Characterising patterns of COVID-19 and long COVID symptoms: evidence from nine UK longitudinal studies.

Multiple studies across global populations have established the primary symptoms characterising Coronavirus Disease 2019 (COVID-19) and long COVID. However, as symptoms may also occur in the absence of COVID-19, a lack of appropriate controls has often meant that specificity of symptoms to acute COVID-19 or long COVID, and the extent and length of time for which they are elevated after COVID-19, could not be examined. We analysed individual symptom prevalences and characterised patterns of COVID-19 and long COVID symptoms across nine UK longitudinal studies, totalling over 42,000 participants. Conducting latent class analyses separately in three groups ('no COVID-19', 'COVID-19 in last 12 weeks', 'COVID-19 > 12 weeks ago'), the data did not support the presence of more than two distinct symptom patterns, representing high and low symptom burden, in each group. Comparing the high symptom burden classes between the 'COVID-19 in last 12 weeks' and 'no COVID-19' groups we identified symptoms characteristic of acute COVID-19, including loss of taste and smell, fatigue, cough, shortness of breath and muscle pains or aches. Comparing the high symptom burden classes between the 'COVID-19 > 12 weeks ago' and 'no COVID-19' groups we identified symptoms characteristic of long COVID, including fatigue, shortness of breath, muscle pain or aches, difficulty concentrating and chest tightness. The identified symptom patterns among individuals with COVID-19 > 12 weeks ago were strongly associated with self-reported length of time unable to function as normal due to COVID-19 symptoms, suggesting that the symptom pattern identified corresponds to long COVID. Building the evidence base regarding typical long COVID symptoms will improve diagnosis of this condition and the ability to elicit underlying biological mechanisms, leading to better patient access to treatment and services.

Pre-pandemic mental health and disruptions to healthcare, economic and housing outcomes during the COVID-19 pandemic: evidence from 12 UK longitudinal studies.

BACKGROUND: The COVID-19 pandemic has disrupted lives and livelihoods, and people already experiencing mental ill health may have been especially vulnerable. AIMS: Quantify mental health inequalities in disruptions to healthcare, economic activity and housing. METHOD: We examined data from 59 482 participants in 12 UK longitudinal studies with data collected before and during the COVID-19 pandemic. Within each study, we estimated the association between psychological distress assessed pre-pandemic and disruptions since the start of the pandemic to healthcare (medication access, procedures or appointments), economic activity (employment, income or working hours) and housing (change of address or household composition). Estimates were pooled across studies. RESULTS: Across the analysed data-sets, 28% to 77% of participants experienced at least one disruption, with 2.3-33.2% experiencing disruptions in two or more domains. We found 1 s.d. higher pre-pandemic psychological distress was associated with (a) increased odds of any healthcare disruptions (odds ratio (OR) 1.30, 95% CI 1.20-1.40), with fully adjusted odds ratios ranging from 1.24 (95% CI 1.09-1.41) for disruption to procedures to 1.33 (95% CI 1.20-1.49) for disruptions to prescriptions or medication access; (b) loss of employment (odds ratio 1.13, 95% CI 1.06-1.21) and income (OR 1.12, 95% CI 1.06 -1.19), and reductions in working hours/furlough (odds ratio 1.05, 95% CI 1.00-1.09) and (c) increased likelihood of experiencing a disruption in at least two domains (OR 1.25, 95% CI 1.18-1.32) or in one domain (OR 1.11, 95% CI 1.07-1.16), relative to no disruption. There were no associations with housing disruptions (OR 1.00, 95% CI 0.97-1.03). CONCLUSIONS: People experiencing psychological distress pre-pandemic were more likely to experience healthcare and economic disruptions, and clusters of disruptions across multiple domains during the pandemic. Failing to address these disruptions risks further widening mental health inequalities.

Using linear and natural cubic splines, SITAR, and latent trajectory models to characterise nonlinear longitudinal growth trajectories in cohort studies.

