A genome-wide association study of total child psychiatric problems scores.

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.

Estimating the influence of body mass index (BMI) on mortality using offspring BMI as an instrumental variable.

OBJECTIVE: High body mass index (BMI) is an important predictor of mortality but estimating underlying causality is hampered by confounding and pre-existing disease. Here, we use information from the offspring to approximate parental BMIs, with an aim to avoid biased estimation of mortality risk caused by reverse causality. METHODS: The analyses were based on information on 9674 offspring-mother and 9096 offspring-father pairs obtained from the 1958 British birth cohort. Parental BMI-mortality associations were analysed using conventional methods and using offspring BMI as a proxy, or instrument, for their parents' BMI. RESULTS: In the conventional analysis, associations between parental BMI and all-cause mortality were U-shaped (Pcurvature < 0.001), while offspring BMI had linear associations with parental mortality (Ptrend < 0.001, Pcurvature > 0.46). Curvature was particularly pronounced for mortality from respiratory diseases and from lung cancer. Instrumental variable analyses suggested a positive association between BMI and mortality from all causes [mothers: HR per SD of BMI 1.43 (95% CI 1.21-1.69), fathers: HR 1.17 (1.00-1.36)] and from coronary heart disease [mothers: HR 1.65 (1.15-2.36), fathers: HR 1.51 (1.17-1.97)]. These were larger than HR from the equivalent conventional analyses, despite some attenuation by adjustment for social indicators and smoking. CONCLUSIONS: Analyses using offspring BMI as a proxy for parental BMI suggest that the apparent adverse consequences of low BMI are considerably overestimated and adverse consequences of overweight are underestimated in conventional epidemiological studies.

An overview of child maltreatment (neglect and abuse) associations with developmental trajectories and long-term outcomes in the 1958 British birth cohort.

Childhood maltreatment types (neglect and psychological, physical, or sexual abuse) are associated with many poor outcomes in adulthood. Yet, research mainly focuses on the cumulative adversity burden rather than specificities and commonalities of associations with adult outcomes and intervening pathways. To build understanding of life-course pathways to a range of outcomes, this overview summarises evidence from several original research studies using the 1958 British Birth Cohort on specific maltreatment types, child development trajectories, adult intermediaries and outcomes. About one-in-five participants were identified as neglected or abused in childhood (~10% were identified for neglect, 10% for psychological abuse, 6% for physical abuse and 1.4% for sexual abuse). Neglect was associated with key dimensions of development, for example, slower height growth, delayed maturation, faster BMI gain, and poorer emotional and cognitive development. Associated adulthood outcomes included harmful behaviours (notably smoking), poorer physical health (e.g. shorter height, excess BMI, poorer blood lipids and glucose, poor-rated health and physical functioning), worse mental health, lower socioeconomic circumstances (e.g. poorer living conditions) and elevated mortality in mid-adulthood. Childhood abuse associations were less widespread and were often only for specific types: most types were unrelated to childhood height and cognitive abilities, but all types were associated with poorer child emotional development, adult mental health, smoking, blood lipids and self-rated health. Additionally, physical abuse was associated with faster BMI gain, higher adult BMI, blood glucose, inflammation and mortality in mid-adulthood; sexual abuse with faster BMI gain, higher adult BMI, poor physical functioning at 50y and higher mortality in mid-adulthood. Adult health measures associated with neglect and abuse are key predictors of serious disease, disability and death. Therefore, neglect and abuse associations with these measures represent an important burden for individuals and society.

National Patient Safety Consortium: Learning from Large-Scale Collaboration.

From 2014 to 2018, the Canadian Patient Safety Institute brought together key partners and established the National Patient Safety Consortium to drive a shared action plan for safer healthcare. With ongoing consensus development on key priorities, an unprecedented level of collaboration and shared leadership with diverse stakeholders and patients and families as full partners, the Consortium and its Integrated Patient Safety Action Plan built a culture of engagement and improvement across Canada.

