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Abstract Background Pinpointing genetic impacts on DNA methylation can improve our understanding of pathways that underlie gene regulation and disease risk. Results We report heritability and methylation quantitative trait locus (meQTL) analysis at 724,499 CpGs profiled with the Illumina Infinium MethylationEPIC array in 2358 blood samples from three UK cohorts. Methylation levels at 34.2% of CpGs are affected by SNPs, and 98% of effects are cis-acting or within 1 Mbp of the tested CpG. Our results are consistent with meQTL analyses based on the former Illumina Infinium HumanMethylation450 array. Both SNPs and CpGs with meQTLs are overrepresented in enhancers, which have improved coverage on this platform compared to previous approaches. Co-localisation analyses across genetic effects on DNA methylation and 56 human traits identify 1520 co-localisations across 1325 unique CpGs and 34 phenotypes, including in disease-relevant genes, such as USP1 and DOCK7 (total cholesterol levels), and ICOSLG (inflammatory bowel disease). Enrichment analysis of meQTLs and integration with expression QTLs give insights into mechanisms underlying cis-meQTLs (e.g. through disruption of transcription factor binding sites for CTCF and SMC3) and trans-meQTLs (e.g. through regulating the expression of ACD and SENP7 which can modulate DNA methylation at distal sites). Conclusions Our findings improve the characterisation of the mechanisms underlying DNA methylation variability and are informative for prioritisation of GWAS variants for functional follow-ups. The MeQTL EPIC Database and viewer are available online at https://epicmeqtl.kcl.ac.uk .

BackgroundBlood pressure, grip strength and lung function are frequently assessed in longitudinal population studies, but the measurement devices used differ between studies and within studies over time. We aimed to compare measurements ascertained from different commonly used devices.MethodsWe used a randomised cross-over study. Participants were 118 men and women aged 45-74 years whose blood pressure, grip strength and lung function were assessed using two sphygmomanometers (Omron 705-CP and Omron HEM-907), four handheld dynamometers (Jamar Hydraulic, Jamar Plus+ Digital, Nottingham Electronic and Smedley) and two spirometers (Micro Medical Plus turbine and ndd Easy on-PC ultrasonic flow-sensor) with multiple measurements taken on each device. Mean differences between pairs of devices were estimated along with limits of agreement from Bland-Altman plots. Sensitivity analyses were carried out using alternative exclusion criteria and summary measures, and using multilevel models to estimate mean differences.ResultsThe mean difference between sphygmomanometers was 3.9mmHg for systolic blood pressure (95% Confidence Interval (CI):2.5,5.2) and 1.4mmHg for diastolic blood pressure (95% CI:0.3,2.4), with the Omron HEM-907 measuring higher. For maximum grip strength, the mean difference when either one of the electronic dynamometers was compared with either the hydraulic or spring-gauge device was 4-5kg, with the electronic devices measuring higher. The differences were small when comparing the two electronic devices (difference = 0.3kg, 95% CI:-0.9,1.4), and when comparing the hydraulic and spring-gauge devices (difference = 0.2kg, 95% CI:-0.8,1.3). In all cases limits of agreement were wide. The mean difference in FEV1 between spirometers was close to zero (95% CI:-0.03,0.03), limits of agreement were reasonably narrow, but a difference of 0.47l was observed for FVC (95% CI:0.53,0.42), with the ndd Easy on-PC measuring higher.ConclusionOur study highlights potentially important differences in measurement of key functions when different devices are used. These differences need to be considered when interpreting results from modelling intra-individual changes in function and when carrying out cross-study comparisons, and sensitivity analyses using correction factors may be helpful.

IntroductionThe one-legged balance test is a common screening tool for fall risk. Yet, there is little empirical evidence assessing its prognostic ability. The study aims were to assess the prognostic accuracy of one-legged balance performance in predicting falls and identify optimal cut-points to classify those at greater risk.MethodsData from up to 2,000 participants from a British birth cohort born in 1,946 were used. The times an individual could stand on one leg with their eyes open and closed were recorded (max: 30 s) at ages 53 and 60–64. Number of falls in the past year was self-reported at ages 53, 60–64 and 68; recurrent falls (0–1 vs. 2+) and any fall (0 vs. 1+) were considered binary outcomes. Four longitudinal associations between balance times and subsequent falls were investigated (age 53 → 60–64; age 53 → 68; age 60–64 → 68; age 53 & 60–64 → 68). For each temporal association, areas under the curve (AUC) were calculated and compared for a base sex-only model, a sex and balance model, a sex and fall history model and a combined model of sex, balance and fall history. The Liu method was used to identify optimal cut-points and sensitivity, specificity, and AUC at corresponding cut-points.ResultsMedian eyes open balance time was 30 s at ages 53 and 60–64; median eyes closed balance times were 5 s and 3 s, respectively. The predictive ability of balance tests in predicting either fall outcome was poor (AUC range for sex and balance models: 0.577–0.600). Prognostic accuracy consistently improved by adding fall history to the model (range: 0.604–0.634). Optimal cut-points ranged from 27 s to 29 s for eyes open and 3 s to 5 s for eyes closed; AUC consistently indicated that using “optimal” cut-points to dichotomise balance time provided no discriminatory ability (AUC range:0.42–0.47), poor sensitivity (0.38–0.61) and poor specificity (0.23–0.56).DiscussionDespite previous observational evidence showing associations between better one-legged balance performance and reduced fall risk, the one-legged balance test had limited prognostic accuracy in predicting recurrent falls. This contradicts ongoing translation of this test into clinical screening tools for falls and highlights the need to consider new and existing screening tools that can reliably predict fall risk.

Abstract Background Older adults are advised to attend a number of preventive health checks to preserve health and identify risk factors for disease. Previous research has identified a number of health and social factors, labelled as predisposing, enabling and need factors, using Andersen’s Behavioural Model of Health Service Use, that are associated with health care utilisation. We aimed to assess associations between factors from childhood and adulthood, and health check attendance in later life in a British birth cohort study. Methods For 2370 study members from the MRC National Survey of Health and Development (NSHD), health check attendance was assessed at age 68. Study members were asked if they: attended blood pressure and cholesterol checks, had their eyes tested, received the influenza vaccine, attended colon cancer screening and dental checks. Health and social factors from childhood and adulthood were used in binomial regression models to test associations with health check attendance in men and women. Results Health check attendance was high; 41% reported attending all six health checks within the recommended time frame. In multivariable models, being a non-smoker and having more health conditions in adulthood were associated with greater health check attendance in men and women. In women, childhood socioeconomic advantage, being more physically active in midlife and previously attending screening procedures, and in men, greater self-organisation in adolescence and being married were associated with attending more health checks in later life, following adjustments for childhood and adulthood factors. Conclusions A number of predisposing, enabling and need factors from childhood and adulthood were found to be associated with health check attendance at age 68, demonstrating the relevance of applying a life course perspective to Andersen’s model in investigating health check attendance in later life. Health related factors were found to be stronger correlates of health check attendance than socioeconomic factors.

