Showing papers by "Debbie A Lawlor published in 2020"

The Trans-Ancestral Genomic Architecture of Glycaemic Traits

Abstract: Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P

Genomic and phenomic insights from an atlas of genetic effects on DNA methylation

Abstract: Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both blood DNAm levels and complex diseases but in most cases these associations do not reflect causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than has previously been hypothesised.

Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Abstract: Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.

Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Abstract: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P < 1.06 × 10− 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Comparisons between countries are essential for the control of COVID-19.

Abstract: On 6 May 2020, the UK Prime Minister Boris Johnson quoted statistician David Spiegelhalter, arguing that it was not appropriate to compare the COVID-19 death rate in the UK with other countries. Within a few hours, Spiegelhalter tweeted a request for the Prime Minister to stop quoting him and affirmed that ‘of course we should now use other countries to try and learn why our numbers are high’. The issue was that, although it is difficult to reliably compare COVID-19 population fatality rates between countries, it is also quite clear that some countries (e.g. UK, USA, Italy, Spain, Belgium, France) have markedly higher burdens of COVID-19 mortality than others (e.g. New Zealand, Australia, Singapore, South Korea, Germany). Although one could not say definitively that the UK was the worst in the world, it was performing worse than some countries which had tried alternative control strategies, and there are things that we can learn from that contrast. Indeed, epidemiology is built on the idea of studying differences between populations. Much of what we have learnt about the causes of disease has had its origins in comparisons of countries. For example, in the 1950s, it was realiz ed that colorectal cancer risks were high in Europe and low in Africa, possibly due to dietary differences in fibre from fruit and vegetable intake. Similarly, liver cancer was common in Asia, which eventually provided a link to hepatitis B. International differences in cervical cancer incidence and mortality suggested an infectious cause, later established as human papillomavirus (HPV). COVID-19 is different. The causative agent, SARSCoV-2, is clear; the task is to learn how to best block the virus’s transmission and to prevent infections from progressing to severe disease and death. As the pandemic unfolds, there are numerous natural experiments in progress, as countries adopt different approaches. Although international comparisons are often disparaged because of different data quality and fears of the ‘ecological fallacy’, if done carefully they can play a major role in our learning what works best for controlling COVID-19. Furthermore, these natural experiments are yielding clear results within weeks or months (e.g. on the success of the Asian approaches). Thus, there needs to be more thoughtful and thorough analyses of country differences, done by experienced epidemiologists, as it is probably the most important and most valid evidence for informing COVID-19 policy in real time. And after all, what is the alternative? It is impossible or unethical to randomize a lockdown, or other aspects of physical distancing. There could be trials of intensive population testing, or prophylactic treatment of household contacts, but few have been launched to date. And all the time, the COVID-19-clock ticks relentlessly on, accumulating more deaths and more survivors with debilitating longterm health problems.

A maternal serum metabolite ratio predicts fetal growth restriction at term.

Abstract: Fetal growth restriction (FGR) is the major single cause of stillbirth1 and is also associated with neonatal morbidity and mortality2,3, impaired health and educational achievement in childhood4,5 and with a range of diseases in later life6. Effective screening and intervention for FGR is an unmet clinical need. Here, we performed ultrahigh performance liquid chromatography–tandem mass spectroscopy (UPLC–MS/MS) metabolomics on maternal serum at 12, 20 and 28 weeks of gestational age (wkGA) using 175 cases of term FGR and 299 controls from the Pregnancy Outcome Prediction (POP) study, conducted in Cambridge, UK, to identify predictive metabolites. Internal validation using 36 wkGA samples demonstrated that a ratio of the products of the relative concentrations of two positively associated metabolites (1-(1-enyl-stearoyl)-2-oleoyl-GPC (P-18:0/18:1) and 1,5-anhydroglucitol) to the product of the relative concentrations of two negatively associated metabolites (5α-androstan-3α,17α-diol disulfate and N1,N12-diacetylspermine) predicted FGR at term. The ratio had approximately double the discrimination as compared to a previously developed angiogenic biomarker7, the soluble fms-like tyrosine kinase 1:placental growth factor (sFLT1:PlGF) ratio (AUC 0.78 versus 0.64, P = 0.0001). We validated the predictive performance of the metabolite ratio in two sub-samples of a demographically dissimilar cohort, Born in Bradford (BiB), conducted in Bradford, UK (P = 0.0002). Screening and intervention using this metabolite ratio in conjunction with ultrasonic imaging at around 36 wkGA could plausibly prevent adverse events through enhanced fetal monitoring and targeted induction of labor. The relative concentrations of four metabolites in maternal blood at 36 weeks of gestation predict fetal growth restriction in infants subsequently born at term, enabling enhanced fetal monitoring in pregnancies at risk.

