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Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Electronic health records were used to undertake the largest genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identified 158 novel signals, more than doubling the number of known associations with TSH, and implicating 112 putative causal genes, of which 78 were not previously implicated. For the first time, we demonstrate that a polygenic score for TSH was associated with TSH levels in all ancestries in UK Biobank, and strongly predicted age of onset of hypothyroidism and hyperthyroidism in European ancestry participants. We developed pathway-specific genetic risk scores for TSH levels and used 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.

SummaryACE inhibitors (ACEIs) are commonly prescribed for hypertension, a global risk factor for cardiovascular disease. Their primary side effect is a dry cough which affects 5-35% of users. As clinical guidelines recommend switching those experiencing cough to an angiotensin-II receptor blocker, we have used this switch as a proxy for ACEI-induced cough. Through a two-stage multi-ancestry genome-wide association study, including up to 7,030 cases and 39,921 controls, we identify five independent genome-wide significant associations implicating six protein-coding genes, including INHBC, KCNIP4, NTSR1 and PREP which encode proteins involved in the nervous system. We also observe genetic overlap between ACEI-induced cough and chronic dry cough through genetic correlation and phenome-wide association studies. In line with existing hypotheses, our findings suggest a neurological basis for the pathology of ACEI-induced cough, particularly the role of proinflammatory mediators in sensory airway sensitivity and cough reflex modulation, and shared biological mechanisms with chronic dry cough.

Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h2SNP) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71–88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h2SNP was comparable (0.25 [SE = 0.04] and 0.19 [SE = 0.02], respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.

Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Background: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.Research Question: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?Study Design and Methods: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10–6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).Results: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10–8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.Interpretation: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC 1

ObjectivesTo investigate how ethnicity and other sociodemographic, work, and physical health factors are related to mental health in UK healthcare and ancillary workers (HCWs), and how structural inequities in these factors may contribute to differences in mental health by ethnicity.DesignCross-sectional analysis of baseline data from the UK-REACH national cohort studySettingHCWs across UK healthcare settings.Participants11,695 HCWs working between December 2020-March 2021.Main outcome measuresAnxiety or depression symptoms (4-item Patient Health Questionnaire, cut-off >3), and Post-Traumatic Stress Disorder (PTSD) symptoms (3-item civilian PTSD Checklist, cut-off >5).ResultsAsian, Black, Mixed/multiple and Other ethnic groups had greater odds of PTSD than the White ethnic group. Differences in anxiety/depression were less pronounced. Younger, female HCWs, and those who were not doctors had increased odds of symptoms of both PTSD and anxiety/depression. Ethnic minority HCWs were more likely to experience the following work factors that were also associated with mental ill-health: workplace discrimination, feeling insecure in raising workplace concerns, seeing more patients with COVID-19, reporting lack of access to personal protective equipment (PPE), and working longer hours and night shifts. Ethnic minority HCWs were also more likely to live in a deprived area and have experienced bereavement due to COVID-19. After adjusting for sociodemographic and work factors, ethnic differences in PTSD were less pronounced and ethnic minority HCWs had lower odds of anxiety/depression compared to White HCWs.ConclusionsEthnic minority HCWs were more likely to experience PTSD and disproportionately experienced work and sociodemographic factors associated with PTSD, anxiety and depression. These findings could help inform future work to develop workplace strategies to safeguard HCWs’ mental health. This will only be possible with adequate investment in staff recruitment and retention, alongside concerted efforts to address inequities due to structural discrimination.Summary boxWhat is already known on this topicThe pandemic is placing healthcare workers under immense pressure, and there is currently a mental health crisis amongst NHS staffEthnic inequities in health outcomes are driven by structural discrimination, which occurs inside and outside the workplaceInvestigating ethnic inequities in the mental health of healthcare workers requires large diverse studies, of which few existWhat this study addsIn UK-REACH (N=11,695), ethnic minority staff had higher odds of Post-Traumatic Stress Disorder symptoms; we report many other factors associated with mental-ill health, including those experienced disproportionately by ethnic minority staff, such as workplace discrimination, contact with more patients with COVID-19, and bereavement due to COVID-19These findings underline the moral and practical need to care for staff mental health and wellbeing, which includes tackling structural inequities in the workplace; improving staff mental health may also reduce workforce understaffing due to absence and attrition