BMI is correlated with circulating metabolites, but few studies discuss other adiposity measures, and little is known about metabolomic correlates of BMI from early life. We investigated associations between different adiposity measures, BMI from childhood through adulthood, and metabolites quantified from serum using 1H NMR spectroscopy in 900 British men and women aged 60–64. We assessed BMI, waist-to-hip ratio (WHR), android-to-gynoid fat ratio (AGR), and BMI from childhood through adulthood. Linear regression with Bonferroni adjustment was performed to assess adiposity and metabolites. Of 233 metabolites, 168; 126; and 133 were associated with BMI, WHR, and AGR at age 60–64, respectively. Associations were strongest for HDL, particularly HDL particle size—e.g., there was 0.08 SD decrease in HDL diameter (95% CI: 0.07–0.10) with each unit increase in BMI. BMI-adjusted AGR or WHR were associated with 31 metabolites where there was no metabolome-wide association with BMI. We identified inverse associations between BMI at age 7 and glucose or glycoprotein at age 60–64 and relatively large LDL cholesteryl ester with postadolescent BMI gains. In summary, we identified metabolomic correlates of central adiposity and earlier-life BMI. These findings support opportunities to leverage metabolomics in early prevention of cardiovascular risk attributable to body fatness.

Carotid intima-media thickness (cIMT) and plaque are associated with subclinical atherosclerosis and coronary heart disease (CHD). Here, the authors identify and prioritize genetic loci for cIMT and plaque by GWAS and colocalization approaches and further demonstrate genetic correlation with CHD and stroke.

Abstract Objective Identifying and recruiting people with early pre-symptomatic Alzheimer’s disease to neuroimaging research studies is increasingly important. The extent to which results of these studies can be generalised depends on the recruitment and representativeness of the participants involved. We now report the recruitment and participation patterns from a neuroscience sub-study of the MRC National Survey of Health and Development, “Insight 46”. This study aimed to recruit 500 participants for extensive clinical and neuropsychological testing, and neuroimaging. We investigate how sociodemographic factors, health conditions and health-related behaviours predict participation at different levels of recruitment. Results We met our target recruitment (n = 502). Higher educational attainment and non-manual socio-economic position (SEP) were consistent predictors of recruitment. Health-related variables were also predictive at every level of recruitment; in particular higher cognition, not smoking and better self-rating health. Sex and APOE-e4 status were not predictors of participation at any level. Whilst recruitment targets were met, individuals with lower SEP, lower cognition, and more health problems are under-represented in Insight 46. Understanding the factors that influence recruitment are important when interpreting results; for Insight 46 it is likely that health-related outcomes and life course risks will under-estimate those seen in the general population.

Objectives To investigate whether cross-sectional and longitudinal associations of body mass index (BMI) and waist circumference (WC) with back pain change with age and extend into later life.Design British birth cohort study.Setting England, Scotland and Wales.Participants Up to 3426 men and women from the MRC National Survey of Health and Development.Primary outcome measures Back pain (sciatica, lumbago or recurring/severe backache all or most of the time) was self-reported during nurse interviews at ages 36, 43, 53 and 60–64 years and in a postal questionnaire using a body manikin at age 68.Results Findings from mixed-effects logistic regression models indicated that higher BMI was consistently associated with increased odds of back pain across adulthood. Sex-adjusted ORs of back pain per 1 SD increase in BMI were: 1.13 (95% CI: 1.01 to 1.26), 1.11 (95% CI: 1.00 to 1.23), 1.17 (95% CI: 1.05 to 1.30), 1.31 (95% CI: 1.15 to 1.48) and 1.08 (95% CI: 0.95 to 1.24) at ages 36, 43, 53, 60–64 and 68–69, respectively. Similar patterns of associations were observed for WC. These associations were maintained when potential confounders, including education, occupational class, height, cigarette smoking status, physical activity and symptoms of anxiety and depression were accounted for. BMI showed stronger associations than WC in models including both measures.Conclusions These findings demonstrate that higher BMI is a persistent risk factor for back pain across adulthood. This highlights the potential lifelong consequences on back pain of the rising prevalence of obesity within the population.

Introduction: Despite its associations with falls, disability, and mortality, balance is an under-recognized and frequently overlooked aspect of aging. Studies investigating associations between factors across life and balance are limited. Understanding the factors related to balance performance could help identify protective factors and appropriate interventions across the life course. This study aimed to: (i) identify socioeconomic, anthropometric, behavioral, health, and cognitive factors that are associated with one-legged balance performance; and (ii) explore how these associations change with age.Methods: Data came from 3,111 members of the MRC National Survey of Health and Development, a British birth cohort study. Multilevel models examined how one-legged standing balance times (assessed at ages 53, 60–64, and 69) were associated with 15 factors across life: sex, maternal education (4 years), paternal occupation (4 years), own education (26 years), own occupation (53 years), and contemporaneous measures (53, 60–64, 69 years) of height, BMI, physical activity, smoking, diabetes, respiratory symptoms, cardiovascular events, knee pain, depression and verbal memory. Age and sex interactions with each variable were assessed.Results: Men had 18.8% (95%CI: 13.6, 23.9) longer balance times than women at age 53, although this difference decreased with age (11.8% at age 60–64 and 7.6% at age 69). Disadvantaged socioeconomic position in childhood and adulthood, low educational attainment, less healthy behaviors, poor health status, lower cognition, higher body mass index (BMI), and shorter height were associated with poorer balance at all three ages. For example, at age 53, those from the lowest paternal occupational classes had 29.6% (22.2, 38.8) worse balance than those from the highest classes. Associations of balance with socioeconomic indicators, cognition and physical activity became smaller with age, while associations with knee pain and depression became larger. There were no sex differences in these associations. In a combined model, the majority of factors remained associated with balance.Discussion: This study identified numerous risk factors across life that are associated with one-legged balance performance and highlighted diverse patterns of association with age, suggesting that there are opportunities to intervene in early, mid and later life. A multifactorial approach to intervention, at both societal and individual levels, may have more benefit than focusing on a single risk factor.

Abstract We aimed to examine whether back pain across adulthood was associated with spine shape at age 60–64 years. Data were from 1405 participants in the MRC National Survey of Health and Development, a nationally representative British birth cohort. Back pain was ascertained during nurse interviews at ages 36, 43, 53 and 60–64 years. Cumulative exposure to back pain was then derived by counting the number of ages at which back pain was reported. Statistical shape modelling was used to characterise thoracolumbar spine shape using lateral dual-energy x-ray absorptiometry images which were ascertained at age 60–64 years. Linear regression models were used to test associations of spine shape modes (SM) with: (1) cumulative exposure to back pain; (2) back pain reports during different periods of adulthood. After adjusting for sex, higher cumulative exposure to back pain across adulthood was associated with wedge-shaped L4-5 disc (lower SM4 scores) and smaller disc spaces (higher SM8 scores) in both sexes. In addition, reporting of back pain at ages 53 and/or 60–64 years was associated with smaller L4-5 disc space (lower SM6 scores) in men but not women. These findings suggest that back pain across adulthood may be associated with specific variations in spine shapes in early old age.