The LifeCycle Project-EU Child Cohort Network: a federated analysis infrastructure and harmonized data of more than 250,000 children and parents.

Abstract: Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life.

Maternal Gestational Diabetes Mellitus and Newborn DNA Methylation: Findings From the Pregnancy and Childhood Epigenetics Consortium

Abstract: OBJECTIVE Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium. RESEARCH DESIGN AND METHODS Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, using DNA methylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations between GDM and DNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate. RESULTS Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345–248100614) was located in the OR2L13 promoter, and the other (chr 10: 135341870–135342620) was located in the gene body of CYP2E1. Individual CpG analyses did not reveal any differentially methylated loci based on a false discovery rate–adjusted P value threshold of 0.05. CONCLUSIONS Maternal GDM was associated with lower cord blood methylation levels within two regions, including the promoter of OR2L13, a gene associated with autism spectrum disorder, and the gene body of CYP2E1, which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences.

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

Abstract: Background: The impact of COVID-19 on mental health is unclear Evidence from longitudinal studies with pre pandemic data are needed to address (1) how mental health has changed from pre-pandemic levels to during the COVID-19 pandemic and (2), whether there are groups at greater risk of poorer mental health during the pandemic? Methods: We used data from COVID-19 surveys (completed through April/May 2020), nested within two large longitudinal population cohorts with harmonised measures of mental health: two generations of the Avon Longitudinal Study of Parents and Children (ALPSAC): the index generation ALSPAC-G1 (n= 2850, mean age 28) and the parents generation ALSPAC-G0 (n= 3720, mean age = 59) and Generation Scotland: Scottish Family Health Study (GS, (n= 4233, mean age = 59), both with validated pre-pandemic measures of mental health and baseline factors To answer question 1, we used ALSPAC-G1, which has identical mental health measures before and during the pandemic Question 2 was addressed using both studies, using pre-pandemic and COVID-19 specific factors to explore associations with depression and anxiety in COVID-19 Findings: In ALSPAC-G1 there was evidence that anxiety and lower wellbeing, but not depression, had increased in COVID-19 from pre-pandemic assessments The percentage of individuals with probable anxiety disorder was almost double during COVID-19: 24% (95% CI 23%, 26%) compared to pre-pandemic levels (13%, 95% CI 12%, 14%), with clinically relevant effect sizes In both ALSPAC and GS, depression and anxiety were greater in younger populations, women, those with pre-existing mental and physical health conditions, those living alone and in socio-economic adversity We did not detect evidence for elevated risk in key workers or health care workers Interpretation: These results suggest increases in anxiety and lower wellbeing that may be related to the COVID-19 pandemic and/or its management, particularly in young people This research highlights that specific groups may be disproportionally at risk of elevated levels of depression and anxiety during COVID-19 and supports recent calls for increasing funds for mental health services Funding: The UK Medical Research Council (MRC), the Wellcome Trust and University of Bristol

Association of BMI category with change in children's physical activity between ages 6 and 11 years: a longitudinal study.

Abstract: To examine the association of body mass index (BMI) with change in children’s physical activity and sedentary time between ages 6 and 11. A total of 2132 children participated from 57 schools in Southwest England, from the B-PROACT1V study. Mean minutes of MVPA and sedentary time per day were derived from accelerometer-based measurements at ages 6, 9 and 11. Linear multilevel models examined the association of BMI categories with MVPA and sedentary time between 6 and 11, adjusting for seasonality, wear time, gender and household education. Differences in change over time were examined using interaction terms. Average weekday MVPA decreased between ages 6 and 11 by 2.2 min/day/year (95% CI: 1.9 to 2.5), with a steeper decline at weekends. Average sedentary time increased at a rate of 12.9 min/day/year (95% CI: 12.2 to 13.6). There were no differences in mean levels of MVPA by BMI categories at age 6, but differences emerged as children aged, with the gap between children who were healthy weight and overweight increasing by 1.7 min/day (95% CI: 0.8–2.6) every year, and between healthy and obese by 2.0 min/day (95% CI: 0.9–3.1) each year. Children who were overweight/obese engaged in less average weekday sedentary time at age 6 than those of healthy weight, but the gap closed by age 11. MVPA declines and sedentary time increases on average for all children between ages 6 and 11. While there are no differences in activity levels by BMI category at age 6, differences in MVPA emerge over time for those who are overweight and obese. Developing interventions that support children to retain activity levels as they approach older childhood, particularly those who are overweight/obese could improve public health.