BACKGROUND: Longitudinal data analysis can improve our understanding of the influences on health trajectories across the life-course. There are a variety of statistical models which can be used, and their fitting and interpretation can be complex, particularly where there is a nonlinear trajectory. Our aim was to provide an accessible guide along with applied examples to using four sophisticated modelling procedures for describing nonlinear growth trajectories. METHODS: This expository paper provides an illustrative guide to summarising nonlinear growth trajectories for repeatedly measured continuous outcomes using (i) linear spline and (ii) natural cubic spline linear mixed-effects (LME) models, (iii) Super Imposition by Translation and Rotation (SITAR) nonlinear mixed effects models, and (iv) latent trajectory models. The underlying model for each approach, their similarities and differences, and their advantages and disadvantages are described. Their application and correct interpretation of their results is illustrated by analysing repeated bone mass measures to characterise bone growth patterns and their sex differences in three cohort studies from the UK, USA, and Canada comprising 8500 individuals and 37,000 measurements from ages 5-40 years. Recommendations for choosing a modelling approach are provided along with a discussion and signposting on further modelling extensions for analysing trajectory exposures and outcomes, and multiple cohorts. RESULTS: Linear and natural cubic spline LME models and SITAR provided similar summary of the mean bone growth trajectory and growth velocity, and the sex differences in growth patterns. Growth velocity (in grams/year) peaked during adolescence, and peaked earlier in females than males e.g., mean age at peak bone mineral content accrual from multicohort SITAR models was 12.2 years in females and 13.9 years in males. Latent trajectory models (with trajectory shapes estimated using a natural cubic spline) identified up to four subgroups of individuals with distinct trajectories throughout adolescence. CONCLUSIONS: LME models with linear and natural cubic splines, SITAR, and latent trajectory models are useful for describing nonlinear growth trajectories, and these methods can be adapted for other complex traits. Choice of method depends on the research aims, complexity of the trajectory, and available data. Scripts and synthetic datasets are provided for readers to replicate trajectory modelling and visualisation using the R statistical computing software.

Mental health before and during the COVID-19 pandemic in two longitudinal UK population cohorts.

BACKGROUND: The COVID-19 pandemic and mitigation measures are likely to have a marked effect on mental health. It is important to use longitudinal data to improve inferences. AIMS: To quantify the prevalence of depression, anxiety and mental well-being before and during the COVID-19 pandemic. Also, to identify groups at risk of depression and/or anxiety during the pandemic. METHOD: Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC) index generation (n = 2850, mean age 28 years) and parent generation (n = 3720, mean age 59 years), and Generation Scotland (n = 4233, mean age 59 years). Depression was measured with the Short Mood and Feelings Questionnaire in ALSPAC and the Patient Health Questionnaire-9 in Generation Scotland. Anxiety and mental well-being were measured with the Generalised Anxiety Disorder Assessment-7 and the Short Warwick Edinburgh Mental Wellbeing Scale. RESULTS: Depression during the pandemic was similar to pre-pandemic levels in the ALSPAC index generation, but those experiencing anxiety had almost doubled, at 24% (95% CI 23-26%) compared with a pre-pandemic level of 13% (95% CI 12-14%). In both studies, anxiety and depression during the pandemic was greater in younger members, women, those with pre-existing mental/physical health conditions and individuals in socioeconomic adversity, even when controlling for pre-pandemic anxiety and depression. CONCLUSIONS: These results provide evidence for increased anxiety in young people that is coincident with the pandemic. Specific groups are at elevated risk of depression and anxiety during the COVID-19 pandemic. This is important for planning current mental health provisions and for long-term impact beyond this pandemic.

Polygenic risk for depression, anxiety and neuroticism are associated with the severity and rate of change in depressive symptoms across adolescence.

BACKGROUND: Adolescence marks a period where depression will commonly onset. Twin studies show that genetic influences play a role in how depression develops and changes across adolescence. Recent genome-wide association studies highlight that common genetic variants - which can be combined into polygenic risk scores (PRS) - are also implicated in depression. However, the role of PRS in adolescent depression and changes in adolescent depression is not yet understood. We aimed to examine associations between PRS for five psychiatric traits and depressive symptoms measured across adolescence using cross-sectional and growth-curve models. The five PRS were as follows: depression (DEP), major depressive disorder (MDD), anxiety (ANX), neuroticism (NEU) and schizophrenia (SCZ). METHODS: We used data from over 6,000 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC) to examine associations between the five PRS and self-reported depressive symptoms (Short Mood and Feelings Questionnaire) over 9 occasions from 10 to 24 years. The PRS were created from well-powered genome-wide association studies conducted in adult populations. We examined cross-sectional associations between the PRS at each age and then again with longitudinal trajectories of depressive symptoms in a repeated measures framework using multilevel growth-curve analysis to examine the severity and the rate of change. RESULTS: There was strong evidence that higher PRS for DEP, MDD and NEU were associated with worse depressive symptoms throughout adolescence and into young adulthood in our cross-sectional analysis, with consistent associations observed across all nine occasions. Growth-curve analyses provided stronger associations (as measured by effect sizes) and additional insights, demonstrating that individuals with higher PRS for DEP, MDD and NEU had steeper trajectories of depressive symptoms across development, all with a greater increasing rate of change during adolescence. Evidence was less consistent for the ANX and SCZ PRS in the cross-sectional analysis, yet there was some evidence for an increasing rate of change in adolescence in the growth-curve analyses with the ANX PRS. CONCLUSIONS: These results show that common genetic variants as indexed by varying psychiatric PRS show patterns of specificity that influence both the severity and rate of change in depressive symptoms throughout adolescence and then into young adulthood. Longitudinal data that make use of repeated measures designs have the potential to provide greater insights how genetic factors influence the onset and persistence of adolescent depression.