Understanding associations of early-life adversities with mid-life inflammatory profiles: Evidence from the UK and USA.

OBJECTIVES: In two cohorts, we aimed to establish associations between early-life adversities and adult inflammation, and whether adult (a) adiposity or (b) socioeconomic disadvantage are key intermediaries. METHODS: In both cohorts (N = 7661, 1958 British birth cohort; N = 1255, MIDUS), information was used on adult inflammatory markers (C-reactive protein (CRP), fibrinogen and (MIDUS only) interleukin-6 (IL-6)), adiposity and socioeconomic disadvantage, and early-life adversities (neglect, emotional neglect, physical, psychological, sexual abuse and childhood disadvantage). RESULTS: Early-life adversities varied from 1.6% (sexual abuse, 1958 cohort) to 14.3% (socioeconomic disadvantage, MIDUS). Across the two cohorts, associations were consistent for physical abuse, e.g. 16.3%(3.01,29.7) and 17.0%(-16.4,50.3) higher CRP in the 1958 cohort and MIDUS respectively. Associations attenuated after accounting for adult adiposity, e.g. physical abuse (1958 cohort) and sexual abuse (MIDUS, non-white participants) associations were abolished. Some associations attenuated after adjustment for adult socioeconomic disadvantage; e.g. 1958 cohort neglect-CRP associations reduced from 23.2%(13.7,32.6) to 17.7%(8.18,27.2). Across the cohorts, no associations were found for psychological abuse or emotional neglect; associations for childhood socioeconomic disadvantage were inconsistent. CONCLUSIONS: Specific early-life adversities are associated with adult inflammation; adiposity is a likely intermediary factor. Weight reduction and obesity prevention may offset pro-inflammatory related adult disease among those who experienced early-life adversities.

Change in health and social factors in mid-adulthood and corresponding changes in leisure-time physical inactivity in a prospective cohort.

BACKGROUND: To identify whether changes in adult health and social factors are associated with simultaneous changes in inactivity. METHODS: Health, social factors and leisure-time inactivity (activity frequency < 1/week) were self-reported at 33y and 50y in the 1958 British birth cohort (N = 12,271). Baseline (33y) health and social factors and also patterns of change in factors 33y-to-50y were related to inactivity 33y-to-50y (never inactive, persistently inactive, deteriorating to inactivity, or improving from inactivity) using multinomial logistic regression. RESULTS: Approximately 31% were inactive at 33y and 50y; 35% changed status 33y-to-50y (17% deteriorating to inactivity, 18% improving from inactivity). Baseline poor health and obesity were associated with subsequent (33y-to-50y) inactivity; e.g. for poor health, relative risk ratios (RRRs) for deteriorating to inactivity (vs never inactive) and improving from inactivity (vs persistently inactive) were 1.38(1.16,1.64) and 0.77(0.63,0.94) respectively. Adverse changes in health and weight were associated with simultaneous adverse changes in inactivity; e.g. worsening health (vs always good/excellent health) was associated with higher risk of deteriorating to inactivity (RRR:2.20(1.85,2.62)) and lower risk of improving from inactivity (RRR:0.61(0.49,0.77)). However, improving health and weight loss were not associated with improving from inactivity. Worsening self-efficacy 33y-to-50y was associated with lower risk of improving from inactivity; there was no association between improving self-efficacy and inactivity change. Downward social mobility was not associated with deteriorating to or improving from inactivity. Changes in depression symptom level, marriage/co-habitation or parenthood 33y-to-50y were not associated with inactivity changes. No associations were observed for employment. CONCLUSIONS: Associated changes in mid-life health factors with deleterious inactivity changes, highlight the importance of maintaining health, weight and self-efficacy across adulthood to deter inactivity.

Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Diurnal cortisol and mental well-being in middle and older age: evidence from four cohort studies.