The Avon Longitudinal Study of Parents and Children - A resource for COVID-19 research: Generation 2 questionnaire data capture May-July 2020

Abstract: The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based cohort study which recruited pregnant women in 1990-1992 from the Bristol area (UK). ALSPAC has followed these women, their partners (Generation 0; G0) and their offspring (Generation 1; G1) ever since. From 2012, ALSPAC has identified G1 participants who were pregnant (or their partner was) or had become parents, and enrolled them, their partners, and children in the ALSPAC-Generation 2 (ALSPAC-G2) study, providing a unique multi-generational cohort. At present, approximately 1,100 G2 children (excluding those in utero) from 810 G1 participants have been enrolled. In response to the COVID-19 pandemic, ALSPAC rapidly deployed two online questionnaires; one during the initial lockdown phase in 2020 (9 th April-15 th May), and another when national lockdown restrictions were eased (26 th May-5 th July). As part of this second questionnaire, G1 parents completed a questionnaire about each of their G2 children. This covered: parental reports of children's feelings and behaviour since lockdown, school attendance, contact patterns, and health. A total of 289 G1 participants completed this questionnaire on behalf of 411 G2 children. This COVID-19 G2 questionnaire data can be combined with pre-pandemic ALSPAC-G2 data, plus ALSPAC-G1 and -G0 data, to understand how children's health and behaviour has been affected by the pandemic and its management. Data from this questionnaire will be complemented with linkage to health records and results of biological testing as they become available. Prospective studies are necessary to understand the impact of this pandemic on children's health and development, yet few relevant studies exist; this resource will aid these efforts. Data has been released as: 1) a freely-available dataset containing participant responses with key sociodemographic variables; and 2) an ALSPAC-held dataset which can be combined with existing ALSPAC data, enabling bespoke research across all areas supported by the study.

Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America: An individual participant data meta-analysis of 229,000 singleton births.

Abstract: BACKGROUND: Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. METHODS AND FINDINGS: We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. CONCLUSIONS: We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.

The genetic architecture of sporadic and multiple consecutive miscarriage.

Abstract: Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10-8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10-8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10-9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10-8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

Mendelian randomization study of maternal influences on birthweight and future cardiometabolic risk in the HUNT cohort.

Abstract: There is a robust observational relationship between lower birthweight and higher risk of cardiometabolic disease in later life. The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that adverse environmental factors in utero increase future risk of cardiometabolic disease. Here, we explore if a genetic risk score (GRS) of maternal SNPs associated with offspring birthweight is also associated with offspring cardiometabolic risk factors, after controlling for offspring GRS, in up to 26,057 mother-offspring pairs (and 19,792 father-offspring pairs) from the Nord-Trondelag Health (HUNT) Study. We find little evidence for a maternal (or paternal) genetic effect of birthweight associated variants on offspring cardiometabolic risk factors after adjusting for offspring GRS. In contrast, offspring GRS is strongly related to many cardiometabolic risk factors, even after conditioning on maternal GRS. Our results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based samples of individuals.

Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria

Abstract: By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of HAO1 (expected ~1 in 30 million outbred people). HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals (>5 sd outliers versus n = 25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has <2% residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong HAO1 knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the diversity of human genetic variation can facilitate drug development.

The Born in Bradford COVID-19 Research Study: Protocol for an adaptive mixed methods research study to gather actionable intelligence on the impact of COVID-19 on health inequalities amongst families living in Bradford.

Abstract: The UK COVID-19 lockdown has included restricting social movement and interaction to slow the spread of disease and reduce demand on NHS acute services. It is likely that the impacts of restrictions will hit the least advantaged disproportionately and will worsen existing structural inequalities amongst deprived and ethnic minority groups. The aim of this study is to deliver rapid intelligence to enable an effective COVID-19 response, including co-production of interventions, that address key issues in the City of Bradford, UK, and nationally. In the longer term we aim to understand the impacts of the response on health trajectories and inequalities in these. In this paper we describe our approach and protocol. We plan an adaptive longitudinal mixed methods approach embedded with Born in Bradford (BiB) birth cohorts which have rich existing data (including questionnaire, routine health and biobank). All work packages (WP) interact and are ongoing. WP1 uses co-production and engagement methods with communities, decision-makers and researchers to continuously set (changing) research priorities and will, longer-term, co-produce interventions to aid the City's recovery. In WP2 repeated quantitative surveys will be administered during lockdown (April-June 2020), with three repeat surveys until 12 months post-lockdown with an ethnically diverse pool of BiB participants (parents, children aged 9-13 years, pregnant women: total sample pool N=7,652, N=5,154, N=1,800). A range of health, social, economic and education outcomes will be assessed. In WP3 priority topics identified in WP1 and WP2 will be explored qualitatively. Initial priority topics include children's mental wellbeing, health beliefs and the peri/post-natal period. Feedback loops will ensure findings are fed directly to decision-makers and communities (via WP1) to enable co-production of acceptable interventions and identify future priority topic areas. Findings will be used to aid development of local and national policy to support recovery from the pandemic and minimise health inequalities.

Dissecting maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes, and adult phenotypes: A mendelian-randomization and haplotype-based genetic score analysis in 10,734 mother-infant pairs.