Effects of state anxiety on gait: a 7.5% carbon dioxide challenge study.

We used the 7.5% carbon dioxide (CO2) model of anxiety induction to investigate the effects of state anxiety on normal gait and gait when navigating an obstacle. Healthy volunteers (n = 22) completed a walking task during inhalations of 7.5% CO2 and medical air (placebo) in a within-subjects design. The order of inhalation was counterbalanced across participants and the gas was administered double-blind. Over a series of trials, participants walked the length of the laboratory, with each trial requiring participants to navigate through an aperture (width adjusted to participant size), with gait parameters measured via a motion capture system. The main findings were that walking speed was slower, but the adjustment in body orientation was greater, during 7.5% CO2 inhalation compared to air. These findings indicate changes in locomotor behaviour during heightened state anxiety that may reflect greater caution when moving in an agitated state. Advances in sensing technology offer the opportunity to monitor locomotor behaviour, and these findings suggest that in doing so, we may be able to infer emotional states from movement in naturalistic settings.

Identifying Critical Points of Trajectories of Depressive Symptoms from Childhood to Young Adulthood.

Depression is a common mental illness and research has focused on late childhood and adolescence in an attempt to prevent or reduce later psychopathology and/or social impairments. It is important to establish and study population-averaged trajectories of depressive symptoms across adolescence as this could characterise specific changes in populations and help identify critical points to intervene with treatment. Multilevel growth-curve models were used to explore adolescent trajectories of depressive symptoms in 9301 individuals (57% female) from the Avon Longitudinal Study of Parents and Children, a UK based pregnancy cohort. Trajectories of depressive symptoms were constructed for males and females using the short mood and feelings questionnaire over 8 occasions, between 10 and 22 years old. Critical points of development such as age of peak velocity for depressive symptoms (the age at which depressive symptoms increase most rapidly) and the age of maximum depressive symptoms were also derived. The results suggested that from similar initial levels of depressive symptoms at age 11, females on average experienced steeper increases in depressive symptoms than males over their teenage and adolescent years until around the age of 20 when levels of depressive symptoms plateaued and started to decrease for both sexes. Females on average also had an earlier age of peak velocity of depressive symptoms that occurred at 13.5 years, compared to males who on average had an age of peak velocity at 16 years old. Evidence was less clear for a difference between the ages of maximum depressive symptoms which were on average 19.6 years for females and 20.4 for males. Identifying critical periods for different population subgroups may provide useful knowledge for treating and preventing depression and could be tailored to be time specific for certain groups. Possible explanations and recommendations are discussed.

Genetic Architectures of Adolescent Depression Trajectories in 2 Longitudinal Population Cohorts.

