Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

Objectives The complexities of the informed consent process for participating in cohort-based medical studies are well-recognised, and the pandemic presented specific challenges related to this. Our response in EXCEED was to build and deploy a local secure eConsent system that was simple to use, provided advanced functionality and improved data linkage. Approach The eConsent system is integrated into a web app (https://exceed.org.uk/) which was written in Python using the Django framework. A unique profile provides participant access to elements of the study, including two-way linkage to REDCap-based surveys and internal bespoke pages (for example an occupation questionnaire backed by a well-established classification) and access to consent to take part in sub-studies. This allowed participants to see which items have been completed or they have taken part in. Administrator tools were also built to enable advanced management and search functionality for dealing with participants queries or data quality issues. Results In 2020, backed by the new eConsent system, and driven by the COVID-19 pandemic, EXCEED undertook both a new wave of recruitment, and re-contacted existing participants to encourage them to take part in COVID related research. Profile registration and management of pre-2020 participants was also enabled by importing their contact details and consent data from legacy tools. Approximately 1000 EXCEED participants gave informed consent using the new system, while ~1000 existing participants registered. Facilitated by improved data quality using the eConsent system, we correctly linked 93% of consented participants to primary care health care records. This high level of data linkage enables research on the causes and consequences of COVID-19 infection, studies of the genomics of disease onset and progression and recall studies. Conclusion We developed a novel eConsent system, which as well as providing online participant registration and improved administration of participants has improved data linkage. Furthermore, the success of the approach has led it to be implemented in other studies with similar requirements.

Background: New data collection in established longitudinal population studies provides an opportunity for studying the risk factors and sequelae of the novel coronavirus disease 2019 (COVID-19), plus the indirect impacts of the COVID-19 pandemic on wellbeing. The Extended Cohort for E-health, Environment and DNA (EXCEED) cohort is a population-based cohort (N>11,000), recruited from 2013 in Leicester, Leicestershire and Rutland. EXCEED includes consent for electronic healthcare record (EHR) linkage, spirometry, genomic data, and questionnaire data. Methods: Between May 2020 and July 2021, a new questionnaire was deployed in EXCEED, which captured COVID-19 symptoms, general physical and mental health, plus socioeconomic and environmental factors during the pandemic. An online system was developed to invite new participants to join EXCEED, with informed consent being provided online. New and existing participants then completed the COVID-19 questionnaire online. A subset of the new questionnaire respondents were invited to participate in COVID-19 serology substudies, using home antibody testing kits. Results: In total, 3,693 participants provided COVID-19 infection status (median age 62.9 (IQR 54.7-69.2), 58.9% female). Trends of monthly incidence proportions of COVID-19 in EXCEED (self-report or symptom-predicted) approximated local and national figures. Regression analysis of 2,768 participants with linked EHR data showed no obvious monotonic relationship between number of chronic diseases (of 16 pre-specified diseases) and COVID-19 infection. There were 2,144 participants with valid results from a kit allowing differentiation between antibodies due to vaccination or infection. Of these, 8.5% had results consistent with previous COVID-19 infection, and 85.9% had evidence of COVID-19 vaccination, but without evidence of infection. Conclusions: Enriching EXCEED with a new COVID-19 questionnaire and serology data may improve understanding of the risk factors, clinical sequelae and broader impacts of the COVID-19 pandemic in the general population. Controlled access to these data for bona fide researchers is via application to the EXCEED study.