Abstract: Background Many maternal traits are associated with a neonate’s gestational duration, birth weight, and birth length. These birth outcomes are subsequently associated with late-onset health conditions. The causal mechanisms and the relative contributions of maternal and fetal genetic effects behind these observed associations are unresolved. Methods and findings Based on 10,734 mother–infant duos of European ancestry from the UK, Northern Europe, Australia, and North America, we constructed haplotype genetic scores using single-nucleotide polymorphisms (SNPs) known to be associated with adult height, body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), and type 2 diabetes (T2D). Using these scores as genetic instruments, we estimated the maternal and fetal genetic effects underlying the observed associations between maternal phenotypes and pregnancy outcomes. We also used infant-specific birth weight genetic scores as instrument and examined the effects of fetal growth on pregnancy outcomes, maternal BP, and glucose levels during pregnancy. The maternal nontransmitted haplotype score for height was significantly associated with gestational duration (p = 2.2 × 10−4). Both maternal and paternal transmitted height haplotype scores were highly significantly associated with birth weight and length (p < 1 × 10−17). The maternal transmitted BMI scores were associated with birth weight with a significant maternal effect (p = 1.6 × 10−4). Both maternal and paternal transmitted BP scores were negatively associated with birth weight with a significant fetal effect (p = 9.4 × 10−3), whereas BP alleles were significantly associated with gestational duration and preterm birth through maternal effects (p = 3.3 × 10−2 and p = 4.5 × 10−3, respectively). The nontransmitted haplotype score for FPG was strongly associated with birth weight (p = 4.7 × 10−6); however, the glucose-increasing alleles in the fetus were associated with reduced birth weight through a fetal effect (p = 2.2 × 10−3). The haplotype scores for T2D were associated with birth weight in a similar way but with a weaker maternal effect (p = 6.4 × 10−3) and a stronger fetal effect (p = 1.3 × 10−5). The paternal transmitted birth weight score was significantly associated with reduced gestational duration (p = 1.8 × 10−4) and increased maternal systolic BP during pregnancy (p = 2.2 × 10−2). The major limitations of the study include missing and heterogenous phenotype data in some data sets and different instrumental strength of genetic scores for different phenotypic traits. Conclusions We found that both maternal height and fetal growth are important factors in shaping the duration of gestation: genetically elevated maternal height is associated with longer gestational duration, whereas alleles that increase fetal growth are associated with shorter gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes: taller maternal stature, higher maternal BMI, and higher maternal blood glucose are associated with larger birth size through maternal effects; in the fetus, the height- and metabolic-risk–increasing alleles are associated with increased and decreased birth size, respectively; alleles raising birth weight in the fetus are associated with shorter gestational duration and higher maternal BP. These maternal and fetal genetic effects may explain the observed associations between the studied maternal phenotypes and birth outcomes, as well as the life-course associations between these birth outcomes and adult phenotypes.

Circulating Fatty Acids and Risk of Coronary Heart Disease and Stroke: Individual Participant Data Meta-Analysis in Up to 16 126 Participants.

Abstract: Background We aimed at investigating the association of circulating fatty acids with coronary heart disease (CHD) and stroke risk. Methods and Results We conducted an individual‐participant data me...

Experiences of lockdown during the Covid-19 pandemic: descriptive findings from a survey of families in the Born in Bradford study

Abstract: Background : Lockdown measures implemented to contain the Covid-19 virus have increased health inequalities, with families from deprived and ethnically diverse backgrounds most likely to be adversely affected. This paper describes the experiences of families living in the multi-ethnic and deprived city of Bradford, England. Methods : A wave of survey data collection using a combination of email, text and phone with postal follow-up during the first Covid-19 UK lockdown (10th April to 30 th June 2020) with parents participating in two longitudinal studies. Cross tabulations explored variation by ethnicity and financial insecurity. Text from open questions was analysed using thematic analysis. Results : Of 7,652 families invited, 2,144 (28%) participated. The results presented are based on the 2,043 (95%) mothers’ responses: 957 (47%) of whom were of Pakistani heritage, 715 (35%) White British and 356 (18%) other ethnicity 971 (46%) lived in the most deprived decile of material deprivation in England. and 738 (37%) were financially insecure. Many families lived in poor quality (N=574, 28%), overcrowded (N=364, 19%) housing. Food (N=396, 20%), employment (N=728, 37%) and housing (N=204, 10%) insecurities were common, particularly in those who were furloughed, self-employed not working or unemployed. Clinically important depression and anxiety were reported by 372 (19%) and 318 (16%) mothers. Ethnic minority and financially insecure families had a worse experience during the lockdown across all domains, with the exception of mental health which appeared worse in White British mothers. Open text responses corroborated these findings and highlighted high levels of anxiety and fear about Covid-19. Conclusions : There is a need for policy makers and commissioners to better support vulnerable families during and after the pandemic. Future work will use longitudinal data from before the pandemic, and from future surveys during the pandemic, to describe trajectories and the long-term consequences of the pandemic on vulnerable populations.