Abstract Background Studies have shown that alcohol intake trajectories differ in their associations with biomarkers of cardiovascular functioning, but it remains unclear if they also differ in their relationship to actual coronary heart disease (CHD) incidence. Using multiple longitudinal cohort studies, we evaluated the association between long-term alcohol consumption trajectories and CHD. Methods Data were drawn from six cohorts (five British and one French). The combined analytic sample comprised 35,132 individuals (62.1% male; individual cohorts ranging from 869 to 14,247 participants) of whom 4.9% experienced an incident (fatal or non-fatal) CHD event. Alcohol intake across three assessment periods of each cohort was used to determine participants’ intake trajectories over approximately 10 years. Time to onset for (i) incident CHD and (ii) fatal CHD was established using surveys and linked medical record data. A meta-analysis of individual participant data was employed to estimate the intake trajectories' association with CHD onset, adjusting for demographic and clinical characteristics. Results Compared to consistently moderate drinkers (males: 1–168 g ethanol/week; females: 1–112 g ethanol/week), inconsistently moderate drinkers had a significantly greater risk of incident CHD [hazard ratio (HR) = 1.18, 95% confidence interval (CI) = 1.02–1.37]. An elevated risk of incident CHD was also found for former drinkers (HR = 1.31, 95% CI = 1.13–1.52) and consistent non-drinkers (HR = 1.47, 95% CI = 1.21–1.78), although, after sex stratification, the latter effect was only evident for females. When examining fatal CHD outcomes alone, only former drinkers had a significantly elevated risk, though hazard ratios for consistent non-drinkers were near identical. No evidence of elevated CHD risk was found for consistently heavy drinkers, and a weak association with fatal CHD for inconsistently heavy drinkers was attenuated following adjustment for confounding factors. Conclusions Using prospectively recorded alcohol data, this study has shown how instability in drinking behaviours over time is associated with risk of CHD. As well as individuals who abstain from drinking (long term or more recently), those who are inconsistently moderate in their alcohol intake have a higher risk of experiencing CHD. This finding suggests that policies and interventions specifically encouraging consistency in adherence to lower-risk drinking guidelines could have public health benefits in reducing the population burden of CHD. The absence of an effect amongst heavy drinkers should be interpreted with caution given the known wider health risks associated with such intake. Trial registration ClinicalTrials.gov, NCT03133689.

Abstract Background Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Here, we investigate whether a sub-set of triacylglycerols (TAGs) were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. Results We conduct direct infusion mass spectrometry of lipids in plasma to study the association between specific TAGs and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study and evaluate clustering of TAGs in the National Survey of Health and Development UK cohort. We find that TAGs containing saturated and monounsaturated fatty acids with 16–18 carbons are specifically associated with hepatic steatosis. These TAGs are additionally associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL is measured in hyperphagic ob/ob mice, mice on a western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs are increased in plasma from patients with biopsy-confirmed steatosis. Conclusion A subset of TAGs is associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in western populations is in part driven by increased DNL following carbohydrate rich meals in addition to the consumption of saturated fat.

Abstract Background To describe the development of polypharmacy and its components in a British birth cohort in its seventh decade and to investigate socioeconomic and gender differences independent of disease burden. Methods Data from the MRC National Survey for Health and Development were analysed to determine the prevalence and composition of polypharmacy at age 69 and changes since ages 60 to 64. Multinomial regression was used to test associations between gender, education and occupational social class and total, cardiological and non-cardiological polypharmacy controlling for disease burden. Results At age 69, 22.8% of individuals were taking more than 5 medications. There was an increase in the use of 5 to 8 medications (+ 2.3%) and over 9 medications (+ 0.8%) between ages 60–64 and 69. The greatest increases were found for cardiovascular (+ 13.4%) and gastrointestinal medications (+ 7.3%). Men experienced greater cardiological polypharmacy, women greater non-cardiological polypharmacy. Higher levels of education were associated with lower polypharmacy independent of disease burden, with strongest effects seen for over five cardiological medications (RRR 0.3, 95% CI 0.2–0.5 p

Abstract Background Delirium affects 25% of older inpatients and is associated with long-term cognitive impairment and future dementia. However, no population studies have systematically ascertained cognitive function before, cognitive deficits during, and cognitive impairment after delirium. Therefore, there is a need to address the following question: does delirium, and its features (including severity, duration, and presumed aetiologies), predict long-term cognitive impairment, independent of cognitive impairment at baseline? Methods The Delirium and Population Health Informatics Cohort (DELPHIC) study is an observational population-based cohort study based in the London Borough of Camden. It is recruiting 2000 individuals aged ≥70 years and prospectively following them for two years, including daily ascertainment of all inpatient episodes for delirium. Daily inpatient assessments include the Memorial Delirium Assessment Scale, the Observational Scale for Level of Arousal, and the Hierarchical Assessment of Balance and Mobility. Data on delirium aetiology is also collected. The primary outcome is the change in the modified Telephone Interview for Cognitive Status at two years. Discussion DELPHIC is the first population sample to assess older persons before, during and after hospitalisation. The cumulative incidence of delirium in the general population aged ≥70 will be described. DELPHIC offers the opportunity to quantify the impact of delirium on cognitive and functional outcomes. Overall, DELPHIC will provide a real-time public health observatory whereby information from primary, secondary, intermediate and social care can be integrated to understand how acute illness is linked to health and social care outcomes.

High impact physical activity (PA) is thought to benefit bone. We examined associations of lifetime walking and weight bearing exercise with accelerometer-measured high impact and overall PA in later life. Data were from 848 participants (66.2% female, mean age=72.4years) from the Cohort for Skeletal Health in Bristol and Avon, Hertfordshire Cohort Study and MRC National Survey of Health and Development. Acceleration peaks from seven-day hip-worn accelerometer recordings were used to derive counts of high impact and overall PA. Walking and weight bearing exercise up to age 18, between 18–29, 30–49 and since age 50 were recalled using questionnaires. Responses in each age category were dichotomised and cumulative scores derived. Linear regression was used for analysis. Greater lifetime walking was related to higher overall, but not high impact PA, whereas greater lifetime weight bearing exercise was related to higher overall and high impact PA. For example, fully-adjusted differences in log-overall and log-high impact PA respectively for highest versus lowest lifetime scores were: walking [0.224 (0.087, 0.362) and 0.239 (−0.058, 0.536)], and weight bearing exercise [0.754 (0.432, 1.076) and 0.587 (0.270, 0.904)]. For both walking and weight bearing exercise, associations were strongest in the ‘since age 50’ category. Those reporting the most walking and weight bearing exercise since age 50 had highest overall and high impact PA, e.g. fully-adjusted difference in log-high impact PA versus least walking and weight bearing exercise=0.588 (0.226, 0.951). Promoting walking and weight bearing exercise from midlife may help increase potentially osteogenic PA levels in later life. Keywords: Accelerometer, Exercise, Life course, Physical activity

Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

Abstract Background Studies assessing associations of childhood psychosocial adversity (e.g. sexual abuse, physical neglect, parental death), as opposed to socioeconomic adversity, with cardiovascular disease (CVD) risk factors in adulthood are scarce. We aimed to assess associations of various forms of psychosocial adversity and cumulative adversity in childhood, with multiple CVD risk factors in mid-life. Methods Participants were from the MRC National Survey of Health and Development. Childhood psychosocial risk factors were reported prospectively by parents from 1950-1957, and retrospectively by participants at mean age 43 years in 1989. CVD risk factors were assessed at mean age 60-64 years in 2006-2011. Associations of a summary score of total psychosocial adversity and CVD risk in adulthood were assessed. Results There was no consistent evidence that cumulative psychosocial adversity, nor any specific form of psychosocial adversity in childhood, was associated with CVD risk factors in late adulthood. There was some evidence that parental death in the first 15 years was associated with higher SBP (Beta: 0.23, 95% confidence interval: 0.06 to 0.40, P=0.01) and DBP (Beta: 0.15, 95% confidence interval: -0.01 to 0.32, P=0.07). Conclusions We found no evidence that exposure to greater psychosocial adversity, or specific forms of psychosocial adversity during childhood is associated with adult CVD risk factors. Further large population studies are needed to clarify whether parental death is associated with higher systolic and diastolic blood pressure.

Abstract The objective was to examine whether: (1) statin use was associated with muscle related outcomes at age 60–64, (2) these associations were modified by 25-hydroxyvitamin D (25(OH)D) status and explained by inflammation, body-size or lifestyle in a British birth cohort. Markers of myalgia (intrusive body pain) and myopathy (self-reported and performance-based measures) were examined in 734 men and 822 women (MRC National Survey of Health and Development). Statin use was associated with intrusive body pain, difficulty climbing stairs and slower chair rise speed. Some associations were modified by 25(OH)D e.g. the association with intrusive body pain was evident in the insufficient (13–20 ng/l) and deficient (20 ng/l (OR = 0.8,95% CI 0.5–1.4) (p = 0.003 for interaction). Associations were maintained in fully adjusted models of intrusive body pain and difficulty climbing stairs, but for chair rise speed they were fully accounted for by inflammation, body-size and lifestyle. In a nationally representative British population in early old age, statin use was associated with lower limb muscle-related outcomes, and some were only apparent in those with 25(OH)D status below 20 ng/l. Given 25(OH)D is modifiable in clinical practice, future studies should consider the links between 25(OH)D status and muscle related outcomes.

Heart rate variability (HRV) describes the individual variation in cardiac cycle duration and is a measure of vagal control of heart rate. Here, the authors identify seventeen single-nucleotide polymorphisms associated with HRV, lending new insight into the vagal regulation of heart rhythm.

Abstract Observational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76; P

Genome-wide association studies (GWAS) have become a key tool to discover genetic markers for complex traits; however, environmental factors that interact with genes are rarely considered. Here, the authors conduct a GWAS of obesity traits, and find that smoking may alter genetic susceptibilities.

Abstract Background Increasing age is the biggest risk factor for dementia, of which Alzheimer’s disease is the commonest cause. The pathological changes underpinning Alzheimer’s disease are thought to develop at least a decade prior to the onset of symptoms. Molecular positron emission tomography and multi-modal magnetic resonance imaging allow key pathological processes underpinning cognitive impairment – including β-amyloid depostion, vascular disease, network breakdown and atrophy – to be assessed repeatedly and non-invasively. This enables potential determinants of dementia to be delineated earlier, and therefore opens a pre-symptomatic window where intervention may prevent the onset of cognitive symptoms. Methods/design This paper outlines the clinical, cognitive and imaging protocol of “Insight 46”, a neuroscience sub-study of the MRC National Survey of Health and Development. This is one of the oldest British birth cohort studies and has followed 5362 individuals since their birth in England, Scotland and Wales during one week in March 1946. These individuals have been tracked in 24 waves of data collection incorporating a wide range of health and functional measures, including repeat measures of cognitive function. Now aged 71 years, a small fraction have overt dementia, but estimates suggest that ~1/3 of individuals in this age group may be in the preclinical stages of Alzheimer’s disease. Insight 46 is recruiting 500 study members selected at random from those who attended a clinical visit at 60–64 years and on whom relevant lifecourse data are available. We describe the sub-study design and protocol which involves a prospective two time-point (0, 24 month) data collection covering clinical, neuropsychological, β-amyloid positron emission tomography and magnetic resonance imaging, biomarker and genetic information. Data collection started in 2015 (age 69) and aims to be completed in 2019 (age 73). Discussion Through the integration of data on the socioeconomic environment and on physical, psychological and cognitive function from 0 to 69 years, coupled with genetics, structural and molecular imaging, and intensive cognitive and neurological phenotyping, Insight 46 aims to identify lifetime factors which influence brain health and cognitive ageing, with particular focus on Alzheimer’s disease and cerebrovascular disease. This will provide an evidence base for the rational design of disease-modifying trials.

OBJECTIVE: Policy in many industrialized countries increasingly emphasizes extended working life. We examined associations between physical and cognitive capability in mid-adulthood and work in late adulthood. METHODS: Using self-reported physical limitations and performance-based physical and cognitive capability at age 53, assessed by trained nurses from the Medical Research Council (MRC) National Survey of Health and Development, we examined prospective associations with extended working (captured by age at and reason for retirement from main occupation, bridge employment in paid work after retirement from the main occupation, and voluntary work participation) up to age 68 among >2000 men and women. RESULTS: Number of reported physical limitations at age 53 was associated with higher likelihood of retiring for negative reasons and lower likelihood of participating in bridge employment, adjusted for occupational class, education, partner’s employment, work disability at age 53, and gender. Better performance on physical and cognitive tests was associated with greater likelihood of participating in bridge or voluntary work. Cognitive capability in the top 10% compared with the middle 80% of the distribution was associated with an odds ratio of bridge employment of 1.71 [95% confidence interval (95% CI) 1.21–2.42]. CONCLUSIONS: The possibility for an extending working life is less likely to be realized by those with poorer midlife physical or cognitive capability, independently of education, and social class. Interventions to promote capability, starting in mid-adulthood or earlier, could have long-term consequences for extending working.

