Work-family life courses and BMI trajectories in three British birth cohorts.

BACKGROUND/OBJECTIVES: Combining work and family responsibilities has previously been associated with improved health in mid-life, yet little is known about how these associations change over time (both biographical and historical) and whether this extends to body mass index (BMI) trajectories for British men and women. The purpose of this study was to investigate relationships between work-family life courses and BMI trajectories across adulthood (16-42 years) for men and women in three British birth cohorts. SUBJECTS/METHODS: Multiply imputed data from three nationally representative British birth cohorts were used-the MRC National Survey of Health and Development (NSHD; 1946 birth cohort, n=3012), the National Child Development Study (NCDS; 1958 birth cohort, n=9614) and the British Cohort Study (BCS; 1970 birth cohort, n=8140). A typology of work-family life course types was developed using multi-channel sequence analysis, linking annual information on work, partnerships and parenthood from 16 to 42 years. Work-family life courses were related to BMI trajectories using multi-level growth models. Analyses adjusted for indicators of prior health, birthweight, child BMI, educational attainment and socioeconomic position across the life course, and were stratified by gender and cohort. RESULTS: Work-family life courses characterised by earlier transitions to parenthood and weaker long-term links to employment were associated with greater increases in BMI across adulthood. Some of these differences, particularly for work-family groups, which are becoming increasingly non-normative, became more pronounced across cohorts (for example, increases in BMI between 16 and 42 years in long-term homemaking women: NSHD: 4.35 kg m-2, 95% confidence interval (CI): 3.44, 5.26; NCDS: 5.53 kg m-2, 95% CI: 5.18, 5.88; BCS: 6.69 kg m-2, 95% CI: 6.36, 7.02). CONCLUSIONS: Becoming a parent earlier and weaker long-term ties to employment are associated with greater increases in BMI across adulthood in British men and women.Rebecca Lacey, Anne McMunn, Amanda Sacker and Meena Kumari received funding from the European Research Council (grant number: ERC-2011-StG_20101124, PI: Anne McMunn). Steven Bell also received funding from the European Research Council (grant number: ERCStG-2012-309337_Alcohol-Lifecourse, PI: Annie Britton) and UK Medical Research Council/Alcohol Research UK (MR/M006638/1). Amanda Sacker, Anne McMunn and Meena Kumari additionally received support from the Economic and Social Research Council’s International Centre for Life Course Studies in Society and Health (grant number: ES/J019119/1). DK is supported by the UK Medical Research Council (MC_UU_12019/1). The MRC National Survey of Health and Development is funded by the UK Medical Research Council. Peggy McDonough and Diana Worts were supported by the Canadian Institutes of Health Research grant MOP 119526 and the Social Sciences and Humanities Research Council grant 43512-1267

A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy

The aim of this study was to characterize the relationship between warfarin concentrations and international normalized ratio (INR) response and to identify predictors important for dose individualization. S- and R-warfarin concentrations, INR, and CYP2C9 and VKORC1 genotypes from 150 patients were used to develop a population pharmacokinetic/ pharmacodynamic model in NONMEM. The anticoagulant response was best described by an inhibitory EMAX model, with S-warfarin concentration as the only exposure predictor for response. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. CYP2C9 genotype and age were identified as predictors for S-warfarin clearance, and VKORC1 genotype as a predictor for warfarin sensitivity. Predicted INR curves indicate important steady-state differences between patients with different sets of covariates; differences that cannot be foreseen from early INR assessments alone. It is important to account for CYP2C9 and VKORC1 genotypes and age to improve a priori and a posteriori individualization of warfarin therapy

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.</p