OBJECTIVES: We conducted an individual participant meta-analysis to test the hypothesis that cortisol patterns indicative of dysregulated hypothalamic-pituitary-adrenal axis functioning would be prospectively associated with poorer well-being at follow-up. SETTING: Four large UK-based cohort studies. PARTICIPANTS: Those providing valid salivary or serum cortisol samples (n=7515 for morning cortisol; n=1612 for cortisol awakening response) at baseline (age 44-82) and well-being data on the Warwick Edinburgh Mental Wellbeing Scale at follow-up (0-8 years) were included. RESULTS: Well-being was not associated with morning cortisol, diurnal slope or awakening response though a borderline association with evening cortisol was found. Adjusting for sex and follow-up time, each 1 SD increase in evening cortisol was associated with a -0.47 (95% CI -1.00 to 0.05) point lower well-being. This was attenuated by adjustment for body mass index, smoking and socioeconomic position. Between-study heterogeneity was low. CONCLUSIONS: This study does not support the hypothesis that diurnal cortisol is prospectively associated with well-being up to 8 years later. However, replication in prospective studies with cortisol samples over multiple days is required.

Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium.

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 < 0·001) and allergic sensitization (OR = 0·74, 95% CI: 0·64, 0·86; P < 0·001), but similar asthma risk (OR = 1·00, 95% CI: 0·91, 1·09; P = 0·967). Mendelian randomization analyses in current smokers showed a slightly lower risk of hay fever (OR = 0·958, 95% CI: 0·920, 0·998; P = 0·041), a lower risk of allergic sensitization (OR = 0·92, 95% CI: 0·84, 1·02; P = 0·117), but higher risk of asthma (OR = 1·06, 95% CI: 1·01, 1·11; P = 0·020) per smoking-increasing allele. Our results suggest that smoking may be causally related to a higher risk of asthma and a slightly lower risk of hay fever. However, the adverse events associated with smoking limit its clinical significance.

Multiple Risk Behavior Interventions: Meta-analyses of RCTs.

CONTEXT: Multiple risk behaviors are common and associated with developing chronic conditions such as heart disease, cancer, or Type 2 diabetes. A systematic review, meta-analysis, and meta-regression of the effectiveness of multiple risk behavior interventions was conducted. EVIDENCE ACQUISITION: Six electronic databases including MEDLINE, EMBASE, and PsycINFO were searched to August 2016. RCTs of non-pharmacologic interventions in general adult populations were selected. Studies targeting specific at-risk groups (such as people screened for cardiovascular risk factors or obesity) were excluded. Studies were screened independently. Study characteristics and outcomes were extracted and risk of bias assessed by one researcher and checked by another. The Behaviour Change Wheel and Oxford Implementation Index were used to code intervention content and context. EVIDENCE SYNTHESIS: Random-effects meta-analyses were conducted. Sixty-nine trials involving 73,873 individuals were included. Interventions mainly comprised education and skills training and were associated with modest improvements in most risk behaviors: increased fruit and vegetable intake (0.31 portions, 95% CI=0.17, 0.45) and physical activity (standardized mean difference, 0.25; 95% CI=0.13, 0.38), and reduced fat intake (standardized mean difference, -0.24; 95% CI=-0.36, -0.12). Although reductions in smoking were found (OR=0.78, 95% CI=0.68, 0.90), they appeared to be negatively associated with improvement in other behaviors (such as diet and physical activity). Preliminary evidence suggests that sequentially changing smoking alongside other risk behaviors was more effective than simultaneous change. But most studies assessed simultaneous rather than sequential change in risk behaviors; therefore, comparisons are sparse. Follow-up period and intervention characteristics impacted effectiveness for some outcomes. CONCLUSIONS: Interventions comprising education (e.g., providing information about behaviors associated with health risks) and skills training (e.g., teaching skills that equip participants to engage in less risky behavior) and targeting multiple risk behaviors concurrently are associated with small changes in diet and physical activity. Although on average smoking was reduced, it appeared changes in smoking were negatively associated with changes in other behaviors, suggesting it may not be optimal to target smoking simultaneously with other risk behaviors.