Summary: Background: Early menopause is linked to an increased risk of cardiovascular disease mortality; however, the association between early menopause and incidence and timing of cardiovascular disease is unclear. We aimed to assess the associations between age at natural menopause and incidence and timing of cardiovascular disease. Methods: We harmonised and pooled individual-level data from 15 observational studies done across five countries and regions (Australia, Scandinavia, the USA, Japan, and the UK) between 1946 and 2013. Women who had reported their menopause status, age at natural menopause (if postmenopausal), and cardiovascular disease status (including coronary heart disease and stroke) were included. We excluded women who had hysterectomy or oophorectomy and women who did not report their age at menopause. The primary endpoint of this study was the occurrence of first non-fatal cardiovascular disease, defined as a composite outcome of incident coronary heart disease (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). We used Cox proportional hazards models to estimate multivariate hazard ratios (HRs) and 95% CIs for the associations between age at menopause and incident cardiovascular disease event. We also adjusted the model to account for smoking status, menopausal hormone therapy status, body-mass index, and education levels. Age at natural menopause was categorised as premenopausal or perimenopausal, younger than 40 years (premature menopause), 40–44 years (early menopause), 45–49 years (relatively early), 50–51 years (reference category), 52–54 years (relatively late), and 55 years or older (late menopause). Findings: Overall, 301 438 women were included in our analysis. Of these 301 438 women, 12 962 (4·3%) had a first non-fatal cardiovascular disease event after menopause, of whom 9369 (3·1%) had coronary heart disease and 4338 (1·4%) had strokes. Compared with women who had menopause at age 50–51 years, the risk of cardiovascular disease was higher in women who had premature menopause (age

Smoking is associated with shorter leucocyte telomere length (LTL), a biomarker of increased morbidity and reduced longevity. This association is widely interpreted as evidence that smoking causes accelerated LTL attrition in adulthood, but the evidence for this is inconsistent. We analysed the association between smoking and LTL dynamics in 18 longitudinal cohorts. The dataset included data from 12 579 adults (4678 current smokers and 7901 non-smokers) over a mean follow-up interval of 8.6 years. Meta-analysis confirmed a cross-sectional difference in LTL between smokers and non-smokers, with mean LTL 84.61 bp shorter in smokers (95% CI: 22.62 to 146.61). However, LTL attrition was only 0.51 bp yr−1 faster in smokers than in non-smokers (95% CI: −2.09 to 1.08), a difference that equates to only 1.32% of the estimated age-related loss of 38.33 bp yr−1. Assuming a linear effect of smoking, 167 years of smoking would be required to generate the observed cross-sectional difference in LTL. Therefore, the difference in LTL between smokers and non-smokers is extremely unlikely to be explained by a linear, causal effect of smoking. Selective adoption, whereby individuals with short telomeres are more likely to start smoking, needs to be considered as a more plausible explanation for the observed pattern of telomere dynamics.

Past genome-wide associate studies have identified hundreds of genetic loci that influence body size and shape when examined one trait at a time. Here, Jeff and colleagues develop an aggregate score of various body traits, and use meta-analysis to find new loci linked to body shape.

BackgroundCigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause.Methods and findingsA total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (ConclusionsThe probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause.

Summary: Background: Evidence of the possible health benefits of social connectedness is increasing. We aimed to examine poor social connectedness as a possible barrier to participation in preventive health services among older people (aged 53–69 years). Methods: We analysed data from a prospective cohort study of 5362 socially stratified births from the Medical Research Council National Survey of Health and Development enrolled in England, Scotland, and Wales in March 1946. At ages 68–69 years, participants reported participation in blood pressure and cholesterol measurement, eyesight and dental check-ups, influenza immunisation, and bowel and breast cancer screening. Our primary outcome measure summed participation across all these tests and services at ages 68–69 years. We tested associations between structural and functional social connectedness from ages 53 years to 69 years and total count of participation in these preventive services in Poisson models controlling for sex, education, occupational class, employment, chronic illnesses, and general practitioner consultations for health problems. Findings: 940 (44%) of 2132 participants attended all preventive services within the recommended timeframes. At ages 68–69 years, being unmarried or not cohabiting (incident rate ratio [IRR] 1·33, 95% CI 1·20–1·47) and small personal social networks (IRR 1·51, 1·32–1·71) were independently associated with non-participation in more services, with associations consistent across most services. High social relationship quality at ages 68–69 years (IRR 0·91, 95% CI 0·87–0·95) and increasing social relationship quality from ages 53 years to 69 years (IRR 0·93, 0·89–0·97) were associated with low risk of non-participation. Interpretation: Individuals with poor social connectedness appear to be at greater risk of not engaging in the full range of preventive services than individuals with good social connectedness. Improvement of access to social contacts and networks in older ages is already recommended for the maintenance of good mental health. This study suggests that social connectedness could also improve participation in a wide range of preventive health services, and hence could improve use of the health-care system and population health. Funding: UK Medical Research Council.

Background We examined associations of objectively measured physical activity (PA) and sedentary time with cardiovascular disease biomarkers at age 60 to 64 years. This included investigation of sex differences and the extent to which associations may be mediated by adiposity. Methods and Results Participants were 795 men and 827 women aged 60 to 64 years from the Medical Research Council National Survey of Health and Development. Combined heart rate and movement sensors worn for 5 consecutive days were used to derive overall PA energy expenditure, kJ/kg per day) and time spent sedentary (3 metabolic equivalent of tasks). Linear regression models were used to relate each PA parameter to inflammatory (C‐reactive protein, interleukin‐6), endothelial (tissue‐plasminogen activator, E‐selectin) and adipokine (leptin, adiponectin) markers extracted from fasting blood samples. Greater time in light PA and moderate‐to‐vigorous intensity PA and less sedentary time were associated with more favorable biomarker levels. For C‐reactive protein, interleukin‐6, and leptin, these differences were greater among women than men. For example, % differences (95% confidence intervals) in leptin for men and women per SD increases in sedentary time: 7.9 (2.7, 13.0) and 20.6 (15.3, 25.8); light intensity PA: −3.8 (−8.9, 12.7) and −17.7 (−23.1, −12.4), moderate‐to‐vigorous intensity PA: −12.9 (−17.9, −8.0) and −18.3 (−23.4, −13.1). Fat mass mediated a greater proportion of these associations in women than men. Conclusions Greater light PA and moderate‐to‐vigorous intensity PA and less sedentary time in early old age were associated with more favorable cardiovascular biomarker profiles. Fat mass partially mediated these associations but more strongly in women than men, which explained sex differences.

Summary: Background: Socioeconomic inequalities in childhood body-mass index (BMI) have been documented in high-income countries; however, uncertainty exists with regard to how they have changed over time, how inequalities in the composite parts (ie, weight and height) of BMI have changed, and whether inequalities differ in magnitude across the outcome distribution. Therefore, we aimed to investigate how socioeconomic inequalities in childhood and adolescent weight, height, and BMI have changed over time in Britain. Methods: We used data from four British longitudinal, observational, birth cohort studies: the 1946 Medical Research Council National Survey of Health and Development (1946 NSHD), 1958 National Child Development Study (1958 NCDS), 1970 British Cohort Study (1970 BCS), and 2001 Millennium Cohort Study (2001 MCS). BMI (kg/m2) was derived in each study from measured weight and height. Childhood socioeconomic position was indicated by the father's occupational social class, measured at the ages of 10–11 years. We examined associations between childhood socioeconomic position and anthropometric outcomes at age 7 years, 11 years, and 15 years to assess socioeconomic inequalities in each cohort using gender-adjusted linear regression models. We also used multilevel models to examine whether these inequalities widened or narrowed from childhood to adolescence, and quantile regression was used to examine whether the magnitude of inequalities differed across the outcome distribution. Findings: In England, Scotland, and Wales, 5362 singleton births were enrolled in 1946, 17 202 in 1958, 17 290 in 1970, and 16 404 in 2001. Low socioeconomic position was associated with lower weight at childhood and adolescent in the earlier-born cohorts (1946–70), but with higher weight in the 2001 MCS cohort. Weight disparities became larger from childhood to adolescence in the 2001 MCS but not the earlier-born cohorts (pinteraction=0·001). Low socioeconomic position was also associated with shorter height in all cohorts, yet the absolute magnitude of this difference narrowed across generations. These disparities widened with age in the 2001 MCS (pinteraction=0·002) but not in the earlier-born cohorts. There was little inequality in childhood BMI in the 1946–70 cohorts, whereas inequalities were present in the 2001 cohort and widened from childhood to adolescence in the 1958–2001 cohorts (pinteraction