Importance: Adolescent depression is characterized by diverse symptom trajectories over time and has a strong genetic influence. Research has determined genetic overlap between depression and other psychiatric conditions; investigating the shared genetic architecture of heterogeneous depression trajectories is crucial for understanding disease etiology, prediction, and early intervention. Objective: To investigate univariate and multivariate genetic risk for adolescent depression trajectories and assess generalizability across ancestries. Design, Setting, and Participants: This cohort study entailed longitudinal growth modeling followed by polygenic risk score (PRS) association testing for individual and multitrait genetic models. Two longitudinal cohorts from the US and UK were used: the Adolescent Brain and Cognitive Development (ABCD; N = 11 876) study and the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 8787) study. Included were adolescents with genetic information and depression measures at up to 8 and 4 occasions, respectively. Study data were analyzed January to July 2023. Main Outcomes and Measures: Trajectories were derived from growth mixture modeling of longitudinal depression symptoms. PRSs were computed for depression, anxiety, neuroticism, bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder, and autism in European ancestry. Genomic structural equation modeling was used to build multitrait genetic models of psychopathology followed by multitrait PRS. Depression PRSs were computed in African, East Asian, and Hispanic ancestries in the ABCD cohort only. Association testing was performed between all PRSs and trajectories for both cohorts. Results: A total sample size of 14 112 adolescents (at baseline: mean [SD] age, 10.5 [0.5] years; 7269 male sex [52%]) from both cohorts were included in this analysis. Distinct depression trajectories (stable low, adolescent persistent, increasing, and decreasing) were replicated in the ALSPAC cohort (6096 participants; 3091 female [51%]) and ABCD cohort (8016 participants; 4274 male [53%]) between ages 10 and 17 years. Most univariate PRSs showed significant uniform associations with persistent trajectories, but fewer were significantly associated with intermediate (increasing and decreasing) trajectories. Multitrait PRSs-derived from a hierarchical factor model-showed the strongest associations for persistent trajectories (ABCD cohort: OR, 1.46; 95% CI, 1.26-1.68; ALSPAC cohort: OR, 1.34; 95% CI, 1.20-1.49), surpassing the effect size of univariate PRS in both cohorts. Multitrait PRSs were associated with intermediate trajectories but to a lesser extent (ABCD cohort: hierarchical increasing, OR, 1.27; 95% CI, 1.13-1.43; decreasing, OR, 1.23; 95% CI, 1.09-1.40; ALSPAC cohort: hierarchical increasing, OR, 1.16; 95% CI, 1.04-1.28; decreasing, OR, 1.32; 95% CI, 1.18-1.47). Transancestral genetic risk for depression showed no evidence for association with trajectories. Conclusions and Relevance: Results of this cohort study revealed a high multitrait genetic loading of persistent symptom trajectories, consistent across traits and cohorts. Variability in univariate genetic association with intermediate trajectories may stem from environmental factors. Multitrait genetics may strengthen depression prediction models, but more diverse data are needed for generalizability.

Mental-health before and during the COVID-19 pandemic in adults with neurodevelopmental disorders.

The COVID-19 pandemic negatively impacted mental health globally. Individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), are at elevated risk of mental health difficulties. We investigated the impact of the pandemic on anxiety, depression and mental wellbeing in adults with NDDs using data from the Avon Longitudinal Study of Parents and Children (n = 3058). Mental health data were collected pre-pandemic (age 21-25) and at three timepoints during the pandemic (ages 27-28) using the Short Mood and Feelings Questionnaire, Generalized Anxiety Disorder Assessment-7, and Warwick Edinburgh Mental Wellbeing Scale. ADHD and ASD were defined using validated cut-points of the Strengths and Difficulties Questionnaire and Autism Spectrum Quotient, self-reported at age 25. We used multi-level mixed-effects models to investigate changes in mental health in those with elevated ADHD/ASD traits compared to those without. Prevalences of depression, anxiety and poor mental wellbeing were higher at all timepoints (pre-pandemic and during pandemic) in those with ADHD and ASD compared to those without. Anxiety increased to a greater extent in those with ADHD (ß = 0.8 [0.2,1.4], p = 0.01) and ASD (ß = 1.2 [-0.1,2.5], p = 0.07), while depression symptoms decreased, particularly in females with ASD (ß = -3.1 [-4.6,-1.5], p = 0.0001). On average, mental wellbeing decreased in all, but to a lesser extent in those with ADHD (ß = 1.3 [0.2,2.5], p = 0.03) and females with ASD (ß = 3.0 [0.2,5.9], p = 0.04). To conclude, anxiety disproportionately increased in adults with NDDs during the pandemic, however, the related lockdowns may have provided a protective environment for depressive symptoms in the same individuals.

Keeping up with the kids: the value of co-production in the study of irritability in youth depression and its underlying neural circuitry.

Irritability is a core symptom of adolescent depression, characterized by an increased proneness to anger or frustration. Irritability in youth is associated with future mental health problems and impaired social functioning, suggesting that it may be an early indicator of emotion regulation difficulties. Adolescence is a period during which behavior is significantly impacted by one's environment. However, existing research on the neural basis of irritability typically use experimental paradigms that overlook the social context in which irritability occurs. Here, we bring together current findings on irritability in adolescent depression and the associated neurobiology and highlight directions for future research. Specifically, we emphasize the importance of co-produced research with young people as a means to improve the construct and ecological validity of research within the field. Ensuring that our research design and methodology accurately reflect to lives of young people today lays a strong foundation upon which to better understand adolescent depression and identify tractable targets for intervention.