A systematic review on the clustering and co-occurrence of multiple risk behaviours.

BACKGROUND: Risk behaviours, such as smoking and physical inactivity account for up to two-thirds of all cardiovascular deaths, and are associated with substantial increased mortality in many conditions including cancer and diabetes. As risk behaviours are thought to co-occur in individuals we conducted a systematic review of studies addressing clustering or co-occurrence of risk behaviours and their predictors. As the main aim of the review was to inform public health policy in England we limited inclusion to studies conducted in the UK. METHODS: Key databases were searched from 1990 to 2016. We included UK based cross-sectional and longitudinal studies that investigated risk behaviours such as smoking, physical inactivity, unhealthy diet. High heterogeneity precluded meta-analyses. RESULTS: Thirty-seven studies were included in the review (32 cross-sectional and five longitudinal). Most studies investigated unhealthy diet, physical inactivity, alcohol misuse, and smoking. In general adult populations, there was relatively strong evidence of clustering between alcohol misuse and smoking; and unhealthy diet and smoking. For young adults, there was evidence of clustering between sexual risk behaviour and smoking, sexual risk behaviour and illicit drug use, and sexual risk behaviour and alcohol misuse. The strongest associations with co-occurrence and clustering of multiple risk behaviours were occupation (up to 4-fold increased odds in lower SES groups) and education (up to 5-fold increased odds in those with no qualifications). CONCLUSIONS: Among general adult populations, alcohol misuse and smoking was the most commonly identified risk behaviour cluster. Among young adults, there was consistent evidence of clustering found between sexual risk behaviour and substance misuse. Socio-economic status was the strongest predictor of engaging in multiple risk behaviours. This suggests the potential for interventions targeting multiple risk behaviours either sequentially or concurrently particularly where there is evidence of clustering. In addition, there is potential for intervening at the social or environmental level due to the strong association with socio-economic status.

Combined early and adult life risk factor associations for mid-life obesity in a prospective birth cohort: assessing potential public health impact.

OBJECTIVE: The combined effect of life-course influences on obesity development and thus their potential public health impact is unclear. We evaluated combined associations and predicted probabilities for early and adult life risk factors with central and general obesity in mid-adulthood. SETTING: 1958 British birth cohort. PARTICIPANTS: 4629 males and 4670 females with data on waist circumference. OUTCOME MEASURES: 45 year obesity measured via waist circumference, waist-hip ratio (WHR) and BMI. RESULTS: At 45 years, approximately a third of the population were centrally obese and a quarter were generally obese. Three factors (parental overweight, maternal smoking during pregnancy and adult inactivity) were consistently associated with central and general obesity. Predicted probabilities for waist obesity increased from those with none to all three risk factors (0.15-0.33 in men; 0.19-0.39 in women (ptrend<0.001)), with a similar trend for general obesity. Additional factors (adult smoking, low fibre and heavy alcohol consumption) were associated with WHR obesity, although varying by gender. Prevalence of risk factors was higher in manual than non-manual groups: for example, in men 38% versus 25%, respectively, had ≥2 risk factors for waist and general obesity. CONCLUSIONS: Early-life and adult factors that are amenable to change are highly prevalent and accumulate in association with central and general obesity in mid-adulthood. The increase in probabilities for mid-adult obesity associated with cumulative levels of risk factors suggests the potential for public health impact.

Effect of smoking on physical and cognitive capability in later life: a multicohort study using observational and genetic approaches.