Key Features of the UK-REACH Cohort (Profile in a nutshell)The UK-REACH Cohort was established to understand why ethnic minority healthcare workers (HCWs) are at risk of poorer outcomes from COVID-19 when compared to their white ethnic counterparts in the United Kingdom (UK). Through study design, it contains a uniquely high percentage of participants from ethnic minority backgrounds about whom a wide range of qualitative and quantitative data has been collected.A total of 17891 HCWs aged 16-89 years (mean age: 44) have been recruited from across the UK via all major healthcare regulators, individual National Health Service (NHS) hospital trusts and UK HCW membership bodies who advertised the study to their registrants/staff to encourage participation in the study.Data available include linked healthcare records for 25 years from the date of consent and consent to obtain genomic sequencing data collected via saliva. Online questionnaires include information on demographics, COVID-19 exposures at work and home, redeployment in the workforce due to COVID-19, mental health measures, workforce attrition, and opinions on COVID-19 vaccines, with baseline (n=15 119), 6 (n=5632) and 12-month follow-up data captured.Request data access and collaborations by following documentation found at https://www.uk-reach.org/main/data_sharing.

BackgroundSeveral countries now have mandatory SARS-CoV-2/COVID-19 vaccination for healthcare workers (HCWs) or the general population. HCWs’ views on this are largely unknown.MethodsWe administered an online questionnaire to 17891 United Kingdom (UK) HCWs in Spring 2021 as part of the United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH) nationwide prospective cohort study. We categorised responses to a free-text question “What should society do if people don’t get vaccinated against COVID-19?” using content analysis. We collapsed categories into a binary variable: favours mandatory vaccination or not and used logistic regression to calculate its demographic predictors, and occupational, health and attitudinal predictors adjusted for demographics.FindingsOf 5633 questionnaire respondents, 3235 answered the freetext question; 18% (n=578) of those favoured mandatory vaccination but the most frequent suggestion was education (32%, n=1047). Older HCWs, HCWs vaccinated against influenza (OR 1.48; 95%CI 1.10 – 1.99, vs none) and with more positive vaccination attitudes generally (OR 1.10; 95%CI 1.06 – 1.14) were more likely to favour mandatory vaccination (OR 1.26; 95%CI 1.17 – 1.37, per decade increase), whereas female HCWs (OR= 0.80, 95%CI 0.65 – 0.99, vs male), Black HCWs (OR= 0.48, 95%CI 0.26 – 0.87, vs White), those hesitant about COVID-19 vaccination (OR= 0.56; 95%CI 0.43 – 0.71, vs not hesitant), in an Allied Health Profession (OR 0.67; 95%CI 0.51 – 0.88, vs Medical), or who trusted their organisation (OR 0.78; 95%CI 0.63 – 0.96) were less likely to.InterpretationOnly one in six of the HCWs in this large, diverse, UK-wide sample favoured mandatory vaccination. Building trust, educating and supporting HCWs who are hesitant about vaccination may be more acceptable, effective and equitable.FundingMRC-UK Research and Innovation grant (MR/V027549/1) and the Department of Health and Social Care via the National Institute for Health Research.