Cross-cohort change in parent-reported emotional problem trajectories across childhood and adolescence in the UK.

BACKGROUND: Over the past three decades, the prevalence of adolescent emotional problems (ie, anxiety and depression) has risen. Although the onset and developmental course of emotional symptoms shows high variability, no study has directly tested secular differences across development. Our aim was to investigate whether and how developmental trajectories of emotional problems have changed across generations. METHODS: We used data from two UK prospective cohorts assessed 10 years apart: the Avon Longitudinal Study of Parents and Children (ALSPAC) including individuals born in 1991-92, and the Millennium Cohort Study (MCS) with individuals born in 2000-02. Our outcome was emotional problems, assessed using the parent-rated emotional subscale of the Strengths and Difficulties Questionnaire (SDQ-E) at approximate ages 4, 7, 8, 10, 11, 13, and 17 years in ALSPAC and ages 3, 5, 7, 11, 14, and 17 years in MCS. Participants were included if the SDQ-E was completed at least once in childhood and at least once in adolescence. Trajectories were generated using multilevel growth curve models using the repeated assessments of the SDQ-E in children aged 3-17 years. FINDINGS: Data were available for 19 418 participants (7012 from ALSPAC and 12 406 from the MCS), of whom 9678 (49·8%) were female and 9740 (50·2%) were male, and 17 572 (90·5%) had White mothers. Individuals born between 2000 and 2002 had higher emotional problem scores from around 9 years (intercept statistic ß 1·75, 95% CI 1·71-1·79) than did individuals born in 1991-92 (1·55, 1·51-1·59). The later cohort had an earlier onset of problems than the earlier cohort, and sustained higher average trajectories from around 11 years, with female adolescents showing the steepest trajectories of emotional problems. Differences between cohorts peaked overall at age 14 years. INTERPRETATION: Our comparison of two cohorts of young people provides evidence that compared with a cohort assessed 10 years prior, emotional problems emerge earlier in development in the more recent cohort, and these are especially pronounced for females during mid-adolescence. Such findings have implications for public health planning and service provision. FUNDING: Wolfson Centre for Young People's Mental Health, Wolfson Foundation.

The role of brain structure in the association between pubertal timing and depression risk in an early adolescent sample (the ABCD Study®): A registered report.

BACKGROUND: Earlier pubertal timing is associated with higher rates of depressive disorders in adolescence. Neuroimaging studies report brain structural associations with both pubertal timing and depression. However, whether brain structure mediates the relationship between pubertal timing and depression remains unclear. METHODS: The current registered report examined associations between pubertal timing (indexed via perceived pubertal development), brain structure (cortical and subcortical metrics, and white matter microstructure) and depressive symptoms in a large sample (N = âˆ¼5000) of adolescents (aged 9-13 years) from the Adolescent Brain Cognitive Development (ABCD) Study. We used three waves of follow-up data when the youth were aged 10-11 years, 11-12 years, and 12-13 years, respectively. We used generalised linear-mixed models (H1) and structural equation modelling (H2 & H3) to test our hypotheses. HYPOTHESES: We hypothesised that earlier pubertal timing at Year 1 would be associated with increased depressive symptoms at Year 3 (H1), and that this relationship would be mediated by global (H2a-b) and regional (H3a-g) brain structural measures at Year 2. Global measures included reduced cortical volume, thickness, surface area and sulcal depth. Regional measures included reduced cortical thickness and volume in temporal and fronto-parietal areas, increased cortical volume in the ventral diencephalon, increased sulcal depth in the pars orbitalis, and reduced fractional anisotropy in the cortico-striatal tract and corpus callosum. These regions of interest were informed by our pilot analyses using baseline ABCD data when the youth were aged 9-10 years. RESULTS: Earlier pubertal timing was associated with increased depressive symptoms two years later. The magnitude of effect was stronger in female youth and the association remained significant when controlling for parental depression, family income, and BMI in females but not in male youth. Our hypothesised brain structural measures did not however mediate the association between earlier pubertal timing and later depressive symptoms. CONCLUSION: The present results demonstrate that youth, particularly females, who begin puberty ahead of their peers are at an increased risk for adolescent-onset depression. Future work should explore additional biological and socio-environmental factors that may affect this association so that we can identify targets for intervention to help these at-risk youth.

