

Air pollution interacts with genetic risk to influence cortical networks implicated in depression

Air pollution is a reversible cause of significant global mortality and morbidity. Epidemiological evidence suggests associations between air pollution exposure and impaired cognition and increased risk for major depressive disorders. However, the neural bases of these associations have been unclear. Here, in healthy human subjects exposed to relatively high air pollution and controlling for socioeconomic, genomic, and other confounders, we examine across multiple levels of brain network function the extent to which particulate matter (PM2.5) exposure influences putative genetic risk mechanisms associated with depression. Increased ambient PM2.5 exposure was associated with poorer reasoning and problem solving and higher-trait anxiety/depression. Working memory and stress-related information transfer (effective connectivity) across cortical and subcortical brain networks were influenced by PM2.5 exposure to differing extents depending on the polygenic risk for depression in gene-by-environment interactions. Effective connectivity patterns from individuals with higher polygenic risk for depression and higher exposures with PM2.5, but not from those with lower genetic risk or lower exposures, correlated spatially with the coexpression of depression-associated genes across corresponding brain regions in the Allen Brain Atlas. These converging data suggest that PM2.5 exposure affects brain network functions implicated in the genetic mechanisms of depression.

Symptoms of major depressive disorder during the COVID-19 pandemic: results from a representative sample of the Canadian population.

Since the outbreak of COVID-19, numerous studies from around the world have reported declines in mental health. However, most of these studies were of low-to-moderate quality and many were based on convenience samples or used mental health measures with low validity, or both. Consequently, it has been difficult to draw conclusions. Both the 2020 Survey on COVID-19 and Mental Health (SCMH) and the Canadian Community Health Survey (CCHS) (2015-2019) used the Patient Health Questionnaire-9 to screen for major depressive disorder (MDD) in adults aged 18 or older. The prevalence of MDD was compared between the SCMH and the CCHS. Risk and protective factors for MDD in the SCMH were examined using bivariate and logistic regression analyses. Based on SCMH data, 15.2% (95% CI: 14.2-16.2) of Canadians screened positive for MDD. The prevalence of MDD was more than two times higher in the SCMH (during COVID-19) than in the CCHS (predating COVID-19). In bivariate analysis, Canadians reporting five or more COVID-19-related risk factors were close to 30 times more likely to have MDD than those reporting no risk factors. Mastery and a sense of community belonging were protective factors for MDD. After remaining stable for two decades, the prevalence of depression among Canadians increased substantially with the onset of COVID-19. Ongoing monitoring of this common condition associated with major morbidity is vital to determine if elevated levels of MDD persist as we progress through and beyond future waves of COVID-19.

Impact of Prediagnosis Risk of Major Depressive Disorder and Health-Related Quality of Life on Treatment Choice for Stage II-III Rectal Cancer

We hypothesized that depressive symptoms and health-related quality of life (HRQOL) reported by patients prior to their cancer diagnoses would be associated with treatment choice for stage II and III rectal cancer. During the period of study and at the time of this writing, the standard of care for stage II-III rectal cancer has been neoadjuvant radiation followed by surgical resection with or without adjuvant chemotherapy.The SEER and Medicare Health Outcomes Survey (SEER-MHOS) linked dataset was used to identify patients with stage II and III rectal adenocarcinoma diagnosed between 2004 and 2013 who had completed the health outcomes survey within 36 months before their cancer diagnoses. Risk for major depressive disorder (MDD) was determined based on responses to screening questions for depressive disorders. HRQOL was assessed using the Mental Component Summary (MCS) and Physical Component Summary (PCS) of the 36-Item Short Form Survey (SF-36) and the Veterans RAND 12-Item Health Survey (VR-12). Using both univariable and multivariable analysis to control for potentially confounding patient characteristics, we assessed for associations between these health survey responses and ultimate treatment choice, specifically regarding whether patients underwent surgery for their rectal cancer.We identified 142 evaluable patients with stage II-III rectal cancer, of whom 109 (76.8%) underwent surgery. Thirty patients (21.1%) met criteria for being at risk for MDD before their cancer diagnoses. Patients at risk for MDD were significantly less likely to undergo surgery than those not at risk (63.3% vs. 80.4%, P = 0.0499), and this association strengthened after adjusting for patient characteristics (OR 0.17, 95% CI 0.04-0.82, P = 0.027). There was a nonsignificant trend between higher MCS scores (equating with higher self-reported mental HRQOL) and increased likelihood of undergoing surgery (P = 0.081). There were no significant associations between the PCS and treatment modality.In patients with stage II-III rectal cancer, there was a significant association between prediagnosis risk of MDD and treatment choice, such that patients at risk for MDD were less likely to undergo standard-of-care treatment with surgery. Further studies are warranted to assess the effect of MDD risk and HRQOL on clinical decision making with this patient population.