BackgroundBody size, nutrition and socioeconomic position (SEP) in early life have been associated with a wide range of long-term health effects. Epigenetics is one possible mechanism through which these early life exposures can impact later life health. We conducted a systematic review examining the observational evidence for the impact of body size, nutrition and SEP in early life on the epigenome in humans.MethodsThis systematic review is registered with the PROSPERO database (registration number: CRD42016050193). Three datasets were simultaneously searched using Ovid and the resulting studies were evaluated by at least two independent reviewers. Studies measuring epigenetic markers either at the same time as, or after, the early life exposure and have a measure of body size, nutrition or SEP in early life (up to 12 years), written in English and from a community-dwelling participants were included.ResultsWe identified 90 eligible studies. Seventeen of these papers examined more than one early life exposure of interest. Fifty six papers examined body size, 37 nutrition and 17 SEP. All of the included papers examined DNA methylation (DNAm) as the epigenetic marker. Overall there was no strong evidence for a consistent association between these early life variables in DNAm which may be due to the heterogeneous study designs, data collection methods and statistical analyses.ConclusionsDespite these inconclusive results, the hypothesis that the early life environment can impact DNAm, potentially persisting into adult life, was supported by some studies and warrants further investigation. We provide recommendations for future studies.

This study investigated associations between measures of adiposity from age 36 and spine shape at 60-64 years. Thoracolumbar spine shape was characterised using statistical shape modelling on lateral dual-energy x-ray absorptiometry images of the spine from 1529 participants of the MRC National Survey of Health and Development, acquired at age 60-64. Associations of spine shape modes with: 1) contemporaneous measures of total and central adiposity (body mass index (BMI), waist circumference (WC)) and body composition (android:gynoid fat mass ratio and lean and fat mass indices, calculated as whole body (excluding the head) lean or fat mass (kg) divided by height2 (m)2); 2) changes in total and central adiposity between age 36 and 60-64 and 3) age at onset of overweight, were tested using linear regression models. Four modes described 79% of the total variance in spine shape. In men, greater lean mass index was associated with a larger lordosis whereas greater fat mass index was associated with straighter spines. Greater current BMI was associated with a more uneven curvature in men and with larger anterior-posterior (a-p) vertebral diameters in both sexes. Greater WC and fat mass index were also associated with a-p diameter in both sexes. There was no clear evidence that gains in BMI and WC during earlier stages of adulthood were associated with spine shape but younger onset of overweight was associated with a more uneven spine and greater a-p diameter. In conclusion, sagittal spine shapes had different associations with total and central adiposity; earlier onset of overweight and prior measures of WC were particularly important.

BackgroundGlycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findingsUsing genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.ConclusionsAs G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

[This corrects the article DOI: 10.1371/journal.pgen.1006528.].

This study explores the association between cognitive ability in childhood and midlife and bone health outcomes in early old age; and the relationships of these bone measures with contemporaneous and subsequent cognitive ability in the MRC National Survey of Health and Development (NSHD). This British birth cohort assessed areal and volumetric bone mineral density (aBMD and vBMD) at age 60–64, derived from peripheral quantitative computed tomography and dual-energy X-ray absorptiometry, and cognitive performance from childhood to age 69, among 866 women and 792 men. Cognitive performance at age 15 was assessed using tests of verbal and non-verbal ability, and mathematics; and memory and search speed tasks were administered at ages 53, 60–64, and 69. Covariates included body size, pubertal timing, smoking, leisure time physical activity, socioeconomic circumstances and menopause timing. Multiple linear regression analyses showed that higher childhood cognitive ability was associated with higher hip aBMD, in women, and greater cortical and trabecular vBMD, in men. For women, there were positive associations between hip aBMD and total vBMD, and contemporaneous cognitive ability with associations also extending to subsequent cognitive ability for total vBMD. For men, some associations with trabecular and total vBMD emerged at ages 60–64 and 69 but only after adjusting for education, occupational class and health behaviors. Our findings highlight that higher cognitive ability in childhood is associated with BMD in early old age and these associations might be explained by social and behavioral pathways. The results suggest that individuals with greater cognitive ability in early life are more likely to engage in healthy behaviors (e.g., leisure time physical activity) in adulthood, which in turn are associated with greater BMD later in life. Associations between bone health and cognitive performance should be considered within a life course framework; and the potential role of smoking and physical activity should be addressed when advising adults at high future risk of osteoporosis and fracture.

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

BackgroundHigh body mass index (BMI) is an important contributor to the global burden of ill-health and health inequality. Lower socioeconomic position (SEP) in both childhood and adulthood is associated with higher adult BMI, but how these associations have changed across time is poorly understood. We used longitudinal data to examine how childhood and adult SEP relates to BMI across adulthood in three national British birth cohorts.Methods and findingsThe sample comprised up to 22,810 participants with 77,115 BMI observations in the 1946 MRC National Survey of Health and Development (ages 20 to 60-64), the 1958 National Child Development Study (ages 23 to 50), and the 1970 British Cohort Study (ages 26 to 42). Harmonized social class-based SEP data (Registrar General's Social Class) was ascertained in childhood (father's class at 10/11 y) and adulthood (42/43 years), and BMI repeatedly across adulthood, spanning 1966 to 2012. Associations between SEP and BMI were examined using linear regression and multilevel models. Lower childhood SEP was associated with higher adult BMI in both genders, and differences were typically larger at older ages and similar in magnitude in each cohort. The strength of association between adult SEP and BMI did not vary with age in any consistent pattern in these cohorts, but were more evident in women than men, and inequalities were larger among women in the 1970 cohort compared with earlier-born cohorts. For example, mean differences in BMI at 42/43 y amongst women in the lowest compared with highest social class were 2.0 kg/m2 (95% CI: -0.1, 4.0) in the 1946 NSHD, 2.3 kg/m2 (1.1, 3.4) in the 1958 NCDS, and 3.9 kg/m2 (2.3, 5.4) the in the 1970 BCS; mean (SD) BMI in the highest and lowest social classes were as follows: 24.9 (0.8) versus 26.8 (0.7) in the 1946 NSHD, 24.2 (0.4) versus 26.5 (0.4) in the 1958 NCDS, and 24.2 (0.3) versus 28.1 (0.8) in the 1970 BCS. Findings did not differ whether using overweight or obesity as an outcome. Limitations of this work include the use of social class as the sole indicator of SEP-while it was available in each cohort in both childhood and adulthood, trends in BMI inequalities may differ according to other dimensions of SEP such as education or income. Although harmonized data were used to aid inferences about birth cohort differences in BMI inequality, differences in other factors may have also contributed to findings-for example, differences in missing data.ConclusionsGiven these persisting inequalities and their public health implications, new and effective policies to reduce inequalities in adult BMI that tackle inequality with respect to both childhood and adult SEP are urgently required.

