Maternal smoking during pregnancy and offspring risk of intellectual disability: a UK-based cohort study.

Background: Observational studies have described associations of maternal smoking during pregnancy with intellectual disability (ID) in the exposed offspring. Whether these results reflect a causal effect or unmeasured confounding is still unclear. Methods: Using a UK-based prospectively collected birth cohort (the Avon Longitudinal Study of Parents and Children) of 13,479 children born between 1991 and 1992, we assessed the relationship between maternal smoking at 18 weeks' gestation and offspring risk of ID, ascertained through multiple sources of linked information including primary care diagnoses and education records. Using confounder-adjusted logistic regression, we performed observational analyses and a negative control analysis that compared maternal with partner smoking in pregnancy under the assumption that if a causal effect were to exist, maternal effect estimates would be of greater magnitude than estimates for partner smoking if the two exposures suffer from comparable biases. Results: In observational analysis, we found an adjusted odds ratio for ID of 0.75 (95% CI = 0.49-1.13) for any maternal smoking and 0.97 (95% CI = 0.71-1.33) per 10-cigarette increase in number of cigarettes smoked per day. In negative control analysis, comparable effect estimates were found for any partner smoking (OR = 0.94; 95% CI = 0.63-1.40) and number of cigarettes smoked per day (OR = 0.94; 95% CI = 0.74-1.20). Conclusions: The results are not consistent with a causal effect of maternal smoking during pregnancy on offspring ID.

Maximizing Insights from Longitudinal Epigenetic Age Data: Simulations, Applications, and Practical Guidance.

Background: Epigenetic Age (EA) is an age estimate, developed using DNA methylation (DNAm) states of selected CpG sites across the genome. Although EA and chronological age are highly correlated, EA may not increase uniformly with time. Departures, known as epigenetic age acceleration (EAA), are common and have been linked to various traits and future disease risk. Limited by available data, most studies investigating these relationships have been cross-sectional - using a single EA measurement. However, the recent growth in longitudinal DNAm studies has led to analyses of associations with EA over time. These studies differ in (i) their choice of model; (ii) the primary outcome (EA vs. EAA); and (iii) in their use of chronological age or age-independent time variables to account for the temporal dynamic. We evaluated the robustness of each approach using simulations and tested our results in two real-world examples, using biological sex and birthweight as predictors of longitudinal EA. Results: Our simulations showed most accurate effect sizes in a linear mixed model or generalized estimating equation, using chronological age as the time variable. The use of EA versus EAA as an outcome did not strongly impact estimates. Applying the optimal model in real-world data uncovered an accelerated EA rate in males and an advanced EA that decelerates over time in children with higher birthweight. Conclusion: Our results can serve as a guide for forthcoming longitudinal EA studies, aiding in methodological decisions that may determine whether an association is accurately estimated, overestimated, or potentially overlooked.

Using instruments for selection to adjust for selection bias in Mendelian randomization.

Selection bias is a common concern in epidemiologic studies. In the literature, selection bias is often viewed as a missing data problem. Popular approaches to adjust for bias due to missing data, such as inverse probability weighting, rely on the assumption that data are missing at random and can yield biased results if this assumption is violated. In observational studies with outcome data missing not at random, Heckman's sample selection model can be used to adjust for bias due to missing data. In this paper, we review Heckman's method and a similar approach proposed by Tchetgen Tchetgen and Wirth (2017). We then discuss how to apply these methods to Mendelian randomization analyses using individual-level data, with missing data for either the exposure or outcome or both. We explore whether genetic variants associated with participation can be used as instruments for selection. We then describe how to obtain missingness-adjusted Wald ratio, two-stage least squares and inverse variance weighted estimates. The two methods are evaluated and compared in simulations, with results suggesting that they can both mitigate selection bias but may yield parameter estimates with large standard errors in some settings. In an illustrative real-data application, we investigate the effects of body mass index on smoking using data from the Avon Longitudinal Study of Parents and Children.

Genetic susceptibility to neurodevelopmental conditions associates with neonatal DNA methylation patterns in the general population: an individual participant data meta-analysis.

Background: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in foetal (neuro)development. While epigenetic processes are considered an important underlying pathway between genetic susceptibility and neurodevelopmental conditions, it is unclear (i) whether genetic susceptibility to these conditions is associated with epigenetic patterns, specifically DNA methylation (DNAm), already at birth; (ii) to what extent DNAm patterns are unique or shared across conditions, and (iii) whether these neonatal DNAm patterns can be leveraged to enhance genetic prediction of (neuro)developmental outcomes. Methods: We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia, quantified using polygenic scores (PGSs) on cord blood DNAm, using four population-based cohorts (n pooled=5,802), all North European. Heterogeneity statistics were used to estimate overlap in DNAm patterns between PGSs. Subsequently, DNAm-based measures of PGSs were built in a target sample, and used as predictors to test incremental variance explained over PGS in 130 (neuro)developmental outcomes spanning birth to 14 years. Outcomes: In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10-8), predominantly in the major histocompatibility complex. Functional characterization of these DNAm loci confirmed strong genetic effects, significant blood-brain concordance and enrichment for immune-related pathways. 8 loci were identified for ASD-PGS (mapping to FDFT1 and MFHAS1), and none for ADHD-PGS. Regional analyses indicated a large number of differentially methylated regions for all PGSs (SCZ-PGS: 157, ASD-PGS: 130, ADHD-PGS: 166). DNAm signals showed little overlap between PGSs. We found suggestive evidence that incorporating DNAm-based measures of genetic susceptibility at birth increases explained variance for several child cognitive and motor outcomes over and above PGS. Interpretation: Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm at birth in a population-based sample, with largely distinct DNAm patterns between PGSs. These findings support an early-origins perspective on schizophrenia. Funding: HorizonEurope; European Research Council.

A novel hypothesis-generating approach for detecting phenotypic associations using epigenetic data.

Aim: Hypotheses about what phenotypes to include in causal analyses, that in turn can have clinical and policy implications, can be guided by hypothesis-free approaches leveraging the epigenome, for example. Materials & methods: Minimally adjusted epigenome-wide association studies (EWAS) using ALSPAC data were performed for example conditions, dysmenorrhea and heavy menstrual bleeding (HMB). Differentially methylated CpGs were searched in the EWAS Catalog and associated traits identified. Traits were compared between those with and without the example conditions in ALSPAC. Results: Seven CpG sites were associated with dysmenorrhea and two with HMB. Smoking and adverse childhood experience score were associated with both conditions in the hypothesis-testing phase. Conclusion: Hypothesis-generating EWAS can help identify associations for future analyses.

To inform policy and improve clinical practice, it is important that researchers who study people's health find out which traits might increase the risk of illness. However, it can be difficult to know which traits should be looked at. In this study, we wanted to look for traits that might increase the risk of painful and heavy periods, using data about the switches that turn our genes on and off. There are some people in the Children of the 90s study that have data on gene switches. We compared all the switches between those with and without painful or heavy periods. For painful periods, we found links with seven switches and for heavy periods, we found two. We then used another data source, called the EWAS Catalog, to see which traits were associated with these switches. The traits we found included body size, smoking and child abuse. Finally, when using data on traits from the wider Children of the 90s group, we found that smoking and more difficult childhoods were some of the traits related to painful and heavy periods. A good thing about this approach is that we could find new traits that might increase the risk of painful or heavy periods; these should be looked at in future studies.

Plasma metabolomic and lipidomic profiles accurately classify mothers of children with congenital heart disease: an observational study.

INTRODUCTION: Congenital heart disease (CHD) is the most common congenital anomaly, representing a significant global disease burden. Limitations exist in our understanding of aetiology, diagnostic methodology and screening, with metabolomics offering promise in addressing these. OBJECTIVE: To evaluate maternal metabolomics and lipidomics in prediction and risk factor identification for childhood CHD. METHODS: We performed an observational study in mothers of children with CHD following pregnancy, using untargeted plasma metabolomics and lipidomics by ultrahigh performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). 190 cases (157 mothers of children with structural CHD (sCHD); 33 mothers of children with genetic CHD (gCHD)) from the children OMACp cohort and 162 controls from the ALSPAC cohort were analysed. CHD diagnoses were stratified by severity and clinical classifications. Univariate, exploratory and supervised chemometric methods were used to identify metabolites and lipids distinguishing cases and controls, alongside predictive modelling. RESULTS: 499 metabolites and lipids were annotated and used to build PLS-DA and SO-CovSel-LDA predictive models to accurately distinguish sCHD and control groups. The best performing model had an sCHD test set mean accuracy of 94.74% (sCHD test group sensitivity 93.33%; specificity 96.00%) utilising only 11 analytes. Similar test performances were seen for gCHD. Across best performing models, 37 analytes contributed to performance including amino acids, lipids, and nucleotides. CONCLUSIONS: Here, maternal metabolomic and lipidomic analysis has facilitated the development of sensitive risk prediction models classifying mothers of children with CHD. Metabolites and lipids identified offer promise for maternal risk factor profiling, and understanding of CHD pathogenesis in the future.

Prenatal Urban Environment and Blood Pressure Trajectories From Childhood to Early Adulthood.

Background: Prenatal urban environmental exposures have been associated with blood pressure in children. The dynamic of these associations across childhood and later ages is unknown. Objectives: The purpose of this study was to assess associations of prenatal urban environmental exposures with blood pressure trajectories from childhood to early adulthood. Methods: Repeated measures of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were collected in up to 7,454 participants from a UK birth cohort. Prenatal urban exposures (n = 43) covered measures of noise, air pollution, built environment, natural spaces, traffic, meteorology, and food environment. An exposome-wide association study approach was used. Linear spline mixed-effects models were used to model associations of each exposure with trajectories of blood pressure. Replication was sought in 4 independent European cohorts (up to 9,261). Results: In discovery analyses, higher humidity was associated with a faster increase (mean yearly change in SBP for an interquartile range increase in humidity: 0.29 mm Hg/y, 95% CI: 0.20-0.39) and higher temperature with a slower increase (mean yearly change in SBP per interquartile range increase in temperature: -0.17 mm Hg/y, 95% CI: -0.28 to -0.07) in SBP in childhood. Higher levels of humidity and air pollution were associated with faster increase in DBP in childhood and slower increase in adolescence. There was little evidence of an association of other exposures with change in SBP or DBP. Results for humidity and temperature, but not for air pollution, were replicated in other cohorts. Conclusions: Replicated findings suggest that higher prenatal humidity and temperature could modulate blood pressure changes across childhood.

Sleep duration, sleep problems and developmental trajectories of urinary incontinence: a prospective cohort study.

To examine if preschool sleep duration and sleep problems are associated with urinary incontinence (UI) at primary school-age. We used multinomial logistic regression to examine the association of child sleep duration/problems (3½ years) with UI trajectories (4-9 years) in 8751 (4507 boys, 4244 girls) from the Avon Longitudinal Study of Parents and Children. We adjusted for sex, socioeconomic indicators, mothers' emotional/practical/financial support, developmental delay, stressful life events, temperament, and emotional/behaviour problems. Preschool children who slept more than 8½ hours per night had a decreased probability of UI at school-age. There was a 33% reduction in odds of daytime wetting per additional hour of sleep (odds ratio [OR] = 0.67, 95% confidence interval [CI] 0.52-0.86). Sleep problems were associated with increased odds of UI e.g., getting up after being put to bed was associated with daytime wetting (OR = 2.20, 95% CI 1.43-3.39); breathing problems whilst sleeping were associated with delayed bladder control (OR = 1.68, 95% CI 1.12-2.52), and night-time waking was associated with persistent (day and night) wetting (OR = 1.53, 95% CI 1.16-2.00). Waking during the night and waking up early in the morning were associated with reduced odds of bedwetting at school-age (OR = 0.76, 95% CI 0.61-0.96 and OR = 0.80, 95% CI 0.64-0.99 respectively). Preschool children who sleep for longer have a lower likelihood of UI at school-age, whilst those with sleep problems are more likely to experience daytime wetting and combined (day and night) wetting, but not bedwetting alone. Short sleep duration and sleep problems in early childhood could be indicators of future problems attaining and maintaining bladder control.

Factors associated with chronic depressive symptoms across adolescence and young adulthood: a UK birth cohort study.

AIMS: Identifying children and/or adolescents who are at highest risk for developing chronic depression is of utmost importance, so that we can develop more effective and targeted interventions to attenuate the risk trajectory of depression. To address this, the objective of this study was to identify young people with persistent depressive symptoms across adolescence and young adulthood and examine the prospective associations between factors and persistent depressive symptoms in young people. METHODS: We used data from 6711 participants in the Avon Longitudinal Study of Parents and Children. Depressive symptoms were assessed at 12.5, 13.5, 16, 17.5, 21 and 22 years with the Short Mood and Feelings Questionnaire, and we further examined the influence of multiple biological, psychological and social factors in explaining chronic depressive symptoms. RESULTS: Using latent class growth analysis, we identified four trajectories of depressive symptoms: persistent high, persistent low, persistent moderate and increasing high. After applying several logistic regression models, we found that loneliness and feeling less connected at school were the most relevant factors for chronic course of depressive symptoms. CONCLUSIONS: Our findings contribute with the identification of those children who are at highest risk for developing chronic depressive symptoms.

Negative association between higher maternal pre-pregnancy body mass index and breastfeeding outcomes is not mediated by DNA methylation.