Longitudinal evidence for persistent anxiety in young adults through COVID-19 restrictions

Abstract: The coronavirus disease 2019 (COVID-19) pandemic and related mitigation measures are associated with poorer mental health in cross-sectional and longitudinal surveys. However, it’s unclear if this represents an adaptive response to an unprecedented event that is short lived, or the beginning of longer mental health problems that persist beyond the initial outbreak of the pandemic. We used data from the index generation of the Avon Longitudinal Study of Parents and Children (young people aged 26-29) to examine anxiety at the beginning of the COVID-19 pandemic (April 2020) and again once restrictions were eased (June 2020). We compared these to two pre-pandemic assessments of anxiety measured 2013/2014 and 2015/17. We found that the percentage of individuals with anxiety was almost double during the COVID-19 assessments compared to pre-pandemic levels, with 15% of individuals having anxiety at both occasions (persistent anxiety). Being female, those with per-existing mental health conditions, a history of financial problems and those who had reported difficulties accessing mental health information were at greater risk of persistent anxiety. Our findings suggest that anxiety in response to COVID-19 is not just an initial reaction but potentially the start of a persistent problem that extends beyond the pandemic. Efforts must be made to address risk groups who could be disproportionally affected as a result of the COVID-19 pandemic and related mitigation measures.

'When will this end? Will it end?' The impact of the March-June 2020 UK Covid-19 lockdown response on mental health: a longitudinal survey of mothers in the Born in Bradford study.

Abstract: Objectives To explore clinically important increases in depression/anxiety from before to during the first UK Covid-19 lockdown and factors related to this change, with a particular focus on ethnic differences. Design Pre-Covid-19 and lockdown surveys nested within two longitudinal Born in Bradford cohort studies. Participants 1,860 mothers with a child aged 0-5 or 9-13, 48% Pakistani heritage Main outcome measures Odds ratios (OR) for a clinically important increase (5 points or more) in depression (PHQ-8) and anxiety (GAD-7) in unadjusted regression analyses, repeated with exposures of interest separated by ethnicity to look for differences in magnitude of associations, and lived experience of mothers captured in open text questions. Results The number of women reporting clinically important depression/anxiety increased from 11% to 20% [10-13%;18-22%] and 10% to 16% [8-11%; 15-18%]) respectively. Increases in depression/anxiety were associated with: loneliness (OR: 8.37, [5.70-12.27]; 8.50, [5.71-12.65] respectively); financial (6.23, [3.96-9.80]; 6.03, [3.82-9.51]); food (3.33 [2.09-5.28]; 3.46 [2.15-5.58]); and housing insecurity (3.29 [2.36-4.58]; 3.0 [2.11-4.25]); a lack of physical activity (3.13 [2.15-4.56]; 2.55 [1.72-3.78]); and a poor partner relationship (3.6 [2.44-5.43]; 5.1 [3.37-7.62]. The magnitude of associations between key exposures and worsening mental health varied between ethnic groups. Responses to open text questions illustrated a complex inter-play of challenges contributing to mental ill health including: acute health anxieties; the mental load of managing multiple responsibilities; loss of social support and coping strategies; pressures of financial and employment insecurity; and being unable to switch off from the pandemic. Conclusions Mental ill health has worsened for many during the Covid-19 lockdown, particularly in those who are lonely and economically insecure. The magnitude of associations between key exposures and worsening mental health varied between ethnic groups. Mental health problems may have longer term consequences for public health and interventions that address the potential causes are needed. STRENGTHS AND LIMITATIONS OF THIS STUDY Three key longitudinal studies have highlighted that the Covid-19 pandemic and lockdowns have had a negative impact on mental health, particular in younger adults, women and those from low socio-economic circumstances, but with participants of predominantly White European ethnicity. The Born in Bradford research programme offers a unique opportunity to investigate the impact of Covid-19 lockdown on mental health in a deprived and ethnically diverse population in whom mental ill health is often reported to be more prevalent. This is a longitudinal study containing linked data collected before the Covid-19 pandemic and during the March-June 2020 lockdown which has allowed us to explore change over that time period in a highly ethnically diverse population, the majority of whom live in the most deprived centiles in the UK. Respondents in this study were mothers of children aged 0-5 and/or 9-13 which may limit the wider generalisability, though our findings are broadly similar (in prevalence and associations) to those from another longitudinal study that included adult men and women. We are not aware of other studies that have explored longitudinal change in mental health from before to during the Covid-19 lockdown in a similar ethnically diverse and deprived population.