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

Objectives (1) To describe changes in objective measures of physical capability between ages 53 and 60–64 years; (2) to investigate the associations of behavioural risk factors (obesity, physical inactivity, smoking) and number of health conditions (range 0–4: hand osteoarthritis (OA); knee OA; severe respiratory symptoms; other disabling or life-threatening conditions (ie, cancer, cardiovascular disease, diabetes)) at age 53 years with these changes.Design Nationally representative prospective birth cohort study.Setting England, Scotland and Wales.Participants Up to 2093 men and women from the Medical Research Council National Survey of Health and Development, who have been followed-up since birth in 1946, and underwent physical capability assessments performed by nurses following standard protocols in 1999 and 2006–2010.Main outcome measures Grip strength and chair rise speed were assessed at ages 53 and 60–64 years. Four categories of change in grip strength and chair rise speed were identified: decline, stable high, stable low, a reference group who maintained physical capability within a ‘normal’ range.Results Less healthy behavioural risk scores and an increase in the number of health conditions experienced were associated in a stepwise fashion with increased risk of decline in physical capability, and also of having low levels at baseline and remaining low. For example, the sex and mutually adjusted relative-risk ratios (95% CI) of being in the stable low versus reference category of chair rise speed were 1.58 (1.35–1.86) and 1.97 (1.57–2.47) per 1 unit change in behavioural risk score and health indicator count, respectively.Conclusions These findings provide evidence of the associations of a range of modifiable factors with age-related changes in physical capability. They suggest the need to target multiple risk factors at least as early as mid-life when aiming to promote maintenance and prevent decline in physical capability in later life.

Red blood cell (RBC) traits are routinely measured in clinical practice as important markers of health. Deviations from the physiological ranges are usually a sign of disease, although variation between healthy individuals also occurs, at least partly due to genetic factors. Recent large scale genetic studies identified loci associated with one or more of these traits; further characterization of known loci and identification of new loci is necessary to better understand their role in health and disease and to identify potential molecular mechanisms. We performed meta-analysis of Metabochip association results for six RBC traits-hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) and red blood cell count (RCC)-in 11 093 Europeans from seven studies of the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium. We identified 394 non-overlapping SNPs in five loci at genome-wide significance: 6p22.1-6p21.33 (with HFE among others), 6q23.2 (with HBS1L among others), 6q23.3 (contains no genes), 9q34.3 (only ABO gene) and 22q13.1 (with TMPRSS6 among others), replicating previous findings of association with RBC traits at these loci and extending them by imputation to 1000 Genomes. We further characterized associations between ABO SNPs and three traits: hemoglobin, hematocrit and red blood cell count, replicating them in an independent cohort. Conditional analyses indicated the independent association of each of these traits with ABO SNPs and a role for blood group O in mediating the association. The 15 most significant RBC-associated ABO SNPs were also associated with five cardiometabolic traits, with discordance in the direction of effect between groups of traits, suggesting that ABO may act through more than one mechanism to influence cardiometabolic risk.

Variations in markers of adolescent self-organization predict a range of economic and health-related outcomes in general population studies. Using a population-based birth cohort study we investigated associations between adolescent self-organization and two common factors over adulthood influencing health, smoking and alcohol consumption. The MRC National Survey of Health and Development (the British 1946 birth cohort) was used to test associations between a dimensional measure of adolescent self-organization derived from teacher ratings, and summary longitudinal measures of smoking and alcohol consumption over the ensuing five decades. Multinomial regression models were adjusted for sex, adolescent emotional and conduct problems, occupational social class of origin, childhood cognition, educational attainment and adult occupational social class. With all covariates adjusted, higher adolescent self-organization was associated with fewer smoking pack years, although not with quitting; there was no association with alcohol consumption across adulthood (none or heavy compared with light to moderate). Adolescent self-organization appears to be protective against smoking, but not against heavy alcohol consumption. Interpretation of this differential effect should be embedded in an understanding of the social and sociodemographic context in which these health behaviours occur over time.

BACKGROUND:Difficulties performing a range of physical tasks of daily living have been shown to develop in older populations in a typically observed sequence, known as the hierarchy of loss. Nearly all previous research has been undertaken using populations aged over 75. This study aimed to use cross-sectional and longitudinal data to test for evidence of the hierarchy of loss from midlife onwards. METHODS:The prevalence of reported difficulty undertaking 16 physical tasks in the MRC National Survey of Health and Development at age 60-64 were calculated, with Mokken scaling used to confirm the hierarchical order. Logistic regression was used to calculate the odds ratios of reporting difficulty performing tasks at the bottom of the hierarchy (i.e. feeding, washing and/or toileting) at age 60-64 by reported difficulty at the top of the hierarchy (i.e. gripping, walking and/or stair climbing) at age 43. RESULTS:At age 60-64, tasks associated with balance, strength and co-ordination, such as climbing stairs, were the first tasks participants reported difficulty with and tasks associated with upper limb mobility, such as feeding yourself, were the last. In a fully-adjusted model, participants who reported difficulty at the top of the hierarchy at age 43 were 2.85 (95% CI: 1.45-5.60) times more likely to report difficulty with tasks at the bottom of the hierarchy at age 60-64. CONCLUSION:This study presents evidence of the hierarchy of loss in a younger population than previously observed suggesting that targeted interventions to prevent functional decline should not be delayed until old age.

The aim was to investigate whether the combined work-family life courses of British men and women were associated with differences in metabolic markers-waist circumference, blood pressure, high density lipoprotein cholesterol, triglycerides, and glycated haemoglobin-in mid-life. We used data from the Medical Research Council's National Survey of Health and Development-the 1946 British birth cohort. Multi-channel sequence analysis was used to create a typology of eight work-family life course types combining information on work, partnerships and parenthood between ages 16-51. Linear regression tested associations between work-family types and metabolic outcomes at age 53 on multiply imputed data (20 imputations) of >2,400 participants. Compared with men with strong ties to employment and early transitions to family life, men who made later transitions to parenthood and maintained strong ties to paid work had smaller waist circumferences (-2.16cm, 95% CI: -3.73, -0.59), lower triglycerides (9.78% lower, 95% CI: 0.81, 17.94) and lower blood pressure (systolic: -4.03mmHg, 95% CI: -6.93, -1.13; diastolic: -2.34mmHg, 95% CI: -4.15, -0.53). Married men and women who didn't have children had increased high density lipoprotein cholesterol (7.23% higher, 95% CI: 0.68, 14.21) and lower waist circumferences (-4.67cm, 95% CI: -8.37, -0.97), respectively. For men later transitions to parenthood combined with strong ties to paid work were linked to reduced metabolic risk in mid-life. Fewer differences between work-family types and metabolic markers were seen for women.