OBJECTIVES: The observed associations between smoking and functional measures at older ages are vulnerable to bias and confounding. Mendelian randomisation (MR) uses genotype as an instrumental variable to estimate unconfounded causal associations. We conducted a meta-analysis of the observational associations and implemented an MR approach using the smoking-related single nucleotide polymorphism rs16969968 to explore their causal nature. SETTING: 9 British cohorts belonging to the HALCyon collaboration. PARTICIPANTS: Individual participant data on N=26,692 individuals of European ancestry (N from earliest phase analysed per study) of mean ages 50-79 years were available for inclusion in observational meta-analyses of the primary outcomes. PRIMARY OUTCOMES: Physical capability, cognitive capability and cognitive decline. The smoking exposures were cigarettes per day, current versus ex-smoker, current versus never smoker and ever versus never smoker. RESULTS: In observational analyses current and ever smoking were generally associated with poorer physical and cognitive capability. For example, current smokers had a general fluid cognition score which was 0.17 z-score units (95% CI -0.221 to -0.124) lower than ex-smokers in cross-sectional analyses. Current smokers had a walk speed which was 0.25 z-score units lower than never smokers (95% CI -0.338 to -0.170). An MR instrumental variable approach for current versus ex-smoker and number of cigarettes smoked per day produced CIs which neither confirmed nor refuted the observational estimates. The number of genetic associations stratified by smoking status were consistent with type I error. CONCLUSIONS: Our observational analysis supports the hypothesis that smoking is detrimental to physical and cognitive capability. Further studies are needed for a suitably powered MR approach.

Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomization Meta-Analysis in the CARTA Consortium.

BACKGROUND: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. METHODS AND RESULTS: Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day. CONCLUSIONS: This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.

Lymphoblastoid cell lines reveal associations of adult DNA methylation with childhood and current adversity that are distinct from whole blood associations.

BACKGROUND: Some cohort studies bank lymphoblastoid cell lines (LCLs) as a renewable source of participant DNA. However, although LCL DNA has proved valuable for genetic studies, its utility in epigenetic epidemiology research is unknown. METHODS: To assess whether LCL DNA can be used for life-course environmental epigenomics, we carried out a pilot methylomic study (using the Illumina Infinium Human Methylation 450 BeadChip) of nil-passage, Epstein-Barr virus (EBV)-transformed LCLs (n = 42) and 28 matched whole-blood (WB) samples. These were from adult male participants of the British 1958 birth cohort, selected for extremes of social economic position (SEP) in childhood and adulthood, with additional information available on childhood abuse and prenatal tobacco exposure. RESULTS: We identified a small number of weak associations between these exposures and methylation levels of both individual CpG sites and genomic regions in WB and LCLs. However, only one of the regional, and none of the individual CpG site associations were common to both sample types. The lack of overlap between the associations detected in LCL compared with those found in WB could either be due to the EBV-transformation process, or to the fact that, unlike WB, LCLs are essentially a single (CD19+) cell type. We provide evidence that the latter is the more potent explanation, by showing that CpG sites known to be differentially methylated between different types of blood cell have significantly lower correlations (R = 0.11) than average (R = 0.2) between WB and LCLs in our datasets, whereas sites known to be affected by EBV-transformation have significantly higher correlations (R = 0.3). CONCLUSIONS: This small pilot study suggests that the DNA methylation profile of LCLs is more closely related to that of B cells than WB and, additionally, that LCLs may nevertheless be useful for life-course environmental epigenomics.

Heavier smoking may lead to a relative increase in waist circumference: evidence for a causal relationship from a Mendelian randomisation meta-analysis. The CARTA consortium.

OBJECTIVES: To investigate, using a Mendelian randomisation approach, whether heavier smoking is associated with a range of regional adiposity phenotypes, in particular those related to abdominal adiposity. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730 in the CHRNA5-CHRNA3-CHRNB4 gene region) as a proxy for smoking heaviness, of the associations of smoking heaviness with a range of adiposity phenotypes. PARTICIPANTS: 148,731 current, former and never-smokers of European ancestry aged ≥ 16 years from 29 studies in the consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Waist and hip circumferences, and waist-hip ratio. RESULTS: The data included up to 66,809 never-smokers, 43,009 former smokers and 38,913 current daily cigarette smokers. Among current smokers, for each extra minor allele, the geometric mean was lower for waist circumference by -0.40% (95% CI -0.57% to -0.22%), with effects on hip circumference, waist-hip ratio and body mass index (BMI) being -0.31% (95% CI -0.42% to -0.19), -0.08% (-0.19% to 0.03%) and -0.74% (-0.96% to -0.51%), respectively. In contrast, among never-smokers, these effects were higher by 0.23% (0.09% to 0.36%), 0.17% (0.08% to 0.26%), 0.07% (-0.01% to 0.15%) and 0.35% (0.18% to 0.52%), respectively. When adjusting the three central adiposity measures for BMI, the effects among current smokers changed direction and were higher by 0.14% (0.05% to 0.22%) for waist circumference, 0.02% (-0.05% to 0.08%) for hip circumference and 0.10% (0.02% to 0.19%) for waist-hip ratio, for each extra minor allele. CONCLUSIONS: For a given BMI, a gene variant associated with increased cigarette consumption was associated with increased waist circumference. Smoking in an effort to control weight may lead to accumulation of central adiposity.

Life-course body mass index trajectories and blood pressure in mid life in two British birth cohorts: stronger associations in the later-born generation.

BACKGROUND: Little is known about the impact of recent increases in obesity and more rapid gains in body mass index (BMI) on cardiovascular risk factors. We investigated life-course BMI trajectories associations with adult blood pressure (BP) across two generations. METHODS: We used the the 1946 and 1958 British birth cohorts. Joint multivariate response models were fitted to longitudinal BMI measures [7, 11, 16, 20, 26, 36, 43 and 50 y (years): 1946 cohort, n = 4787; 7, 11, 16, 23, 33 and 45 y: 1958 cohort, n = 16,820] and mid-adult BP. We adopted linear spline models with random coefficients to characterize childhood and adult BMI slopes. RESULTS: Mean systolic BP (SBP) decreased from the earlier- to later-born cohort by 2.8 mmHg in females, not males; mean diastolic BP (DBP) decreased by 3.2-3.3 mmHg (both sexes). Adult BMI was higher in the later- than the earlier-born cohort by 1.3-1.8 kg/m(2), slopes of BMI trajectory were steeper from early adulthood and associations with adult BP were stronger. Associations between adult BMI and SBP were stronger in the later-born cohort. For males, childhood BMI slope was associated with SBP only in the later-born cohort; the association for adult BMI slope was stronger in the later-born cohort: correlation coefficient r = 0.28 [95% confidence interval (CI): 0.25,0.33] versus 0.13 (0.06,0.20). For females, childhood slope was associated with SBP in both cohorts; adult slope was associated with SBP only in the 1958 cohort [r = 0.34 (0.31,0.37)]. Patterns of child-to-adult BMI associations were similar in relation to DBP. CONCLUSIONS: BP did not increase between two generations born 12 y apart despite higher BMI levels. A stronger association between BMI trajectory and BP in the later-born cohort suggests that BMI-related effects may have been offset by improvements in other factors linked to BP, such as diet and smoking.

Early Life Factors and Adult Leisure Time Physical Inactivity Stability and Change.

PURPOSE: Physical inactivity has a high prevalence and associated disease burden. A better understanding of influences on sustaining and changing inactive lifestyles is needed. We aimed to establish whether leisure time inactivity was stable in midadulthood and whether early life factors were associated with inactivity patterns. METHODS: In the 1958 British birth cohort (n = 12,271), leisure time inactivity (frequency, less than once a week) assessed at 33 and 50 yr was categorized as "never inactive," "persistently inactive," "deteriorating," or "improving." Early life factors (birth to 16 yr) were categorized into three (physical, social, and behavioral) domains. Using multinomial logistic regression, we assessed associations with inactivity persistence and change of factors within each early life domain and the three domains combined with and without adjustment for adult factors. RESULTS: Inactivity prevalence was similar at 33 and 50 yr (approximately 31%), but 17% deteriorated and 18% improved with age. In models adjusted for all domains simultaneously, factors associated with inactivity persistence versus never inactive were prepubertal stature (8% lower risk/height SD), poor hand control/coordination (17% higher risk/increase on four-point scale), cognition (16% lower/SD in ability) (physical); parental divorce (25% higher), class at birth (7% higher/reduction on four-point scale), minimal parental education (16% higher), household amenities (2% higher/increase in 19-point score (high = poor)) (social); and inactivity (22% higher/reduction in activity on four-point scale), low sports aptitude (47% higher), smoking (30% higher) (behavioral). All except stature, parental education, sports aptitude, and smoking were associated also with inactivity deterioration. Poor hand control/coordination was the only factor associated with improved status (13% lower/increase on four-point scale) versus persistently inactive. CONCLUSIONS: Adult leisure time inactivity is moderately stable. Early life factors are associated with persistent and deteriorating inactivity over decades in midadulthood but rarely with improvement.

Lifecourse social position and D-dimer; findings from the 1958 British birth cohort.

The aim is to examine the association of lifecourse socioeconomic position (SEP) on circulating levels of D-dimer. Data from the 1958 British birth cohort were used, social class was determined at three stages of respondents' life: at birth, at 23 and at 42 years. A cumulative indicator score of SEP (CIS) was calculated ranging from 0 (always in the highest social class) to 9 (always in the lowest social class). In men and women, associations were observed between CIS and D-dimer (P<0.05). Thus, the respondents in more disadvantaged social classes had elevated levels of D-dimer compared to respondents in less disadvantaged social class. In multivariate analyses, the association of disadvantaged social position with D-dimer was largely explained by fibrinogen, C-reactive protein and von Willebrand Factor in women, and additionally by smoking, alcohol consumption and physical activity in men. Socioeconomic circumstances across the lifecourse at various stages also contribute independently to raised levels of D-dimer in middle age in women only. Risk exposure related to SEP accumulates across life and contributes to raised levels of D-dimer. The association of haemostatic markers and social differences in health may be mediated by inflammatory and other markers.

25-Hydroxyvitamin D and cognitive performance in mid-life.

Hypovitaminosis D has been linked with poor cognitive function, particularly in older adults, but studies lack a lifespan approach; hence, the effects of reverse causality remain unknown. In the present study, we aimed to assess the relationship between 25-hydroxyvitamin D (25(OH)D) concentrations and subsequent cognitive performance in mid-adulthood and the influence of earlier life factors, including childhood cognitive ability, on this association. Information for the present study was obtained from the members of the 1958 British birth cohort (n 6496). Serum 25(OH)D concentration, indicating vitamin D status, was measured at age 45 years. Verbal memory (immediate and delayed word recall), verbal fluency (animal naming) and speed of processing were tested at age 50 years. Information on childhood cognitive ability, educational attainment, vitamin D-related behaviours and other covariates was collected prospectively from participants throughout their life. Childhood cognitive ability and educational attainment by age 42 years were strongly correlated with cognitive performance at age 50 years and with several vitamin D-related behaviours in mid-adulthood, but not with 25(OH)D concentrations at age 45 years. Participants with both low (<25 nmol/l) and high (≥75 nmol/l) 25(OH)D concentrations at age 45 years performed significantly worse on immediate word recall. The associations attenuated after adjustment for childhood cognitive ability, education, and socio-economic position; however, for the immediate word recall test, there was a non-linear association with 25(OH)D after further adjustment for obesity, menopausal status, smoking, alcohol consumption, physical activity and depressive symptoms at age 45 years (P(curvature)=0·01). The present study demonstrated that 25(OH)D concentrations were non-linearly associated with immediate word recall in mid-life. A clarification of the level of 25(OH)D concentrations that is most beneficial for predicting better cognitive performance in mid-life is required.