Identifying potential causal effects of age at menarche: a Mendelian randomization phenome-wide association study

Abstract: Background: Age at menarche has been associated with various health outcomes. We aimed to identify potential causal effects of age at menarche on health-related traits in a hypothesis-free manner. Methods: We conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) of age at menarche with 17,893 health-related traits in UK Biobank (n = 181,318) using PHESANT. The exposure of interest was the genetic risk score for age at menarche. We conducted a second MR-pheWAS after excluding SNPs associated with BMI from the genetic risk score, to examine whether results might be due to the genetic overlap between age at menarche and BMI. We followed up a subset of health-related traits to investigate MR assumptions and seek replication in independent study populations. Results: Of the 17,893 tests performed in our MR-pheWAS, we identified 619 associations with the genetic risk score for age at menarche at a 5% false discovery rate threshold, of which 295 were below a Bonferroni-corrected P value threshold. These included potential effects of younger age at menarche on lower lung function, higher heel bone-mineral density, greater burden of psychosocial/mental health problems, younger age at first birth, higher risk of childhood sexual abuse, poorer cardiometabolic health, and lower physical activity. After exclusion of variants associated with BMI, the genetic risk score for age at menarche was related to 37 traits at a 5% false discovery rate, of which 29 were below a Bonferroni-corrected P value threshold. We attempted to replicate findings for bone-mineral density, lung function, neuroticism, and childhood sexual abuse using 5 independent cohorts/consortia. While estimates for lung function, higher bone-mineral density, neuroticism, and childhood sexual abuse in replication cohorts were consistent with UK Biobank estimates, confidence intervals were wide and often included the null. Conclusions: The genetic risk score for age at menarche was related to a broad range of health-related traits. Follow-up analyses indicated imprecise evidence of an effect of younger age at menarche on greater bone-mineral density, lower lung function, higher neuroticism score, and greater risk of childhood sexual abuse in the smaller replication samples available; hence, these findings need further exploration when larger independent samples become available.

4-Hydroxyglutamate is a novel predictor of pre-eclampsia.

Abstract: BACKGROUND Pre-term pre-eclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide. A multi-centre randomized-controlled trial has shown that first-trimester screening followed by treatment of high-risk women with aspirin reduces the risk of pre-term pre-eclampsia. However, the biomarkers currently employed in risk prediction are only weakly associated with the outcome. METHODS We conducted a case-cohort study within the Pregnancy Outcome Prediction study to analyse untargeted maternal serum metabolomics in samples from 12, 20, 28 and 36 weeks of gestational age (wkGA) in women with pre-eclampsia delivering at term (n = 165) and pre-term (n = 29), plus a random sample of the cohort (n = 325). We used longitudinal linear mixed models to identify candidate metabolites at 20/28 wkGA that differed by term pre-eclampsia status. Candidates were validated using measurements at 36 wkGA in the same women. We then tested the association between the 12-, 20- and 28-wkGA measurements and pre-term pre-eclampsia. We externally validated the association using 24- to 28-wkGA samples from the Born in Bradford study (25 cases and 953 controls). RESULTS We identified 100 metabolites that differed most at 20/28 wkGA in term pre-eclampsia. Thirty-three of these were validated (P < 0.0005) at 36 wkGA. 4-Hydroxyglutamate and C-glycosyltryptophan were independently predictive at 36 wkGA of term pre-eclampsia. 4-Hydroxyglutamate was also predictive (area under the receiver operating characteristic curve, 95% confidence interval) of pre-term pre-eclampsia at 12 (0.673, 0.558-0.787), 20 (0.731, 0.657-0.806) and 28 wkGA (0.733, 0.627-0.839). The predictive ability of 4-hydroxyglutamate at 12 wkGA was stronger than two existing protein biomarkers, namely PAPP-A (0.567, 0.439-0.695) and placenta growth factor (0.589, 0.463-0.714). Finally, 4-hydroxyglutamate at 24-28 wkGA was positively associated with pre-eclampsia (term or pre-term) among women from the Born in Bradford study. CONCLUSIONS 4-hydroxyglutamate is a novel biochemical predictor of pre-eclampsia that provides better first-trimester prediction of pre-term disease than currently employed protein biomarkers.

Population implications of cessation of IVF during the COVID-19 pandemic.

