A multivariant recall-by-genotype study of the metabolomic signature of BMI.

OBJECTIVE: This study estimated the effect of BMI on circulating metabolites in young adults using a recall-by-genotype study design. METHODS: A recall-by-genotype study was implemented in the Avon Longitudinal Study of Parents and Children. Samples from 756 participants were selected for untargeted metabolomics analysis based on low versus high genetic liability for higher BMI defined by a genetic risk score (GRS). Regression analyses were performed to investigate associations between BMI GRS group and relative abundance of 973 metabolites. RESULTS: After correction for multiple testing, 29 metabolites were associated with BMI GRS group. Bilirubin was among the most strongly associated metabolites, with reduced levels measured in individuals in the high-BMI GRS group (ß = -0.32, 95% CI: -0.46 to -0.18, Benjamini-Hochberg adjusted p = 0.005). This study observed associations between BMI GRS group and the levels of several potentially diet-related metabolites, including hippurate, which had lower mean abundance in individuals in the high-BMI GRS group (ß = -0.29, 95% CI: -0.44 to -0.15, Benjamini-Hochberg adjusted p = 0.008). CONCLUSIONS: Together with existing literature, these results suggest that a genetic predisposition to higher BMI captures differences in metabolism leading to adiposity gain. In the absence of prospective data, separating these effects from the downstream consequences of weight gain is challenging.

The Effect of Pre-Analytical Conditions on Blood Metabolomics in Epidemiological Studies.

Serum and plasma are commonly used in metabolomic-epidemiology studies. Their metabolome is susceptible to differences in pre-analytical conditions and the impact of this is unclear. Participant-matched EDTA-plasma and serum samples were collected from 37 non-fasting volunteers and profiled using a targeted nuclear magnetic resonance (NMR) metabolomics platform (n = 151 traits). Correlations and differences in mean of metabolite concentrations were compared between reference (pre-storage: 4 °C, 1.5 h; post-storage: no buffer addition delay or NMR analysis delay) and four pre-storage blood processing conditions, where samples were incubated at (i) 4 °C, 24 h; (ii) 4 °C, 48 h; (iii) 21 °C, 24 h; and (iv) 21 °C, 48 h, before centrifugation; and two post-storage sample processing conditions in which samples thawed overnight (i) then left for 24 h before addition of sodium buffer followed by immediate NMR analysis; and (ii) addition of sodium buffer, then left for 24 h before NMR profiling. We used multilevel linear regression models and Spearman's rank correlation coefficients to analyse the data. Most metabolic traits had high rank correlation and minimal differences in mean concentrations between samples subjected to reference and the different conditions tested, that may commonly occur in studies. However, glycolysis metabolites, histidine, acetate and diacylglycerol concentrations may be compromised and this could bias results in association/causal analyses.

The second generation of The Avon Longitudinal Study of Parents and Children (ALSPAC-G2): a cohort profile.

Background: The Avon Longitudinal Study of Parents and Children-Generation 2 (ALSPAC-G2) was set up to provide a unique multi-generational cohort. It builds on the existing ALSPAC resource, which recruited 14,541 pregnancies to women resident in the South West of England who were expected to deliver between 01/04/1991 and 31/12/1992. Those women and their partners (Generation 0; ALSPAC-G0) and their offspring (ALSPAC-G1) have been followed for the last 26 years. This profile describes recruitment and data collection on the next generation (ALSPAC-G2)-the grandchildren of ALSPAC-G0 and children of ALSPAC-G1. Recruitment: Recruitment began on the 6 th of June 2012 and we present details of recruitment and participants up to 30 th June 2018 (~6 years). We knew at the start of recruitment that some ALSPAC-G1 participants had already become parents and ALSPAC-G2 is an open cohort; we recruit at any age. We hope to continue recruiting until all ALSPAC-G1 participants have completed their families. Up to 30 th June 2018 we recruited 810 ALSPAC-G2 participants from 548 families. Of these 810, 389 (48%) were recruited during their mother's pregnancy, 287 (35%) before age 3 years, 104 (13%) between 3-6 years and 30 (4%) after 6 years. Over 70% of those invited to early pregnancy, late pregnancy, second week of life, 6-, 12- and 24-month assessments (whether for their recruitment, or a follow-up, visit) have attended, with attendance being over 60% for subsequent visits up to 7 years (to few are eligible for the 9- and 11-year assessments to analyse). Data collection: We collect a wide-range of social, lifestyle, clinical, anthropometric and biological data on all family members repeatedly. Biological samples include blood (including cord-blood), urine, meconium and faeces, and placental tissue. In subgroups detailed data collection, such as continuous glucose monitoring and videos of parent-child interactions, are being collected.