Although it is recognized that risks of cardiovascular diseases associated with heart failure develop over the life course, no studies have reported whether life course socioeconomic inequalities exist for heart failure risk. The Medical Research Council's National Survey of Health and Development was used to investigate associations between occupational socioeconomic position during childhood, early adulthood and middle age and measures of cardiac structure [left ventricular (LV) mass index and relative wall thickness (RWT)] and function [systolic: ejection fraction (EF) and midwall fractional shortening (mFS); diastolic: left atrial (LA) volume, E/A ratio and E/e' ratio)]. Different life course models were compared with a saturated model to ascertain the nature of the relationship between socioeconomic position across the life course and each cardiac marker. Findings showed that models where socioeconomic position accumulated over multiple time points in life provided the best fit for 3 of the 7 cardiac markers: childhood and early adulthood periods for the E/A ratio and E/e' ratio, and all three life periods for LV mass index. These associations were attenuated by adjustment for adiposity, but were little affected by adjustment for other established or novel cardio-metabolic risk factors. There was no evidence of a relationship between socioeconomic position at any time point and RWT, EF, mFS or LA volume index. In conclusion, socioeconomic position across multiple points of the lifecourse, particularly earlier in life, is an important determinant of some measures of LV structure and function. BMI may be an important mediator of these associations.

Nature Communications 8: Article number: 15805 (2017); Published: 14 June 2017; Updated: 2 August 2017 In Supplementary Fig. 10 of this Article, images for panels a and b were inadvertently omitted. The correct version of Supplementary Fig. 10 is provided as Supplementary Information associated withthis Erratum.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR

There is a paucity of information on secular trends in the age-related process by which people develop overweight or obesity. Utilizing longitudinal data in the United Kingdom birth cohort studies, we investigated shifts over the past nearly 70 years in the distribution of body mass index (BMI) and development of overweight or obesity across childhood and adulthood.The sample comprised 56,632 participants with 273,843 BMI observations in the 1946 Medical Research Council National Survey of Health and Development (NSHD; ages 2-64 years), 1958 National Child Development Study (NCDS; 7-50), 1970 British Cohort Study (BCS; 10-42), 1991 Avon Longitudinal Study of Parents and Children (ALSPAC; 7-18), or 2001 Millennium Cohort Study (MCS; 3-11). Growth references showed a secular trend toward positive skewing of the BMI distribution at younger ages. During childhood, the 50th centiles for all studies lay in the middle of the International Obesity Task Force normal weight range, but during adulthood, the age when a 50th centile first entered the overweight range (i.e., 25-29.9 kg/m2) decreased across NSHD, NCDS, and BCS from 41 to 33 to 30 years in males and 48 to 44 to 41 years in females. Trajectories of overweight or obesity showed that more recently born cohorts developed greater probabilities of overweight or obesity at younger ages. Overweight or obesity became more probable in NCDS than NSHD in early adulthood, but more probable in BCS than NCDS and NSHD in adolescence, for example. By age 10 years, the estimated probabilities of overweight or obesity in cohorts born after the 1980s were 2-3 times greater than those born before the 1980s (e.g., 0.229 [95% CI 0.219-0.240] in MCS males; 0.071 [0.065-0.078] in NSHD males). It was not possible to (1) model separate trajectories for overweight and obesity, because there were few obesity cases at young ages in the earliest-born cohorts, or (2) consider ethnic minority groups. The end date for analyses was August 2014.Our results demonstrate how younger generations are likely to accumulate greater exposure to overweight or obesity throughout their lives and, thus, increased risk for chronic health conditions such as coronary heart disease and type 2 diabetes mellitus. In the absence of effective intervention, overweight and obesity will have severe public health consequences in decades to come.

To investigate the associations of time spent sedentary, in moderate-to-vigorous-intensity physical activity (MVPA) and physical activity energy expenditure (PAEE) with physical capability measures at age 60-64 years.Time spent sedentary and in MVPA and, PAEE were assessed using individually calibrated combined heart rate and movement sensing among 1727 participants from the MRC National Survey of Health and Development in England, Scotland and Wales as part of a detailed clinical assessment undertaken in 2006-2010. Multivariable linear regression models were used to examine the cross-sectional associations between standardised measures of each of these behavioural variables with grip strength, chair rise and timed up-&-go (TUG) speed and standing balance time.Greater time spent in MVPA was associated with higher levels of physical capability; adjusted mean differences in each capability measure per 1 standard deviation increase in MVPA time were: grip strength (0.477 kg, 95% confidence interval (CI): 0.015 to 0.939), chair rise speed (0.429 stands/min, 95% CI: 0.093 to 0.764), standing balance time (0.028 s, 95% CI: 0.003 to 0.053) and TUG speed (0.019 m/s, 95% CI: 0.011 to 0.026). In contrast, time spent sedentary was associated with lower grip strength (-0.540 kg, 95% CI: -1.013 to -0.066) and TUG speed (-0.011 m/s, 95% CI: -0.019 to -0.004). Associations for PAEE were similar to those for MVPA.Higher levels of MVPA and overall physical activity (PAEE) are associated with greater levels of physical capability whereas time spent sedentary is associated with lower levels of capability. Future intervention studies in older adults should focus on both the promotion of physical activity and reduction in time spent sedentary.

We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00 × 10(-10)), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38 × 10(-5)). An interaction test confirmed that these estimates differed from each other (P = 4.95 × 10(-13)). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.

Abstract Objective: To explore endocrine‐related and general symptoms among three groups of middle‐aged women defined by country of birth and country of residence, in the context of debates about biological, cultural and other factors in menopause. Methods: British‐born women participating in a British birth cohort study (n=1,362) and age‐matched Australian‐born (n=1,724) and British‐born (n=233) Australian women selected from the Australian Longitudinal Study on Women's Health (ALSWH) responded to two waves of surveys at ages 48 and 50. Results: Australian‐Australian and British‐Australian women report reaching menopause later than British‐British women, even after accounting for smoking status and parity. Hormone replacement therapy (HRT) use was lower and hysterectomy was more common among both Australian groups, probably reflecting differences in health services between Britain and Australia. The Australian‐Australian and British‐Australian groups were more likely to report endocrine‐related symptoms than the British‐British group, even after adjusting for menopausal status. British‐British women were more likely to report some general symptoms. Conclusions: Symptom reporting is high among Australian and British midlife women and varies by country of residence, country of birth and menopausal status. Implications: The data do not support either a simple cultural or a simple biological explanation for differences in menopause experience.