Genome-wide Association Study of Long COVID (preprint)

Infections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers after human papillomavirus, or rheumatic fever after streptococcal infections(1,2). Similarly, infection by SARS-CoV-2 can result in Long COVID, a condition characterized by symptoms of fatigue and pulmonary and cognitive dysfunction(3-5). The biological mechanisms that contribute to the development of Long COVID remain to be clarified. We leveraged the COVID-19 Host Genetics Initiative(6,7) to perform a genome-wide association study for Long COVID including up to 6,450 Long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We identified the first genome-wide significant association for Long COVID at the FOXP4 locus. FOXP4 has been previously associated with COVID-19 severity(6), lung function(8), and cancers(9), suggesting a broader role for lung function in the pathophysiology of Long COVID. While we identify COVID-19 severity as a causal risk factor for Long COVID, the impact of the genetic risk factor located in the FOXP4 locus could not be solely explained by its association to severe COVID-19. Our findings further support the role of pulmonary dysfunction and COVID-19 severity in the development of Long COVID.

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

Objectives: To describe the mental health gap between those who live alone and those who live with others, and to examine whether the COVID-19 pandemic had an impact on this gap. Design: Ten population based prospective cohort studies, and a retrospective descriptive cohort study based on electronic health records (EHRs). Setting: UK Longitudinal population-based surveys (LPS), and primary and secondary care records within the OpenSAFELY-TPP database. Participants: Participants from the LPS were included if they had information on living status in early 2020, valid data on mental ill-health at the closest pre-pandemic assessment and at least once during the pandemic, and valid data on a key minimum set of covariates. The EHR dataset included 16 million adults registered with primary care practices in England using TPP SystmOne software on 1st February 2020, with at least three months of registration, valid address data, and living in households of <16 people. Main outcome measures: In the LPS, self-reported survey measures of psychological distress and life satisfaction were assessed in the nearest pre-pandemic sweep and three periods during the pandemic: April-June 2020, July-October 2020, and November 2020-March 2021. In the EHR analyses, outcomes were morbidity codes recorded in primary or secondary care between March 2018 and January 2022 reflecting the diagnoses of depression, self-harm, anxiety, obsessive compulsive disorder, eating disorders, and severe mental illnesses. Results: The LPS consisted of 37,544 participants (15.2% living alone) and we found greater psychological distress (SMD: 0.09 (95% CI: 0.04, 0.14) and lower life satisfaction (SMD: -0.22 (95% CI: -0.30, -0.15) in those living alone pre-pandemic, and the gap between the two groups stayed similar after the onset of the pandemic. In the EHR analysis of almost 16 million records (21.4% living alone), codes indicating mental health conditions were more common in those who lived alone compared to those who lived with others (e.g., depression 26 and severe mental illness 58 cases more per 100,000). Recording of mental health conditions fell during the pandemic for common mental health disorders and the gap between the two groups narrowed. Conclusions: Multiple sources of data indicate that those who live alone experience greater levels of common and severe mental illnesses, and lower life satisfaction. During the pandemic this gap in need remained, however, there was a narrowing of the gap in service use, suggesting greater barriers to healthcare access for those who live alone.

Trajectories of Child Emotional and Behavioural Difficulties Before and During the COVID-19 Pandemic in a Longitudinal UK Cohort (preprint)

Background: There are concerns that the COVID-19 pandemic and its associated public health mitigation measures will have detrimental effects on emotional and behavioural problems in children. However, longitudinal studies with pre-pandemic data are scarce. In a UK cohort, we quantify the impact of the COVID-19 pandemic on trajectories of children’s emotional and behavioural difficulties measured before and during the pandemic.Methods: Data were from 708 children (Mean age = 3·45 years, SD = 3·13) part of the third generation of a birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). Study sample comprised children whose parents provided previous pre-pandemic surveys and a survey between 26 May and 5 July 2020 that focused on the impact of the COVID-19 pandemic as restrictions in the UK were eased. The children had up to seven measurements of emotional and behavioural difficulties from infancy to late childhood (including the most recent measures during the pandemic). We employed multi-level mixed effects modelling with random intercepts and slopes to examine whether children’s trajectories of emotional and behavioural difficulties (a combined “total difficulties score”) during the pandemic differ from expected pre-pandemic trajectories. Findings: We found that children’s emotional and behavioural difficulties increased during infancy, peaked around the age of 2, and then declined throughout the rest of childhood. Pre-pandemic, the decline in difficulties scores after age 2 was 0·6 points per month; but was approximately one third of that in post-pandemic trajectories (there was a difference in mean rate of decline after age 2 of 0·2 points per month in pre vs during pandemic trajectories [95 % CI: 0·1 to 0·3, p <0·001]). This lower decline in scores over the years translated to older children having pandemic difficulty scores higher than would be expected from pre-pandemic trajectories (for example, an estimated 10-point higher score (95% CI: 5·0 to 15·0) by age 8·5 years). Results remained similar although somewhat attenuated after adjusting for maternal anxiety and age. Interpretation: The COVID-19 pandemic may be associated with greater persistence of emotional and behavioural difficulties after the age 2. Further evidence and monitoring of emotional and behavioural difficulties are required to fully understand the impact of the pandemic on this population, given ongoing and likely further periods of restrictions.Funding: This work was supported by the UK Medical Research Council and Wellcome (Grants 217065/Z/19/Z and 102215), the European Research Commission grant (Grant Ref: 758813 MHINT), the Elizabeth Blackwell Institute, University of Bristol, with funding from QR SPF (Quality-Related Strategic Priorities Fund), and UKRI Research England the Faculty Research Director’s discretionary fund and the University of Bristol. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf).Declaration of Interests: All authors declare no conflicts of interest.Ethics Approval Statement: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. All participants provided fully informed consent and the study is GDPR compliant.