Background: New data collection in established longitudinal population studies provides an opportunity for studying the risk factors and sequelae of the novel coronavirus disease 2019 (COVID-19), plus the indirect impacts of the COVID-19 pandemic on wellbeing. The Extended Cohort for E-health, Environment and DNA (EXCEED) cohort is a population-based cohort (N>11,000), recruited from 2013 in Leicester, Leicestershire and Rutland. EXCEED includes consent for electronic healthcare record (EHR) linkage, spirometry, genomic data, and questionnaire data. Methods: Between May 2020 and July 2021, a new questionnaire was deployed in EXCEED, which captured COVID-19 symptoms, general physical and mental health, plus socioeconomic and environmental factors during the pandemic. An online system was developed to invite new participants to join EXCEED, with informed consent being provided online. New and existing participants then completed the COVID-19 questionnaire online. A subset of the new questionnaire respondents were invited to participate in COVID-19 serology substudies, using home antibody testing kits. Results: In total, 3,693 participants provided COVID-19 infection status (median age 62.9 (IQR 54.7-69.2), 58.9% female). Trends of monthly incidence proportions of COVID-19 in EXCEED (self-report or symptom-predicted) approximated local and national figures. Regression analysis of 2,768 participants with linked EHR data showed no obvious monotonic relationship between number of chronic diseases (of 16 pre-specified diseases) and COVID-19 infection. There were 2,144 participants with valid results from a kit allowing differentiation between antibodies due to vaccination or infection. Of these, 8.5% had results consistent with previous COVID-19 infection, and 85.9% had evidence of COVID-19 vaccination, but without evidence of infection. Conclusions: Enriching EXCEED with a new COVID-19 questionnaire and serology data may improve understanding of the risk factors, clinical sequelae and broader impacts of the COVID-19 pandemic in the general population. Controlled access to these data for bona fide researchers is via application to the EXCEED study.

Cohort Profile: Extended Cohort for E-health, Environment and DNA (EXCEED) Catherine John,* Nicola F Reeve , Robert C Free, Alexander T Williams, Ioanna Ntalla and Aliki-Eleni Farmaki, Jane Bethea, Linda M Barton, Nick Shrine, Chiara Batini, Richard Packer, Sarah Terry, Beverley Hargadon, Qingning Wang, Carl A Melbourne, Emma L Adams, Catherine E Bee, Kyla Harrington, José Miola, Nigel J Brunskill, Christopher E Brightling, Julian Barwell, Susan E Wallace, Ron Hsu, David J Shepherd, Edward J Hollox, Louise V Wain and Martin D Tobin Department of Health Sciences, University of Leicester, Leicester, UK, NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK, Department of Respiratory Sciences, University of Leicester, Leicester, UK, Department of Clinical Pharmacology, William Harvey Research Institute, Barts & The London Medical School, Queen Mary University of London, Charterhouse Square, London, UK, Department of Population Science and Experimental Medicine, Institute of Cardiovascular Science, University College London, London, UK, Department of Haematology, University Hospitals of Leicester NHS Trust, Leicester, UK, Leicester Law School, University of Leicester, Leicester, UK, Department of Cardiovascular Sciences University of Leicester, Leicester, UK and Department of Genetics and Genome Biology, University of Leicester, Leicester, UK

Cohort Profile: Extended Cohort for E-health, Environment and DNA (EXCEED) Catherine John,* Nicola F Reeve , Robert C Free, Alexander T Williams, Ioanna Ntalla and Aliki-Eleni Farmaki, Jane Bethea, Linda M Barton, Nick Shrine, Chiara Batini, Richard Packer, Sarah Terry, Beverley Hargadon, Qingning Wang, Carl A Melbourne, Emma L Adams, Catherine E Bee, Kyla Harrington, José Miola, Nigel J Brunskill, Christopher E Brightling, Julian Barwell, Susan E Wallace, Ron Hsu, David J Shepherd, Edward J Hollox, Louise V Wain and Martin D Tobin Department of Health Sciences, University of Leicester, Leicester, UK, NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK, Department of Respiratory Sciences, University of Leicester, Leicester, UK, Department of Clinical Pharmacology, William Harvey Research Institute, Barts & The London Medical School, Queen Mary University of London, Charterhouse Square, London, UK, Department of Population Science and Experimental Medicine, Institute of Cardiovascular Science, University College London, London, UK, Department of Haematology, University Hospitals of Leicester NHS Trust, Leicester, UK, Leicester Law School, University of Leicester, Leicester, UK, Department of Cardiovascular Sciences University of Leicester, Leicester, UK and Department of Genetics and Genome Biology, University of Leicester, Leicester, UK