IntroductionHealthcare workers (HCWs), particularly those from ethnic minority groups, have been shown to be at disproportionately higher risk of infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) compared to the general population. However, there is insufficient evidence on how demographic and occupational factors influence infection risk among ethnic minority HCWs.MethodsWe conducted a cross-sectional analysis using data from the United Kingdom Research study into Ethnicity And COVID-19 Outcomes in Healthcare workers (UK-REACH) cohort study. We used logistic regression to examine associations of demographic, household and occupational predictor variables with SARS-CoV-2 infection (defined by PCR, serology or suspected COVID-19) in a diverse group of HCWs.Results2,496 of the 10,772 HCWs (23.2%) who worked during the first UK national lockdown in March 2020 reported previous SARS-CoV-2 infection. In an adjusted model, demographic and household factors associated with increased odds of infection included younger age, living with other key workers and higher religiosity. Important occupational risk factors associated with increased odds of infection included attending to a higher number of COVID-19 positive patients (aOR 2.49, 95%CI 2.03–3.05 for ≥21 patients per week vs none), working in a nursing or midwifery role (1.35, 1.15– 1.58, compared to doctors), reporting a lack of access to personal protective equipment (1.27, 1.15 – 1.41) and working in an ambulance (1.95, 1.52–2.50) or hospital inpatient setting (1.54, 1.37 – 1.74). Those who worked in Intensive Care Units were less likely to have been infected (0.76, 0.63–0.90) than those who did not. Black HCWs were more likely to have been infected than their White colleagues, an effect which attenuated after adjustment for other known predictors.ConclusionsWe identified key sociodemographic and occupational risk factors associated with SARS-CoV-2 infection amongst UK HCWs, and have determined factors that might contribute to a disproportionate odds of infection in HCWs from Black ethnic groups. These findings demonstrate the importance of social and occupational factors in driving ethnic disparities in COVID-19 outcomes, and should inform policies, including targeted vaccination strategies and risk assessments aimed at protecting HCWs in future waves of the COVID-19 pandemic.Trial registrationISRCTN 11811602

BackgroundVaccination is key to successful prevention of COVID-19 particularly nosocomial acquired infection in health care workers (HCWs). ‘Vaccine hesitancy’ is common in the population and in HCWs, and like COVID-19 itself, hesitancy is more frequent in ethnic minority groups. UK-REACH (United Kingdom Research study into Ethnicity and COVID-19 outcomes) is a large-scale study of COVID-19 in UK HCWs from diverse ethnic backgrounds, which includes measures of vaccine hesitancy. The present study explores predictors of vaccine hesitancy using a ‘phenomic approach’, considering several hundred questionnaire-based measures.MethodsUK-REACH includes a questionnaire study encompassing 12,431 HCWs who were recruited from December 2020 to March 2021 and completed a lengthy online questionnaire (785 raw items; 392 derived measures; 260 final measures). Ethnicity was classified using the Office for National Statistics’ five (ONS5) and eighteen (ONS18) categories. Missing data were handled by multiple imputation. Variable selection used theislassopackage inR, which provides standard errors so that results from imputations could be combined using Rubin’s rules. The data were modelled using path analysis, so that predictors, and predictors of predictors could be assessed. Significance testing used the Bayesian approach of Kass and Raftery, a ‘very strong’ Bayes Factor of 150, N=12,431, and a Bonferroni correction giving a criterion of p−8for the main regression, and p−10for variables in the path analysis.ResultsAt the first step of the phenomic analysis, six variables were direct predictors of greater vaccine hesitancy: Lower pro-vaccination attitudes; no flu vaccination in 2019-20; pregnancy; higher COVID-19 conspiracy beliefs; younger age; and lower optimism the roll-out of population vaccination. Overall 44 lower variables in total were direct or indirect predictors of hesitancy, with the remaining 215 variables in the phenomic analysis not independently predicting vaccine hesitancy. Key variables for predicting hesitancy were belief in conspiracy theories of COVID-19 infection, and a low belief in vaccines in general. Conspiracy beliefs had two main sets of influences:Higher Fatalism, which was influenced a) by high external and chance locus of control and higher need for closure, which in turn were associated with neuroticism, conscientiousness, extraversion and agreeableness; and b) by religion being important in everyday life, and being Muslim.receiving information via social media, not having higher education, and perceiving greater risks to self, the latter being influenced by higher concerns about spreading COVID, greater exposure to COVID-19, and financial concerns.There were indirect effects of ethnicity, mediated by religion. Religion was more important for Pakistani and African HCWs, and less important for White and Chinese groups. Lower age had a direct effect on hesitancy, and age and female sex also had several indirect effects on hesitancy.ConclusionsThe phenomic approach, coupled with a path analysis revealed a complex network of social, cognitive, and behavioural influences on SARS-Cov-2 vaccine hesitancy from 44 measures, 6 direct and 38 indirect, with the remaining 215 measures not having direct or indirect effects on hesitancy. It is likely that issues of trust underpin many associations with hesitancy. Understanding such a network of influences may help in tailoring interventions to address vaccine concerns and facilitate uptake in more hesistant groups.FundingUKMRI-MRC and NIHR

ObjectivesTo determine the prevalence and predictors of self-reported access to appropriate personal protective equipment (aPPE) for healthcare workers (HCWs) in the United Kingdom (UK) during the first UK national COVID-19 lockdown (March 2020) and at the time of questionnaire response (December 2020 – February 2021).DesignTwo cross sectional analyses using data from a questionnaire-based cohort study.SettingNationwide questionnaire from 4th December 2020 to 28th February 2021.ParticipantsA representative sample of HCWs or ancillary workers in a UK healthcare setting aged 16 or over, registered with one of seven main UK healthcare regulatory bodies.Main outcome measureBinary measure of self-reported aPPE (access all of the time vs access most of the time or less frequently) at two timepoints: the first national lockdown in the UK (primary analysis) and at the time of questionnaire response (secondary analysis).Results10,508 HCWs were included in the primary analysis, and 12,252 in the secondary analysis. 3702 (35.2%) of HCWs reported aPPE at all times in the primary analysis; 6806 (83.9%) reported aPPE at all times in the secondary analysis. After adjustment (for age, sex, ethnicity, migration status, occupation, aerosol generating procedure exposure, work sector, work region, working hours, night shift frequency and trust in employing organisation), older HCWs (per decade increase in age: aOR 1.2, 95% CI 1.16-1.26, pConclusionsWe found that only a third of HCWs in the UK reported aPPE at all times during the period of the first lockdown and that aPPE had improved later in the pandemic. We also identified key sociodemographic and occupational determinants of aPPE during the first UK lockdown, the majority of which have persisted since lockdown was eased. These findings have important public health implications for HCWs, particularly as cases of infection and long-COVID continue to rise in the UK.Trial registrationISRCTN 11811602What is already known on this topicAccess to personal protective equipment (PPE) is crucial to protect healthcare workers (HCWs) from infection. Limited data exist concerning the prevalence of, and factors relating to, PPE access for HCWs in the United Kingdom (UK) during the COVID-19 pandemic.What this study addsOnly a third of HCWs reported having access to appropriate PPE all of the time during the first UK national lockdown. Older HCWs, those working in Intensive Care Units and those who trusted their employing organisation to deal with concerns about unsafe clinical practice, were more likely to report access to adequate PPE. Those from Asian ethnic groups (compared to White ethnic groups) and those who saw a high number of COVID-19 were less likely to report access to adequate PPE. Our findings have important implications for the mental and physical health of HCWs working during the pandemic in the UK.

IntroductionThe COVID-19 pandemic has resulted in significant morbidity and mortality and devastated economies globally. Among groups at increased risk are healthcare workers (HCWs) and ethnic minority groups. Emerging evidence suggests that HCWs from ethnic minority groups are at increased risk of adverse COVID-19-related outcomes. To date, there has been no large-scale analysis of these risks in UK HCWs or ancillary workers in healthcare settings, stratified by ethnicity or occupation, and adjusted for confounders. This paper reports the protocol for a prospective longitudinal questionnaire study of UK HCWs, as part of the UK-REACH programme (The United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers).Methods and analysisA baseline questionnaire will be administered to a national cohort of UK HCWs and ancillary workers in healthcare settings, and those registered with UK healthcare regulators, with follow-up questionnaires administered at 4 and 8 months. With consent, questionnaire data will be linked to health records with 25-year follow-up. Univariate associations between ethnicity and clinical COVID-19 outcomes, physical and mental health, and key confounders/explanatory variables will be tested. Multivariable analyses will test for associations between ethnicity and key outcomes adjusted for the confounder/explanatory variables. We will model changes over time by ethnic group, facilitating understanding of absolute and relative risks in different ethnic groups, and generalisability of findings.Ethics and disseminationThe study is approved by Health Research Authority (reference 20/HRA/4718), and carries minimal risk. We aim to manage the small risk of participant distress about questions on sensitive topics by clearly participant information that the questionnaire covers sensitive topics and there is no obligation to answer these or any other questions, and by providing support organisation links. Results will be disseminated with reports to Government and papers submitted to pre-print servers and peer reviewed journals.Trial registration numberISRCTN11811602; Pre-results.

Background Antibiotic resistance is a major global threat. We hypothesised that the chronic obstructive pulmonary disease (COPD) airway is a reservoir of antimicrobial resistance genes (ARGs) that associate with microbiome-specific COPD subgroups. Objective To determine the resistance gene profiles in respiratory samples from COPD patients and healthy volunteers. Methods Quantitative PCR targeting 279 specific ARGs was used to profile the resistomes in sputum from subjects with COPD at stable, exacerbation and recovery visits (n=55; COPD-BEAT study), healthy controls with (n=7) or without (n=22) exposure to antibiotics in the preceding 12 months (EXCEED study) and in bronchial brush samples from COPD (n=8) and healthy controls (n=7) (EvA study). Results ARG mean (SEM) prevalence was greater in stable COPD samples (35.2 (1.6)) than in healthy controls (27.6 (1.7); p=0.004) and correlated with total bacterial abundance (r2=0.23; p

Background and aimsNon-alcoholic fatty liver disease (NAFLD) is a complex trait that has a global prevalence estimated as 25%. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes.MethodsExome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison to healthy non-carriers and wild type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human induced pluripotent stem cells generated from homozygous donor skin fibroblasts. The phenotype was assessed using imaging, targeted RNA analysis and molecular expression arrays.ResultsWe identified a rare causal variant in MTTP, c.1691T>C p.I564T (rs745447480) encoding microsomal triglyceride transfer protein (MTP) associated with progressive non-alcoholic fatty liver disease, unrelated to metabolic syndrome. Although other described mutations in MTTP cause abetalipoproteinemia, neither homozygotes nor heterozygotes exhibited characteristic manifestations of this severe disease. HLCs derived from a homozygote donor had lower lipoprotein ApoB secretion, compared to wild type cells. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators and production of reactive oxygen species.ConclusionWe have identified and characterized a rare causal variant in MTTP and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinemia.

IntroductionCOVID-19 has spread rapidly worldwide, causing significant morbidity and mortality. People from ethnic minorities, particularly those working in healthcare settings, have been disproportionately affected. Current evidence of the association between ethnicity and COVID-19 outcomes in people working in healthcare settings is insufficient to inform plans to address health inequalities.Methods and analysisThis study combines anonymised human resource databases with professional registration and National Health Service data sets to assess associations between ethnicity and COVID-19 diagnosis, hospitalisation and death in healthcare workers in the UK. Adverse COVID-19 outcomes will be assessed between 1 February 2020 (date following first confirmed COVID-19 case in UK) and study end date (31 January 2021), allowing 1-year of follow-up. Planned analyses include multivariable Poisson, logistic and flexible parametric time-to-event regression within each country, adjusting for core predictors, followed by meta-analysis of country-specific results to produce combined effect estimates for the UK. Mediation analysis methods will be explored to examine the direct, indirect and mediated interactive effects between ethnicity, occupational group and COVID-19 outcomes.Ethics and disseminationEthical approval for the UK-REACH programme has been obtained via the expedited HRA COVID-19 processes (REC ref: 20/HRA/4718, IRAS ID: 288316). Research information will be anonymised via the Secure Anonymised Information Linkage Databank before release to researchers. Study results will be submitted for publication in an open access peer-reviewed journal and made available on our dedicated website (https://uk-reach.org/).Trial registration numberISRCTN11811602.

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.

Royal Academy of Engineering and NIHR HPRU in Environmental Exposures and Health at the University of Leicester.

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P-8) interactions with sex on lung function, and 21 showed suggestive interactions (P-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.

Homozygosity for the SERPINA1 Z allele causes α1-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory phenotypes, and on lung function in the general population, remain unclear. We conducted a large, population-based study to determine Z allele effects on >2400 phenotypes in the UK Biobank (N=303 353). Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10−68), and with other nonrespiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV1) (β=19.36 mL, p=9.21×10−4) and FEV1/forced vital capacity (β=0.0031, p=1.22×10−5) in nonsmokers, whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function. We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with nonrespiratory health-related traits and disease risk. Tweetable abstract @ERSpublications click to tweet Heterozygosity for the SERPINA1 Z allele is associated with higher lung function in nonsmokers (but this advantage is abolished by smoking) as well as a variety of nonrespiratory diseases and traits, including liver-, heart- and bone-related conditions https://bit.ly/37XC0Yg Introduction Homozygosity for the SERPINA1 Z allele (rs28929474(T)) is the commonest cause of severe α1-antitrypsin deficiency (AATD) and is a well-established genetic risk factor for lung diseases such as chronic obstructive pulmonary disease (COPD). However, the health consequences of heterozygosity for the Z allele are not as well-understood [1]. Given that approximately one in 30 Europeans is heterozygous for the Z allele, the phenotypic consequences of carriage of this allele could have important public health implications. Some previous studies have sought to characterise the effect of Z allele heterozygosity on nonrespiratory traits, particularly liver diseases [2–6]. However, these have often been carried out in small sample sizes and/or clinical subgroups. The recent development of phenome-wide association studies (PheWASs) and the availability of the well-phenotyped UK Biobank population-based cohort provides a platform for systematic investigation of the effects of heterozygosity for the Z allele on nonrespiratory traits. PheWASs test the association between genetic variants and a large number of phenotypic traits, including diseases and their subtypes, and potential intermediate phenotypes [7]. This differs from genome-wide association studies, which test a large number of variants across the genome for association with only one trait. The effect of Z allele heterozygosity on lung function traits and lung disease has been the subject of many studies. Recent COPD case–control and family-based studies have shown reduced lung function and increased risk of COPD in heterozygous current and former smokers [8–11]. However, a population-based study demonstrated no significant reductions in lung function in heterozygous smokers, despite having greater numbers of heterozygous smokers compared to previous studies [12]. It also showed enhanced lung function in heterozygous individuals overall, partially explained by strong association of the Z allele with increased height. This discrepancy may be due, in part, to the fact that identifying and recruiting study participants based on their health status (as in case–control studies [8, 9]) or based on the health status of a family member [10, 11] can lead to causal estimates that are subject to ascertainment bias [13], whereas population-based studies [12, 14] overcome these biases. The effects of the Z allele on lung function in relation to smoking status therefore remain uncertain. Finally, despite evidence for sex-differential effects of Z allele homozygosity on lung function [15, 16], we are not aware of any studies that have compared the effect of Z allele heterozygosity on lung function in males versus females. We therefore systematically evaluated the effects of Z allele heterozygosity in the UK biobank population, which in total includes >18 000 Z allele heterozygotes. We aimed: 1) to undertake the most extensive PheWAS to date, including blood biomarkers, for Z allele heterozygosity and homozygosity to identify effects beyond the respiratory system; and 2) to fully define the effects of Z allele heterozygosity on lung function measures (forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)) in smokers and nonsmokers and in males and females.

IntroductionThe COVID-19 pandemic has resulted in significant morbidity and mortality, and has devastated economies in many countries. Amongst the groups identified as being at increased risk from COVID-19 are healthcare workers (HCWs) and ethnic minority groups. Emerging evidence suggests HCWs from ethnic minority groups are at increased risk of adverse COVID-19-related physical and mental health outcomes. To date there has been no large-scale analysis of these risks in UK healthcare workers or ancillary workers in healthcare settings, stratified by ethnicity or occupation type, and adjusted for potential confounders. This paper reports the protocol for a prospective longitudinal questionnaire study of UK HCWs, as part of the UK-REACH programme (The United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers).Methods and analysisA baseline questionnaire with follow-up questionnaires at 4 and 8 months will be administered to a national cohort of UK healthcare workers and ancillary workers in healthcare settings, and those registered with UK healthcare regulators. With consent, data will be linked to health records, and participants followed up for 25 years.Univariate associations between ethnicity and primary outcome measures (clinical COVID-19 outcomes, and physical and mental health) and key confounders/explanatory variables will be tested, followed by multivariable analyses to test for associations between ethnicity and key outcomes adjusted for the confounder/explanatory variables, with interactions included as appropriate. Using follow-up data, multilevel models will be used to model changes over time by ethnic group, facilitating understanding of absolute and relative risks in different ethnic groups, and generalisability of findings.Ethics and disseminationThe study is approved by Health Research Authority (reference 20/HRA/4718), and carries minimal risk to participants. We aim to manage the small risk of participant distress due to being asked questions on sensitive topics by clearly indicating on the participant information sheet that the questionnaire covers sensitive topics and that participants are under no obligation to answer these, or indeed any other, questions, and by providing links to support organisations. Results will be disseminated with reports to Government and papers uploaded to pre-print servers and submitted to peer reviewed journals.Registration detailsTrial ID: ISRCTN11811602STRENGTHS AND LIMITATIONS OF THIS STUDYNational, UK-wide, study, aiming to capture variety of healthcare worker job roles including ancillary workers in healthcare settings.Longitudinal study including three waves of questionnaire data collection, and linkage to administrative data over 25 years, with consent.Unique support from all major UK healthcare worker regulators, relevant healthcare worker organisations, and a Professional Expert Panel to increase participant uptake and the validity of findings.Potential for self-selection bias and low response rates, and the use of electronic invitations and online data collection makes it harder to reach ancillary workers without regular access to work email addresses.

To assess the cost effectiveness of buprenorphine versus methadone in the management of opioid use disorder (OUD) during pregnancy.We designed a decision-analytic model to evaluate the costs and outcomes associated with buprenorphine compared to methadone for pregnant people with OUD. We used a theoretical cohort of 22,400 pregnant people, which is an estimation of pregnancies affected by OUD per year in the United States. Outcomes included maternal retention in maintenance treatment, neonatal opioid withdrawal syndrome, preterm birth, fetal growth restriction, cerebral palsy, and maternal overdose in addition to cost and quality-adjusted life-years (QALYs). We used a willingness-to-pay threshold of $100,000/QALY. All model inputs were derived from the literature and varied in sensitivity analyses to assess the robustness of our baseline inputs.In our theoretical cohort, treatment of OUD with buprenorphine during pregnancy resulted in 2413 fewer cases of neonatal opioid withdrawal syndrome, 1089 fewer preterm births, 299 fewer cases of fetal growth restriction, 32 fewer stillbirths, and 13 fewer cases of cerebral palsy compared to methadone treatment. Despite lower rates of retention, buprenorphine treatment saved nearly 123 million healthcare dollars and resulted in 558 additional QALYs, making it the dominant strategy compared to methadone treatment. Our findings were robust over a wide range of assumptions.Our data suggest that buprenorphine should be considered a cost effective treatment option for OUD in pregnancy, as it is associated with improved neonatal outcomes compared to methadone despite the risk of treatment discontinuation.

Some individuals have characteristics of both asthma and COPD (asthma-COPD overlap, ACO), and evidence suggests they experience worse outcomes than those with either condition alone. Improved knowledge of the genetic architecture would contribute to understanding whether determinants of risk in this group differ from those in COPD or asthma.We conducted a genome-wide association study in 8,068 cases and 40,360 controls of European ancestry from UK Biobank (stage 1). After excluding variants only associated with asthma or COPD we selected 31 variants for further investigation in 12 additional cohorts (stage 2), and discovered eight novel signals for ACO in a meta-analysis of stage 1 and 2 studies.Our signals include an intergenic signal on chromosome 5 not previously associated with asthma, COPD or lung function, and suggest a spectrum of shared and distinct genetic influences in asthma, COPD and ACO. A number of signals may represent loci that predispose to serious long-term consequences in people with asthma.