Abstract: Research question Discontinuation of IVF cycles has been part of the radical transformation of healthcare provision to enable reallocation of staff and resources to deal with the COVID-19 pandemic. This study sought to estimate the impact of cessation of treatment on individual prognosis and US population live birth rates. Design Data from 271,438 ovarian stimulation UK IVF cycles was used to model the effect of age as a continuous, yet non-linear, function on cumulative live birth rate. This model was recalibrated to cumulative live birth rates reported for the 135,673 stimulation cycles undertaken in the USA in 2016, with live birth follow-up to October 2018. The effect of a 1-month, 3-month and 6-month shutdown in IVF treatment was calculated as the effect of the equivalent increase in a woman's age, stratified by age group. Results The average reduction in cumulative live birth rate would be 0.3% (95% confidence interval [CI] 0.3–0.3), 0.8% (95% CI 0.8–0.8) and 1.6% (95% CI 1.6–1.6) for 1-month, 3-month and 6-month shutdowns. This corresponds to a reduction of 369 (95% CI 360–378), 1098 (95% CI 1071–1123) and 2166 (95% CI 2116–2216) live births in the cohort, respectively. Th e greatest contribution to this reduction was from older mothers. Conclusions The study demonstrated that the discontinuation of fertility treatment for even 1 month in the USA could result in 369 fewer women having a live birth, due to the increase in patients’ age during the shutdown. As a result of reductions in cumulative live birth rate, more cycles may be required to overcome infertility at individual and population levels.

Age at period cessation and trajectories of cardiovascular risk factors across mid and later life.

Abstract: Objective To examine the association between age at period cessation and trajectories of anthropometry, blood pressure, lipids and glycated haemoglobin (HbA1c) from midlife to age 69 years. Methods We used data from the UK Medical Research Council National Survey of Health and Development to examine the association between age at period cessation and trajectories of systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI) and waist circumference (WC) from 36 to 69 years and trajectories of triglyceride, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and HbA1c from 53 to 69 years. Results We found no evidence that age at period cessation was associated with trajectories of log triglyceride, LDL-C and HDL-C from 53 to 69 years and trajectories of SBP or DBP from 36 to 69 years, regardless of whether period cessation occurred naturally or due to hysterectomy. While we found some evidence of associations of age at period cessation with log BMI, log WC and log HbA1c, patterns were not consistent and differences were small at age 69 years, with confidence intervals that spanned the null value. Conclusion How and when women experience period cessation is unlikely to adversely affect conventional cardiovascular risk factors across mid and later life. Women and clinicians concerned about the impact of type and timing of period cessation on conventional cardiovascular intermediates from midlife should be reassured that the impact over the long term is small.

UK stillbirth trends in over 11 million births provide no evidence to support effectiveness of Growth Assessment Protocol program.

Abstract: Objective Use of the Growth Assessment Protocol (GAP) has increased internationally under the assumption that it reduces the stillbirth rate. The evidence for this is limited and based largely on an ecological time-trend study. Discordance in the uptake of the GAP program between Scotland and England/Wales enabled us to assess the assertion that implementation of GAP leads to a reduced stillbirth rate. Methods We analyzed data from the National Records for Scotland and the Office for National Statistics on the number of singleton maternities and stillbirths in Scotland and in England and Wales, respectively, from 1 January 2000 to 31 December 2015. National uptake of the GAP program over time in each of the regions was recorded. Stillbirth rate per 1000 maternities was calculated, according to year of delivery, and compared between Scotland and England/Wales. Results During the study period, there were 870 632 singleton maternities in Scotland, of which 4243 were stillbirths, and there were 10 469 120 singleton maternities in England and Wales, of which 51 562 were stillbirths. There was a marked difference in uptake of the GAP program between the two regions, with substantially fewer maternity units in Scotland implementing the program. Stillbirth rates were static up to 2010, with a decline thereafter in both regions, to 3.75 (95% CI, 3.25-4.30) per 1000 maternities in Scotland and 4.30 (95% CI, 4.15-4.46) per 1000 maternities in England and Wales in 2015. From 2010 onwards, the decline in Scotland was faster, equating to 48 (95% CI, 47.9-48.1) fewer stillbirths per 100 000 maternities in Scotland than in England and Wales from 2010 to 2015 compared with 2000 to 2009. Conclusions We observed a decline in stillbirth rate in England and Wales, which coincided with implementation of the GAP program. However, a concurrent decline in stillbirth rate was observed in Scotland in the absence of increased implementation of GAP. The secular rates of change in stillbirth rate in England and Wales cannot be used to infer efficacy of the GAP program. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Physical Activity Throughout Adolescence and Peak Hip Strength in Young Adults