A genetically informed Registered Report on adverse childhood experiences and mental health.

Children who experience adversities have an elevated risk of mental health problems. However, the extent to which adverse childhood experiences (ACEs) cause mental health problems remains unclear, as previous associations may partly reflect genetic confounding. In this Registered Report, we used DNA from 11,407 children from the United Kingdom and the United States to investigate gene-environment correlations and genetic confounding of the associations between ACEs and mental health. Regarding gene-environment correlations, children with higher polygenic scores for mental health problems had a small increase in odds of ACEs. Regarding genetic confounding, elevated risk of mental health problems in children exposed to ACEs was at least partially due to pre-existing genetic risk. However, some ACEs (such as childhood maltreatment and parental mental illness) remained associated with mental health problems independent of genetic confounding. These findings suggest that interventions addressing heritable psychiatric vulnerabilities in children exposed to ACEs may help reduce their risk of mental health problems.

Antibody levels following vaccination against SARS-CoV-2: associations with post-vaccination infection and risk factors in two UK longitudinal studies.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody levels can be used to assess humoral immune responses following SARS-CoV-2 infection or vaccination, and may predict risk of future infection. Higher levels of SARS-CoV-2 anti-Spike antibodies are known to be associated with increased protection against future SARS-CoV-2 infection. However, variation in antibody levels and risk factors for lower antibody levels following each round of SARS-CoV-2 vaccination have not been explored across a wide range of socio-demographic, SARS-CoV-2 infection and vaccination, and health factors within population-based cohorts. Methods: Samples were collected from 9361 individuals from TwinsUK and ALSPAC UK population-based longitudinal studies and tested for SARS-CoV-2 antibodies. Cross-sectional sampling was undertaken jointly in April-May 2021 (TwinsUK, N=4256; ALSPAC, N=4622), and in TwinsUK only in November 2021-January 2022 (N=3575). Variation in antibody levels after first, second, and third SARS-CoV-2 vaccination with health, socio-demographic, SARS-CoV-2 infection, and SARS-CoV-2 vaccination variables were analysed. Using multivariable logistic regression models, we tested associations between antibody levels following vaccination and: (1) SARS-CoV-2 infection following vaccination(s); (2) health, socio-demographic, SARS-CoV-2 infection, and SARS-CoV-2 vaccination variables. Results: Within TwinsUK, single-vaccinated individuals with the lowest 20% of anti-Spike antibody levels at initial testing had threefold greater odds of SARS-CoV-2 infection over the next 6-9 months (OR = 2.9, 95% CI: 1.4, 6.0), compared to the top 20%. In TwinsUK and ALSPAC, individuals identified as at increased risk of COVID-19 complication through the UK 'Shielded Patient List' had consistently greater odds (two- to fourfold) of having antibody levels in the lowest 10%. Third vaccination increased absolute antibody levels for almost all individuals, and reduced relative disparities compared with earlier vaccinations. Conclusions: These findings quantify the association between antibody level and risk of subsequent infection, and support a policy of triple vaccination for the generation of protective antibodies. Funding: Antibody testing was funded by UK Health Security Agency. The National Core Studies program is funded by COVID-19 Longitudinal Health and Wellbeing - National Core Study (LHW-NCS) HMT/UKRI/MRC ([MC_PC_20030] and [MC_PC_20059]). Related funding was also provided by the NIHR 606 (CONVALESCENCE grant [COV-LT-0009]). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. The UK Medical Research Council and Wellcome (Grant ref: [217065/Z/19/Z]) and the University of Bristol provide core support for ALSPAC.

Vaccination against the virus that causes COVID-19 triggers the body to produce antibodies that help fight future infections. But some people generate more antibodies after vaccination than others. People with lower levels of antibodies are more likely to get COVID-19 in the future. Identifying people with low antibody levels after COVID-19 vaccination is important. It could help decide who receives priority for future vaccination. Previous studies show that people with certain health conditions produce fewer antibodies after one or two doses of a COVID-19 vaccine. For example, people with weakened immune systems. Now that third booster doses are available, it is vital to determine if they increase antibody levels for those most at risk of severe COVID-19. Cheetham et al. show that a third booster dose of a COVID-19 vaccine boosts antibodies to high levels in 90% of individuals, including those at increased risk. In the experiments, Cheetham et al. measured antibodies against the virus that causes COVID-19 in 9,361 individuals participating in two large long-term health studies in the United Kingdom. The experiments found that UK individuals advised to shield from the virus because they were at increased risk of complications had lower levels of antibodies after one or two vaccine doses than individuals without such risk factors. This difference was also seen after a third booster dose, but overall antibody levels had large increases. People who received the Oxford/AstraZeneca vaccine as their first dose also had lower antibody levels after one or two doses than those who received the Pfizer/BioNTech vaccine first. Positively, this difference in antibody levels was no longer seen after a third booster dose. Individuals with lower antibody levels after their first dose were also more likely to have a case of COVID-19 in the following months. Antibody levels were high in most individuals after the third dose. The results may help governments and public health officials identify individuals who may need extra protection after the first two vaccine doses. They also support current policies promoting booster doses of the vaccine and may support prioritizing booster doses for those at the highest risk from COVID-19 in future vaccination campaigns.

