Background Impairment in daily activities, such as work and socialising, is part of the diagnostic criteria for major depressive disorder (MDD) and most anxiety disorders. Despite evidence suggesting that symptom severity and functional impairment are partially distinct, functional impairment is often overlooked. We aimed to estimate the heritabilities of, and genetic correlations between, key measures of depression symptoms, anxiety symptoms and functional impairment, to assess whether functional impairment captures diagnostically relevant genetic liability beyond that of symptoms. Methods In a sample of 17,130 individuals with lifetime depression or anxiety from the Genetic Links to Anxiety and Depression (GLAD) Study, we analysed total scores from the Patient Health Questionnaire-9 (PHQ-9; depression symptoms), Generalised Anxiety Disorder-7 (GAD-7; anxiety symptoms), and Work and Social Adjustment Scale (WSAS; functional impairment). A genome-wide association study of each phenotype was performed with REGENIE software. Heritability was estimated with GCTA-GREML and genetic correlations with bivariate-GREML. Results Phenotypic correlations were moderate across the three measures (Pearson’s r = 0.50 - 0.69). All three scales were found to be under significant genetic influence (h2SNP = 0.11 - 0.19) with high genetic correlations between them (rg = 0.79 - 0.87). Conclusions Within individuals with lifetime depression or anxiety, the genetic variants that underlie symptom severity are largely the same as those influencing functional impairment. This suggests that the genetic factors associated with self-reported functional impairment, which is clinically relevant for diagnosis and treatment outcomes, can be sufficiently captured by symptom-based measures of depression or anxiety.
Abstract Genome-wide studies often exclude family members, even though they are a valuable source of information. We identified parent-offspring pairs, siblings and couples in the UK Biobank and implemented a family-based DNA-derived heritability method to capture additional genetic effects and multiple sources of environmental influence on neuroticism and years of education. Compared to estimates from unrelated individuals, heritability increased from 10% to 27% and from 19% to 57% for neuroticism and education respectively by including family-based genetic effects. We detected no family environmental influences on neuroticism, but years of education was substantially influenced by couple similarity (38%). Overall, our genetic and environmental estimates closely replicate previous findings from an independent sample, but more research is required to dissect contributions to the additional heritability, particularly rare and structural genetic effects and residual environmental confounding. The latter is especially relevant for years of education, a highly socially-contingent variable, for which our heritability estimate is at the upper end of twin estimates in the literature. Family-based genetic effects narrow the gap between twin and DNA-based heritability methods, and could be harnessed to improve polygenic prediction.
The majority of those who experience clinical anxiety and/or depressive symptoms in the population do not receive treatment. Studies investigating inequalities in treatment outcomes rarely consider that individuals respond differently to their experience of the environment. Much of our environment is under genetic influence, via our behaviour, whereby individuals actively select their experiences. If genes influence who seeks and receives treatment, selection bias will confound genomic studies of treatment response. Furthermore, if some individuals are at high genetic risk of needing but not commencing treatment, then greater efforts could be made to engage them. The role of common genetic variation on four lifetime treatment-seeking behaviours (treatment-seeking, treatment-receipt, self-help, self-medication with alcohol/drugs) was examined in participants of the UK Biobank (sample size range: 48,106 - 75,322). Treatment-related behaviours were only modestly heritable in these data. Nonetheless, genetic correlations reveal substantial genetic overlap between lifetime treatment-related behaviours and psychiatric disorders, symptoms and behavioural traits. To our knowledge, this is the first study to examine genetic influences on treatment-related behaviours. Further work is required to determine whether genetic factors could be used alongside clinical, social and demographic factors to identify at risk groups and inform strategies which target early intervention.
Abstract Context Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are established therapeutics for type 2 diabetes and obesity. Among other mechanisms, they slow gastric emptying and motility of the small intestine. This helps limiting postprandial glycemic excursions and reducing chylomicron formation and triglyceride absorption. Conversely, motility effects may have detrimental consequences, e.g., retained gastric contents at endoscopy or general anesthesia, potentially complicated by pulmonary aspiration, or bowel obstruction. Evidence Acquisition We searched the PubMed database for studies involving GLP-1RA therapy and adverse gastrointestinal/biliary events. Evidence Synthesis Retained gastric contents at the time of upper gastrointestinal endoscopy are found more frequently with GLP-1 RAs, but rarely are associated with pulmonary aspiration. Well-justified recommendations for the peri-procedural management of GLP-1RAs (e.g., whether to withhold these medications, and for how long) are compromised by limited evidence. Important aspects to be considered are (a) their long half-lives, (b) the capacity of GLP-1 receptor agonism to slow gastric emptying even at physiological GLP-1 concentrations, (c) tachyphylaxis observed with prolonged treatment, and (d) the limited effect on gastric emptying in individuals with slow gastric emptying before initiating treatment. Little information is available on the influence of diabetes mellitus itself (i.e., in the absence of GLP-1 RA treatment) on retained gastric contents and pulmonary aspiration. Conclusions Prolonged fasting periods regarding solid meal components, point-of-care ultrasound examination for retained gastric content, and the use of prokinetic medications like erythromycin may prove helpful, and are an important area needing further study to increase patient safety for those treated with GLP-1 RAs.
Abstract Background This study aimed to develop, validate and compare the performance of models predicting post-treatment outcomes for depressed adults based on pre-treatment data. Methods Individual patient data from all six eligible randomised controlled trials were used to develop ( k = 3, n = 1722) and test ( k = 3, n = 918) nine models. Predictors included depressive and anxiety symptoms, social support, life events and alcohol use. Weighted sum scores were developed using coefficient weights derived from network centrality statistics (models 1–3) and factor loadings from a confirmatory factor analysis (model 4). Unweighted sum score models were tested using elastic net regularised (ENR) and ordinary least squares (OLS) regression (models 5 and 6). Individual items were then included in ENR and OLS (models 7 and 8). All models were compared to one another and to a null model (mean post-baseline Beck Depression Inventory Second Edition (BDI-II) score in the training data: model 9). Primary outcome: BDI-II scores at 3–4 months. Results Models 1–7 all outperformed the null model and model 8. Model performance was very similar across models 1–6, meaning that differential weights applied to the baseline sum scores had little impact. Conclusions Any of the modelling techniques (models 1–7) could be used to inform prognostic predictions for depressed adults with differences in the proportions of patients reaching remission based on the predicted severity of depressive symptoms post-treatment. However, the majority of variance in prognosis remained unexplained. It may be necessary to include a broader range of biopsychosocial variables to better adjudicate between competing models, and to derive models with greater clinical utility for treatment-seeking adults with depression.
Decades of research have shown that environmental exposures, including self-reports of trauma, are partly heritable. Heritable characteristics may influence exposure to and interpretations of environmental factors. Identifying heritable factors associated with self-reported trauma could improve our understanding of vulnerability to exposure and the interpretation of life events.
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