Abstract: Importance Peak bone strength, which occurs in early adulthood, is an important marker of the future risk of osteoporosis. It is therefore important to identify modifiable early life factors that are associated with the attainment of peak hip strength. Objective To investigate the association of time spent in moderate to vigorous–intensity and light-intensity physical activity throughout adolescence with peak hip strength in adulthood. Design, Setting, and Participants The Avon Longitudinal Study of Parents and Children is a prospective birth cohort study that initially recruited all pregnant women residing within the catchment area of 3 health authorities in southwest England who had an expected delivery date between April 1, 1991, and December 31, 1992. In total, 15 454 eligible pregnant women were enrolled, and 15 589 infants were delivered. Of those, 14 901 infants were alive at age 1 year. The present analysis examined 2569 healthy offspring who had valid physical activity measurements obtained during a clinical assessment for at least 1 age (12, 14, 16, and/or 25 years), with up to 4 repeated accelerometer assessments performed (1 per age-associated clinical visit). Data were analyzed from June 2019 to June 2020. Exposures Trajectories of accelerometer-assessed time spent in moderate to vigorous–intensity and light-intensity physical activity at ages 12, 14, 16, and 25 years (measured in minutes per day) were identified using latent trajectory modeling. Moderate to vigorous–intensity and light-intensity physical activity were determined using established thresholds of acceleration counts per minute. Main Outcomes and Measures Femur neck bone mineral density (BMD; measured in g/cm2) at age 25 years assessed by dual-energy radiography absorptiometry scans of the hip. Results A total of 2569 participants (1588 female participants [62%]) were included in the analysis. Male participants spent more time in moderate to vigorous–intensity activity at each age and had greater adult femur neck BMD than female participants. For each sex, 3 moderate to vigorous–intensity trajectory subgroups and 3 light-intensity trajectory subgroups were identified. With regard to the moderate to vigorous–intensity trajectories, most male participants (85%) were in the low adolescent subgroup, with only 6% and 9% in the high early-adolescent and high mid-adolescent subgroups, respectively. Moderate to vigorous–intensity trajectories in female participants were divided into low adolescent-low adult (73%), low adolescent-high adult (8%), and high adolescent (19%) subgroups. Light-intensity physical activity trajectories were classified into low nonlinear, moderate decreasing, and high decreasing subgroups for both sexes. Femur neck BMD in male participants was greater in the high early-adolescent subgroup (0.38 g/cm2; 95% CI, 0.11-0.66 g/cm2) and the high mid-adolescent subgroup (0.33 g/cm2; 95% CI, 0.07-0.60 g/cm2) compared with the low adolescent (reference) subgroup. Femur neck BMD in female participants was greater in the high adolescent subgroup (0.28 g/cm2; 95% CI, 0.15-0.41 g/cm2) but not in the low adolescent-high adult subgroup (−0.12 g/cm2; 95% CI, −0.44 to 0.20 g/cm2) compared with the low adolescent-low adult (reference) subgroup. A sensitivity analysis using a negative-outcome control variable to explore unmeasured confounding supported these findings. The light-intensity trajectories were not associated with femur neck BMD; for example, differences in femur neck BMD between the high decreasing and low nonlinear subgroups were 0.16 g/cm2(95% CI, −0.08 to 0.40 g/cm2) in male participants and 0.20 g/cm2(95% CI, −0.05 to 0.44 g/cm2) in female participants. Conclusions and Relevance Supporting high-intensity physical activity throughout early life may help to maximize peak hip strength and prevent osteoporosis in later life. Replication of our findings in independent studies will be important.

The Born in Bradford COVID-19 Research Study: Protocol for an adaptive mixed methods research study to gather actionable intelligence on the impact of COVID-19 on health inequalities amongst families living in Bradford [version 1;peer review: awaiting peer review]

Abstract: The UK COVID-19 lockdown has included restricting social movement and interaction to slow the spread of disease and reduce demand on NHS acute services It is likely that the impacts of restrictions will hit the least advantaged disproportionately and will worsen existing structural inequalities amongst deprived and ethnic minority groups The aim of this study is to deliver rapid intelligence to enable an effective COVID-19 response, including co-production of interventions, that address key issues in the City of Bradford, UK, and nationally In the longer term we aim to understand the impacts of the response on health trajectories and inequalities in these In this paper we describe our approach and protocol We plan an adaptive longitudinal mixed methods approach embedded with Born in Bradford (BiB) birth cohorts which have rich existing data (including questionnaire, routine health and biobank) All work packages (WP) interact and are ongoing WP1 uses co-production and engagement methods with communities, decision-makers and researchers to continuously set (changing) research priorities and will, longer-term, co-produce interventions to aid the City’s recovery In WP2 repeated quantitative surveys will be administered during lockdown (April-June 2020), with three repeat surveys until 12 months post-lockdown with an ethnically diverse pool of BiB participants (parents, children aged 9-13 years, pregnant women: total sample pool N=7,652, N=5,154, N=1,800) A range of health, social, economic and education outcomes will be assessed In WP3 priority topics identified in WP1 and WP2 will be explored qualitatively Initial priority topics include children’s mental wellbeing, health beliefs and the peri/post-natal period Feedback loops will ensure findings are fed directly to decision-makers and communities (via WP1) to enable co-production of acceptable interventions and identify future priority topic areas Findings will be used to aid development of local and national policy to support recovery from the pandemic and minimise health inequalities