Polygenic score analyses on antidepressant response in late-life depression, results from the IRL-GRey study
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Using twin-pairs to assess potential bias in polygenic prediction of externalising behaviours across development
Prediction from polygenic scores may be confounded by sources of passive gene-environment correlation (rGE; e.g. population stratification, assortative mating, and environmentally mediated effects of parental genotype on child phenotype). Using genomic data from 10 000 twin pairs, we asked whether polygenic scores from the most recent externalising genome-wide association study predict conduct problems, ADHD symptomology and callous-unemotional traits, and whether these predictions are biased by rGE. We ran regression models including within-family and between-family polygenic scores, to separate the direct genetic influence on a trait from environmental influences that correlate with genes (indirect genetic effects). Findings suggested that this externalising polygenic score is a good index of direct genetic influence on conduct and ADHD-related symptoms across development, with minimal bias from rGE, although the polygenic score predicted less variance in CU traits. Post-hoc analyses showed some indirect genetic effects acting on a common factor indexing stability of conduct problems across time and contexts.
Polygenic scores for cardiovascular risk factors improve estimation of clinical outcomes in CCB treatment compared to pharmacogenetic variants alone
Pharmacogenetic variants are associated with clinical outcomes during Calcium Channel Blocker (CCB) treatment, yet whether the effects are modified by genetically predicted clinical risk factors is unknown. We analyzed 32,000 UK Biobank participants treated with dihydropiridine CCBs (mean 5.9 years), including 23 pharmacogenetic variants, and calculated polygenic scores for systolic and diastolic blood pressures, body fat mass, and other patient characteristics. Outcomes included treatment discontinuation and heart failure. Pharmacogenetic variant rs10898815-A (NUMA1) increased discontinuation rates, highest in those with high polygenic scores for fat mass. The RYR3 variant rs877087 T-allele alone modestly increased heart failure risks versus non-carriers (HR:1.13, p = 0.02); in patients with high polygenic scores for fat mass, lean mass, and lipoprotein A, risks were substantially elevated (HR:1.55, p = 4 × 10−5). Incorporating polygenic scores for adiposity and lipoprotein A may improve risk estimates of key clinical outcomes in CCB treatment such as treatment discontinuation and heart failure, compared to pharmacogenetic variants alone.
Increased odds of metabolic syndrome among adults with depressive symptoms or antidepressant use
Metabolic syndrome (MetS) is a condition that includes a cluster of risk factors for cardiovascular disease. In this paper, we aimed to evaluate the association between depressive symptoms, antidepressant use, duration of antidepressant use, antidepressant type and MetS. Data from the 2005–2018 National Health and Nutrition Examination Surveys were used in this study. Adults were included if they responded to the depressive symptoms and prescription medications questionnaires and had measures of blood pressure, waist circumference, triglycerides, high-density lipoprotein, and fasting plasma glucose. Participants were categorized by their antidepressant use (yes/no), type, and duration. This study included 14,875 participants (50.45% females), with 3616 (23.45%) meeting the criteria for MetS. Participants with higher depressive symptom scores (aOR = 1.04, 95% CI: 1.02, 1.05, p < 0.001) or those with depressive symptoms (aOR = 1.42, 95% CI: 1.17, 1.73, p = 0.001) had higher odds of MetS. A similar associations was seen among those who were on antidepressants compared to those who were not on antidepressants (aOR = 1.24, 95% CI: 1.03, 1.50, p = 0.025). Duration of antidepressant use was not significantly associated with MetS. Participants on tricyclic antidepressants had greater odds of MetS compared to those not taking any antidepressants (aOR = 2.27, 95% CI: 1.31, 3.93, p = 0.004). Our study provides evidence of the association between depressive symptoms, antidepressant use, and MetS, highlighting the importance of monitoring metabolic and cardiovascular alterations in individuals of depression.
Alzheimer’s disease with depression: clinical characteristics and potential mechanisms involving orexin and brain atrophy
This study aimed to explore the clinical characteristics and alteration of orexinergic level in cerebrospinal fluid (CSF) and the volumes of brain grey and white matters, and investigate the roles of orexinergic level on the association between brain atrophy and depression in Alzheimer’s disease (AD) patients. The demographic variables of 156 participants were collected. Orexinergic level in CSF and the volumes of brain grey and white matters were evaluated. The correlations of orexinergic level in CSF with depression and brain volume in AD patients were analyzed. The mediating effect of orexinergic level in CSF on the association between brain atrophy and depression in AD patients was investigated. The joint predictive value of orexinergic level in CSF and brain volume for depression in AD patients was established. AD with depression patients showed significantly elevated levels of orexin A and orexin B in CSF; orexin A level in CSF was positively correlated with HAMD score in AD patients. The elevated orexin A level in CSF mediated 49.6% of total association between the decreased grey matter volume of right dorsal medial thalamic nucleus and depression, and 50.3% of total association between the reduced white matter volume of left amygdala and depression. Combinations of above parameters could predict depression in AD patients with a significantly high area under the curve (AUC = 0.841). Therefore, the elevated orexin A level in CSF mediates its effect on the atrophy of the right dorsal medial thalamic nucleus and the white matter of the left amygdala, eventually alleviating depression in AD.
Cardiovascular health (“Life’s Essential 8”), risk of depression and anxiety: a prospective cohort study
There is a growing interest in the linkage of cardiovascular health (CVH) with depression/anxiety but the evidence of “Life’s Essential 8” CVH score is scarce. We evaluated the associations of CVH score with risk of incident depression/anxiety among ~0.4 million participants. During follow-up, 17,554 incident events with symptoms of either disorder were recorded. Per 100-point decrease in CVH score was associated with an increased risk of incident either disorder (Hazard ratio [HR] = 1.133, 95% confidence interval [CI]:1.114–1.153), depression (HR = 1.205, 95% CI:1.180–1.231), and anxiety (HR = 1.042, 95% CI:1.017–1.069). Per 100-point decrease in health assessments or health behaviors was associated with an increased risk of incident either disorder (HRhealth assessments = 1.085, 95% CI: 1.058–1.113, HRhealth behaviors = 1.217, 95% CI: 1.186–1.250). Poor CVH is a risk factor for the incident late-life depression/anxiety symptoms of middle-aged and older adults, and healthy behaviors could be targeted for the risk assessment and intervention of depression/anxiety.
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