Dataset Information

Polygenic risk of major depressive disorder as a risk factor for venous thromboembolism.

ABSTRACT: Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with an increased risk of cardiovascular diseases, including venous thromboembolism (VTE). The reasons for this are complex and include obesity, smoking, and use of hormones and psychotropic medications. Genetic studies have increasingly provided evidence of the shared genetic risk of psychiatric and cardiometabolic illnesses. This study aimed to determine whether a genetic predisposition to MDD, BD, or SCZ is associated with an increased risk of VTE. Genetic correlations using the largest genome-wide genetic meta-analyses summary statistics for MDD, BD, and SCZ (Psychiatric Genetics Consortium) and a recent genome-wide genetic meta-analysis of VTE (INVENT Consortium) demonstrated a positive association between VTE and MDD but not BD or SCZ. The same summary statistics were used to construct polygenic risk scores for MDD, BD, and SCZ in UK Biobank participants of self-reported White British ancestry. These were assessed for impact on self-reported VTE risk (10 786 cases, 285 124 controls), using logistic regression, in sex-specific and sex-combined analyses. We identified significant positive associations between polygenic risk for MDD and the risk of VTE in men, women, and sex-combined analyses, independent of the known risk factors. Secondary analyses demonstrated that this association was not driven by those with lifetime experience of mental illness. Meta-analyses of individual data from 6 additional independent cohorts replicated the sex-combined association. This report provides evidence for shared biological mechanisms leading to MDD and VTE and suggests that, in the absence of genetic data, a family history of MDD might be considered when assessing the risk of VTE.

SUBMITTER: Ward J

PROVIDER: S-EPMC10506044 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Polygenic risk of major depressive disorder as a risk factor for venous thromboembolism.

Ward Joey J Le Ngoc-Quynh NQ Suryakant Suryakant S Brody Jennifer A JA Amouyel Philippe P Boland Anne A Bown Rosemary R Cullen Breda B Debette Stéphanie S Deleuze Jean-François JF Emmerich Joseph J Graham Nicholas N Germain Marine M Anderson Jana J JJ Pell Jill P JP Lyall Donald M DM Lyall Laura M LM Smith Daniel J DJ Wiggins Kerri L KL Soria José Manuel JM Souto Juan Carlos JC Morange Pierre-Emmanuel PE Smith Nicholas L NL Trégouët David-Alexandre DA Sabater-Lleal Maria M Strawbridge Rona J RJ

Blood advances 20230901 18

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with an increased risk of cardiovascular diseases, including venous thromboembolism (VTE). The reasons for this are complex and include obesity, smoking, and use of hormones and psychotropic medications. Genetic studies have increasingly provided evidence of the shared genetic risk of psychiatric and cardiometabolic illnesses. This study aimed to determine whether a genetic predisposition to MDD, BD, o ...[more]