Genetic structure of major depression symptoms across clinical and community cohorts.

Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and aetiological subtypes. There are several challenges to integrating symptom data from genetically-informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data. We conducted genome-wide association studies of major depressive symptoms in three clinical cohorts that were enriched for affected participants (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors. The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for missing data patterns in the community cohorts (use of Depression and Anhedonia as gating symptoms). The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analysing genetic association data.

Living alone and mental health: parallel analyses in UK longitudinal population surveys and electronic health records prior to and during the COVID-19 pandemic.

BACKGROUND: People who live alone experience greater levels of mental illness; however, it is unclear whether the COVID-19 pandemic had a disproportionately negative impact on this demographic. OBJECTIVE: To describe the mental health gap between those who live alone and with others in the UK prior to and during the COVID-19 pandemic. METHODS: Self-reported psychological distress and life satisfaction in 10 prospective longitudinal population surveys (LPSs) assessed in the nearest pre-pandemic sweep and three periods during the pandemic. Recorded diagnosis of common and severe mental illnesses between March 2018 and January 2022 in electronic healthcare records (EHRs) within the OpenSAFELY-TPP. FINDINGS: In 37 544 LPS participants, pooled models showed greater psychological distress (standardised mean difference (SMD): 0.09 (95% CI: 0.04; 0.14); relative risk: 1.25 (95% CI: 1.12; 1.39)) and lower life satisfaction (SMD: -0.22 (95% CI: -0.30; -0.15)) for those living alone pre-pandemic. This gap did not change during the pandemic. In the EHR analysis of c.16 million records, mental health conditions were more common in those who lived alone (eg, depression 26 (95% CI: 18 to 33) and severe mental illness 58 (95% CI: 54 to 62) more cases more per 100 000). For common mental health disorders, the gap in recorded cases in EHRs narrowed during the pandemic. CONCLUSIONS: People living alone have poorer mental health and lower life satisfaction. During the pandemic, this gap in self-reported distress remained; however, there was a narrowing of the gap in service use. CLINICAL IMPLICATIONS: Greater mental health need and potentially greater barriers to mental healthcare access for those who live alone need to be considered in healthcare planning.

Father absence and trajectories of offspring mental health across adolescence and young adulthood: Findings from a UK-birth cohort.

BACKGROUND: High prevalence of parental separation and resulting biological father absence raises important questions regarding its impact on offspring mental health across the life course. We specifically examined whether these relationships vary by sex and the timing of exposure to father absence (early or middle childhood). METHODS: This study is based on up to 8409 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants provided self-reports of depression (Clinical Interview Schedule-Revised) at age 24 years and depressive symptoms (Short Mood and Feelings Questionnaire) between the ages of 10 and 24 years. Biological father absence in childhood was assessed through maternal questionnaires at regular intervals from birth to 10 years. We estimated the association between biological father absence and trajectories of depressive symptoms using multilevel growth-curve modelling. RESULTS: Early but not middle childhood father absence was strongly associated with increased odds of offspring depression and greater depressive symptoms at age 24 years. Early childhood father absence was associated with higher trajectories of depressive symptoms during adolescence and early adulthood compared with father presence. Differences in the level of depressive symptoms between middle childhood father absent and father present groups narrowed into adulthood. LIMITATIONS: This study could be biased by attrition and residual confounding. CONCLUSIONS: We found evidence that father absence in childhood is persistently associated with offspring depression in adolescence and early adulthood. This relationship varies by sex and timing of father's departure, with early childhood father absence emerging as the strongest risk factor for adverse offspring mental health trajectories Further research is needed to identify mechanisms that could inform preventative interventions to reduce the risk of depression in children who experience father absence.

Genome-by-Trauma Exposure Interactions in Adults With Depression in the UK Biobank.

Importance: Self-reported trauma exposure has consistently been found to be a risk factor for major depressive disorder (MDD), and several studies have reported interactions with genetic liability. To date, most studies have examined gene-environment interactions with trauma exposure using genome-wide variants (single-nucleotide variations [SNVs]) or polygenic scores, both typically capturing less than 3% of phenotypic risk variance. Objective: To reexamine genome-by-trauma interaction associations using genetic measures using all available genotyped data and thus, maximizing accounted variance. Design, Setting, and Participants: The UK Biobank study was conducted from April 2007 to May 1, 2016 (follow-up mental health questionnaire). The current study used available cross-sectional genomic and trauma exposure data from UK Biobank. Participants who completed the mental health questionnaire and had available genetic, trauma experience, depressive symptoms, and/or neuroticism information were included. Data were analyzed from April 1 to August 30, 2021. Exposures: Trauma and genome-by-trauma exposure interactions. Main Outcomes and Measures: Measures of self-reported depression, neuroticism, and trauma exposure with whole-genome SNV data are available from the UK Biobank study. Here, a mixed-model statistical approach using genetic, trauma exposure, and genome-by-trauma exposure interaction similarity matrices was used to explore sources of variation in depression and neuroticism. Results: Analyses were conducted on 148 129 participants (mean [SD] age, 56 [7] years) of which 76 995 were female (52.0%). The study approach estimated the heritability (SE) of MDD to be approximately 0.160 (0.016). Subtypes of self-reported trauma exposure (catastrophic, adult, childhood, and full trauma) accounted for a significant proportion of the variance of MDD, with heritability (SE) ranging from 0.056 (0.013) to 0.176 (0.025). The proportion of MDD risk variance accounted for by significant genome-by-trauma interaction revealed estimates (SD) ranging from 0.074 (0.006) to 0.201 (0.009). Results from sex-specific analyses found genome-by-trauma interaction variance estimates approximately 5-fold greater for MDD in male participants (0.441 [0.018]) than in female participants (0.086 [0.009]). Conclusions and Relevance: This cross-sectional study used an approach combining all genome-wide SNV data when exploring genome-by-trauma interactions in individuals with MDD; findings suggest that such interactions were associated with depression manifestation. Genome-by-trauma interaction accounts for greater trait variance in male individuals, which points to potential differences in depression etiology between the sexes. The methodology used in this study can be extrapolated to other environmental factors to identify modifiable risk environments and at-risk groups to target with interventions.

Comparing personalized brain-based and genetic risk scores for major depressive disorder in large population samples of adults and adolescents.

BACKGROUND: Major depressive disorder (MDD) is a polygenic disorder associated with brain alterations but until recently, there have been no brain-based metrics to quantify individual-level variation in brain morphology. Here, we evaluated and compared the performance of a new brain-based 'Regional Vulnerability Index' (RVI) with polygenic risk scores (PRS), in the context of MDD. We assessed associations with syndromal MDD in an adult sample (N = 702, age = 59 ± 10) and with subclinical depressive symptoms in a longitudinal adolescent sample (baseline N = 3,825, age = 10 ± 1; 2-year follow-up N = 2,081, age = 12 ± 1). METHODS: MDD-RVIs quantify the correlation of the individual's corresponding brain metric with the expected pattern for MDD derived in an independent sample. Using the same methodology across samples, subject-specific MDD-PRS and six MDD-RVIs based on different brain modalities (subcortical volume, cortical thickness, cortical surface area, mean diffusivity, fractional anisotropy, and multimodal) were computed. RESULTS: In adults, MDD-RVIs (based on white matter and multimodal measures) were more strongly associated with MDD (ß = 0.099-0.281, PFDR = 0.001-0.043) than MDD-PRS (ß = 0.056-0.152, PFDR = 0.140-0.140). In adolescents, depressive symptoms were associated with MDD-PRS at baseline and follow-up (ß = 0.084-0.086, p = 1.38 × 10-4-4.77 × 10-4) but not with any MDD-RVIs (ß < 0.05, p > 0.05). CONCLUSIONS: Our results potentially indicate the ability of brain-based risk scores to capture a broader range of risk exposures than genetic risk scores in adults and are also useful in helping us to understand the temporal origins of depression-related brain features. Longitudinal data, specific to the developmental period and on white matter measures, will be useful in informing risk for subsequent psychiatric illness.