Adolescent cannabis and tobacco use and educational outcomes at age 16: birth cohort study.

AIMS: To investigate the relationship between cannabis and tobacco use by age 15 and subsequent educational outcomes. DESIGN: Birth cohort study. SETTING: England. PARTICIPANTS: The sample was drawn from the Avon Longitudinal Study of Parents and Children; a core sample of 1155 individuals had complete information on all the variables. MEASUREMENTS: The main exposures were cannabis and tobacco use at age 15 assessed in clinic by computer-assisted questionnaire and serum cotinine. The main outcomes were performance in standardized assessments at 16 [Key Stage 4, General Certificate of Secondary Education (GCSE)] in English and mathematics (mean scores), completion of five or more assessments at grade C level or higher and leaving school having achieved no qualifications. Analyses were sequentially adjusted for multiple covariates using a hierarchical approach. Covariates considered were: maternal substance use (ever tobacco or cannabis use, alcohol use above recommended limits); life course socio-economic position (family occupational class, maternal education, family income); child sex; month and year of birth; child educational attainment prior to age 11 (Key Stage 2); child substance use (tobacco, alcohol and cannabis) prior to age 15 and child conduct disorder. FINDINGS: In fully adjusted models both cannabis and tobacco use at age 15 were associated with subsequent adverse educational outcomes. In general, the dose-response effect seen was consistent across all educational outcomes assessed. Weekly cannabis use was associated negatively with English GCSE results [grade point difference (GPD), -5.93, 95% confidence interval (CI) = -8.34, -3.53] and with mathematics GCSE results (GPD, -6.91, 95% CI = -9.92, -3.89). Daily tobacco smoking was associated negatively with English GCSE (GPD, -11.90, 95% CI = -13.47, -10.33) and with mathematics GCSE (GPD, -16.72, 95% CI = -18.57, -14.86). The greatest attenuation of these effects was seen on adjustment for other substance use and conduct disorder. Following adjustment, tobacco appeared to have a consistently stronger effect than cannabis. CONCLUSIONS: Both cannabis and tobacco use in adolescence are associated strongly with subsequent adverse educational outcomes. Given the non-specific patterns of association seen and the attenuation of estimates on adjustment, it is possible that these effects arise through non-causal mechanisms, although a causal explanation cannot be discounted. © 2015 Society for the Study of Addiction.

Association of maternal smoking with child cotinine levels.

INTRODUCTION: Our aim was to understand the strength of association between parental smoking and child environmental tobacco smoke (ETS) exposure in order to inform the development of future tobacco control policies. ETS was measured using child cotinine levels below the active smoking threshold. METHODS: Participants were drawn from the Avon Longitudinal Study of Parents and Children and included 3,128 participants at age 7 years and 1,868 participants at age 15 years. The primary outcome was cotinine levels of nonsmoking children, to investigate the relationship between maternal smoking and child cotinine levels. The secondary outcome was cotinine levels of all individuals to investigate the relationship between child smoking and child cotinine levels. Maternal and child smoking behavior was assessed by self-report questionnaire. We adjusted for several sociodemographic variables. RESULTS: We found an association between maternal smoking and child cotinine at age 7 years (mean cotinine = 1.16ng/ml serum, ratio of geometric means = 3.94, 95% CI = 2.86-5.42) and at age 15 years (mean cotinine = 0.94ng/ml serum, ratio of geometric means = 5.26, 95% CI = 3.06-9.03), after adjustment for potential confounders. CONCLUSIONS: The magnitude of this association for children whose mothers were heavy smokers was comparable with the quantity of half the levels of cotinine observed among children who were irregular (i.e., nonweekly) active smokers, and it was greater than five times higher than that seen in nonsmoking children whose mothers didn't smoke. This provides further evidence for the importance of public health interventions to reduce smoking exposure in the home.