PMID: 37399490

Similar Datasets

Project description:ImportanceMajor depressive disorder (MDD) and alcohol dependence (AD) are heritable disorders with significant public health burdens, and they are frequently comorbid. Common genetic factors that influence the co-occurrence of MDD and AD have been sought in family, twin, and adoption studies, and results to date have been promising but inconclusive.ObjectiveTo examine whether AD and MDD overlap genetically, using a polygenic score approach.Design, settings, and participantsAssociation analyses were conducted between MDD polygenic risk score (PRS) and AD case-control status in European ancestry samples from 4 independent genome-wide association study (GWAS) data sets: the Collaborative Study on the Genetics of Alcoholism (COGA); the Study of Addiction, Genetics, and Environment (SAGE); the Yale-Penn genetic study of substance dependence; and the National Health and Resilience in Veterans Study (NHRVS). Results from a meta-analysis of MDD (9240 patients with MDD and 9519 controls) from the Psychiatric Genomics Consortium were applied to calculate PRS at thresholds from P < .05 to P ≤ .99 in each AD GWAS data set.Main outcomes and measuresAssociation between MDD PRS and AD.ResultsParticipants analyzed included 788 cases (548 [69.5%] men; mean [SD] age, 38.2 [10.8] years) and 522 controls (151 [28.9.%] men; age [SD], 43.9 [11.6] years) from COGA; 631 cases (333 [52.8%] men; age [SD], 35.0 [7.7] years) and 756 controls (260 [34.4%] male; age [SD] 36.1 [7.7] years) from SAGE; 2135 cases (1375 [64.4%] men; age [SD], 39.4 [11.5] years) and 350 controls (126 [36.0%] men; age [SD], 43.5 [13.9] years) from Yale-Penn; and 317 cases (295 [93.1%] men; age [SD], 59.1 [13.1] years) and 1719 controls (1545 [89.9%] men; age [SD], 64.5 [13.3] years) from NHRVS. Higher MDD PRS was associated with a significantly increased risk of AD in all samples (COGA: best P = 1.7 × 10-6, R2 = 0.026; SAGE: best P = .001, R2 = 0.01; Yale-Penn: best P = .035, R2 = 0.0018; and NHRVS: best P = .004, R2 = 0.0074), with stronger evidence for association after meta-analysis of the 4 samples (best P = 3.3 × 10-9). In analyses adjusted for MDD status in 3 AD GWAS data sets, similar patterns of association were observed (COGA: best P = 7.6 × 10-6, R2 = 0.023; Yale-Penn: best P = .08, R2 = 0.0013; and NHRVS: best P = .006, R2 = 0.0072). After recalculating MDD PRS using MDD GWAS data sets without comorbid MDD-AD cases, significant evidence was observed for an association between the MDD PRS and AD in the meta-analysis of 3 GWAS AD samples without MDD cases (best P = .007).Conclusions and relevanceThese results suggest that shared genetic susceptibility contributes modestly to MDD and AD comorbidity. Individuals with elevated polygenic risk for MDD may also be at risk for AD.

Project description:BackgroundUp to 30% of severely injured patients on prophylactic anticoagulation experience venous thromboembolism (VTE). Our previous work shows that acquired antithrombin (AT) deficiency [AT<80%] occurs in approximately 20% of trauma patients upon admission and drives poor responsiveness to enoxaparin. However, changes in AT over time and its association with VTE remain unknown. The aim of this study was to determine the relationship between acquired AT deficiency and VTE in severely injured patients.MethodsA secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) clinical trial was performed. Patients who died within 24 h of hemorrhage were excluded from analysis. Demographics, mechanism and severity of injury, transfusions volumes, and outcomes were compared between patients who did and did not develop VTE. Non-parametric statistical tests were used to compare patients with and without VTE. Logistic regression analyses were performed to identify predictors of VTE risk, controlling for AT deficiency (over first 72 h), age, gender, race, body mass index, study site, randomization group and injury severity. A Cox proportional hazards model was used to assess the contribution of AT deficiency to the risk of VTE, while censoring for early deaths.ResultsOf the 680 patients enrolled in PROPPR, 101 died of hemorrhage. Of the remaining 579 patients, 86 (14.9%) developed VTE. The median time to VTE was 6 days (IQR 3, 13). No differences in demographics, injuries, or transfusion volumes were identified between VTE cases and controls. AT deficiency at 72 h post-admission was independently associated with VTE. Patients who experienced AT deficiency at 72 h had a 3.3 fold increased risk of VTE [p < 0.01; 95% CI 1.56, 6.98]. Lastly, patients who developed VTE had worse outcomes as displayed by significantly fewer hospital-free days compared to non-VTE patients [0 (0, 8) vs. 4 (0, 18), p < 0.01, respectively].ConclusionsAcquired AT deficiency (AT<80%) is an important risk factor for VTE in severely injured patients. These data indicate that intervening, perhaps through AT supplementation, in the first three days after injury could mitigate the risk of VTE and improve patient outcomes.

Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Dataset Information

Polygenic risk of major depressive disorder as a risk factor for venous thromboembolism.

Publications

Polygenic risk of major depressive disorder as a risk factor for venous thromboembolism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets