Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 diseaseassociated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg=0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

The frequency of, and risk factors for, long COVID are unclear among community-based individuals with a history of COVID-19. To elucidate the burden and possible causes of long COVID in the community, we coordinated analyses of survey data from 6907 individuals with self-reported COVID-19 from 10 UK longitudinal study (LS) samples and 1.1 million individuals with COVID-19 diagnostic codes in electronic healthcare records (EHR) collected by spring 2021. Proportions of presumed COVID-19 cases in LS reporting any symptoms for 12+ weeks ranged from 7.8% and 17% (with 1.2 to 4.8% reporting debilitating symptoms). Increasing age, female sex, white ethnicity, poor pre-pandemic general and mental health, overweight/obesity, and asthma were associated with prolonged symptoms in both LS and EHR data, but findings for other factors, such as cardio-metabolic parameters, were inconclusive.

The FI is a valid measure of frailty in UK Biobank. The cohort's data are open access for researchers to use, and we provide script for deriving this tool to facilitate future studies on frailty.

Background SARS-CoV-2 serology is used to identify prior infection at individual and at population level. Extended longitudinal studies with multi-timepoint sampling to evaluate dynamic changes in antibody levels are required to identify the time horizon in which these applications of serology are valid, and to explore the longevity of protective humoral immunity. Methods Healthcare workers were recruited to a prospective cohort study from the first SARS-CoV-2 epidemic peak in London, undergoing weekly symptom screen, viral PCR and blood sampling over 16–21 weeks. Serological analysis ( n =12,990) was performed using semi-quantitative Euroimmun IgG to viral spike S1 domain and Roche total antibody to viral nucleocapsid protein (NP) assays. Comparisons were made to pseudovirus neutralizing antibody measurements. Findings A total of 157/729 (21.5%) participants developed positive SARS-CoV-2 serology by one or other assay, of whom 31.0% were asymptomatic and there were no deaths. Peak Euroimmun anti-S1 and Roche anti-NP measurements correlated ( r = 0.57, p <0.0001) but only anti-S1 measurements correlated with near-contemporary pseudovirus neutralising antibody titres (measured at 16–18 weeks, r = 0.57, p <0.0001). By 21 weeks’ follow-up, 31/143 (21.7%) anti-S1 and 6/150 (4.0%) anti-NP measurements reverted to negative. Mathematical modelling revealed faster clearance of anti-S1 compared to anti-NP (median half-life of 2.5 weeks versus 4.0 weeks), earlier transition to lower levels of antibody production (median of 8 versus 13 weeks), and greater reductions in relative antibody production rate after the transition (median of 35% versus 50%). Interpretation Mild SARS-CoV-2 infection is associated with heterogeneous serological responses in Euroimmun anti-S1 and Roche anti-NP assays. Anti-S1 responses showed faster rates of clearance, more rapid transition from high to low level production rate and greater reduction in production rate after this transition. In mild infection, anti-S1 serology alone may underestimate incident infections. The mechanisms that underpin faster clearance and lower rates of sustained anti-S1 production may impact on the longevity of humoral immunity. Funding Charitable donations via Barts Charity, Wellcome Trust, NIHR.

BackgroundIncreasing evidence suggests a role for mineral metabolism in cardiovascular disease risk. 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), and calcium may be directly associated with cardiovascular risk factors or mediated by each other.Methodology/Principal FindingsWe combined data for adult participants in three cycles of the National Health and Nutrition Examination Survey (2001–2, 2003–4, 2005–6), a representative sample of the civilian, non-institutionalized US population (N = 3,958). Using this data we examined joint associations of 25(OH)D, PTH and calcium with a range of cardiovascular risk factors. 25(OH)D was inversely associated with fasting insulin (mean difference in insulin per 1 standard deviation 25(OH)D: −0.053 (95%CI: −0.091, −0.015)), glucose (−0.046 95%CI: −0.081, −0.012) and systolic blood pressure (SBP) (−0.032 95%CI: −0.062, −0.001), and positively associated with high density lipoprotein cholesterol HDL-c (0.088 95%CI: 0.044, 0.148), after adjustment for ethnicity, smoking, socio-economic status and waist circumference. PTH was positively associated with diastolic blood pressure (0.110, 95%CI: 0.055, 0.164) in confounder adjusted models, but was not associated with other cardiovascular risk factors. Albumin adjusted calcium was associated with triglycerides (0.102 95%CI: 0.063, 0.141), postload glucose (0.078, 95%CI: 0.025, 0.130), fasting insulin (0.074, 95%CI: 0.044, 0.104), HbA1c (0.070, 95%CI: 0.036, 0.105), SBP (0.064, 95%CI: 0.028, 0.100), fasting glucose (0.055, 95%CI: 0.018, 0.092) and low density lipoprotein cholesterol (0.052, 95%CI: 0.014, 0.091). With mutual adjustment for each other, these associations remained essentially unchanged.Conclusions/SignificanceLower levels of 25(OH)D and higher levels of calcium and PTH appear to be associated with different cardiovascular risk factors and may therefore affect cardiovascular disease risk through different mechanisms.

The impact of long COVID is increasingly recognised, but risk factors are poorly characterised. We analysed questionnaire data on symptom duration from 10 longitudinal study (LS) samples and electronic healthcare records (EHR) to investigate sociodemographic and health risk factors associated with long COVID, as part of the UK National Core Study for Longitudinal Health and Wellbeing.MethodsAnalysis was conducted on 6,899 adults self-reporting COVID-19 from 45,096 participants of the UK LS, and on 3,327 cases assigned a long COVID code in primary care EHR out of 1,199,812 adults diagnosed with acute COVID-19. In LS, we derived two outcomes: symptoms lasting 4+ weeks and symptoms lasting 12+ weeks. Associations of potential risk factors (age, sex, ethnicity, socioeconomic factors, smoking, general and mental health, overweight/obesity, diabetes, hypertension, hypercholesterolaemia, and asthma) with these two outcomes were assessed, using logistic regression, with meta-analyses of findings presented alongside equivalent results from EHR analyses.ResultsFunctionally limiting long COVID for 12+ weeks affected between 1.2% (age 20), and 4.8% (age 63) of people reporting COVID-19 in LS. The proportion reporting symptoms overall for 12+ weeks ranged from 7.8 (mean age 28) to 17% (mean age 58) and for 4+ weeks 4.2% (age 20) to 33.1% (age 56). Age was associated with a linear increase in long COVID between age 20-70. Being female (LS: OR=1.49; 95%CI:1.24-1.79; EHR: OR=1.51 [1.41-1.61]), poor pre-pandemic mental health (LS: OR=1.46 [1.17-1.83]; EHR: OR=1.57 [1.47-1.68]) and poor general health (LS: OR=1.62 [1.25-2.09]; EHR: OR=1.26; [1.18-1.35]) were associated with higher risk of long COVID. Individuals with asthma also had higher risk (LS: OR=1.32 [1.07-1.62]; EHR: OR=1.56 [1.46-1.67]), as did those categorised as overweight or obese (LS: OR=1.25 [1.01-1.55]; EHR: OR=1.31 [1.21-1.42]) though associations for symptoms lasting 12+ weeks were less pronounced. Non-white ethnic minority groups had lower 4+ week symptom risk (LS: OR=0.32 [0.22-0.47]), a finding consistent in EHR. Associations were not observed for other risk factors. Few participants in the studies had been admitted to hospital (0.8-5.2%).ConclusionsLong COVID is clearly distributed differentially according to several sociodemographic and pre-existing health factors. Establishing which of these risk factors are causal and predisposing is necessary to further inform strategies for preventing and treating long COVID.

Objective-To examine independent associations of serum 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH) and calcium with a range of cardiovascular risk factors in adolescents.Design-Cross-sectional population-based study.Setting-A nationally representative sample of the US adolescent population. Conclusion-Higher calcium levels might be a more important predictor of increased cardiovascular risk in adolescents than lower 25(OH)D levels or PTH levels, but the findings require replication in additional studies and examination in prospective studies.