The benefits of breastfeeding for the health and wellbeing of both infants and mothers are well documented, yet global breastfeeding rates are low. One factor associated with low breast feeding is maternal body mass index (BMI), which is used as a measure of obesity. The negative relationship between maternal obesity and breastfeeding is likely caused by a variety of social, psychological, and physiological factors. Maternal obesity may also have a direct biological association with breastfeeding through changes in maternal DNA methylation. Here, we investigate this potential biological association using data from a UK-based cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). We find that pre-pregnancy body mass index (BMI) is associated with lower initiation to breastfeed and shorter breastfeeding duration. We conduct epigenome-wide association studies (EWAS) of pre-pregnancy BMI and breastfeeding outcomes, and run candidate-gene analysis of methylation sites associated with BMI identified via previous meta-EWAS. We find that DNA methylation at cg11453712, annotated to PHTP1, is associated with pre-pregnancy BMI. From our results, neither this association nor those at candidate-gene sites are likely to mediate the link between pre-pregnancy BMI and breastfeeding.

Incident psychotic experiences following self-reported use of high-potency cannabis: Results from a longitudinal cohort study.

BACKGROUND AND AIMS: High-potency cannabis has been associated with increased risk of psychosis, but a lack of prospective data hinders understanding of causality in this relationship. This study aimed to combine prospective report of cannabis use with retrospective report of potency to infer the potency of cannabis used in adolescence and explore whether use of cannabis, and the use of high-potency cannabis, in adolescence is associated with incident psychotic experiences. DESIGN: Population-based birth cohort study. SETTING: United Kingdom. PARTICIPANTS: n = 5570 participants who reported on any cannabis use (yes/no) age 16 and 18 years, and n = 1560 participants from this group who also retrospectively reported on cannabis potency. MEASUREMENTS: In questionnaires at ages 16 and 18, individuals self-reported lifetime cannabis use, and at age 24, participants reported the type of cannabis they most commonly used in the whole time since first using cannabis. Psychotic experiences were assessed at age 24 years using the semi-structured Psychosis-Like Symptom Interview, with incident defined as new-onset occurring between ages 19 and 24 years. FINDINGS: Use of high-potency cannabis at age 16 or 18 was associated with twice the likelihood of experiencing incident psychotic experiences from age 19-24 (Odds Ratio 2.15, 95% Confidence Intervals 1.13-4.06). There was less evidence for an effect of any cannabis use on incident psychotic experiences (Odds Ratio 1.45, 95% Confidence Intervals 0.94-2.12). CONCLUSIONS: Use of high-potency cannabis appears to be associated with increased likelihood of psychotic experiences.

Counterfactual Mediation Analysis with a Latent Class Exposure.

Latent classes are a useful tool in developmental research, however there are challenges associated with embedding them within a counterfactual mediation model. We develop and test a new method "updated pseudo class draws (uPCD)" to examine the association between a latent class exposure and distal outcome that could easily be extended to allow the use of any counterfactual mediation method. UPCD extends an existing group of methods (based on pseudo class draws) that assume that the true values of the latent class variable are missing, and need to be multiply imputed using class membership probabilities. We simulate data based on the Avon Longitudinal Study of Parents and Children, examine performance for existing techniques to relate a latent class exposure to a distal outcome ("one-step," "bias-adjusted three-step," "modal class assignment," "non-inclusive pseudo class draws," and "inclusive pseudo class draws") and compare bias in parameter estimates and their precision to uPCD when estimating counterfactual mediation effects. We found that uPCD shows minimal bias when estimating counterfactual mediation effects across all levels of entropy. UPCD performs similarly to recommended methods (one-step and bias-adjusted three-step), but provides greater flexibility and scope for incorporating the latent grouping within any commonly-used counterfactual mediation approach.

Metabolome-wide Mendelian randomization for age at menarche and age at natural menopause.

BACKGROUND: The role of metabolism in the variation of age at menarche (AAM) and age at natural menopause (ANM) in the female population is not entirely known. We aimed to investigate the causal role of circulating metabolites in AAM and ANM using Mendelian randomization (MR). METHODS: We combined MR with genetic colocalization to investigate potential causal associations between 658 metabolites and AAM and between 684 metabolites and ANM. We extracted genetic instruments for our exposures from four genome-wide association studies (GWAS) on circulating metabolites and queried the effects of these variants on the outcomes in two large GWAS from the ReproGen consortium. Additionally, we assessed the mediating role of the body mass index (BMI) in these associations, identified metabolic pathways implicated in AAM and ANM, and sought validation for selected metabolites in the Avon Longitudinal Study of Parents and Children (ALSPAC). RESULTS: Our analysis identified 10 candidate metabolites for AAM, but none of them colocalized with AAM. For ANM, 76 metabolites were prioritized (FDR-adjusted MR P-value ≤ 0.05), with 17 colocalizing, primarily in the glycerophosphocholines class, including the omega-3 fatty acid and phosphatidylcholine (PC) categories. Pathway analyses and validation in ALSPAC mothers also highlighted the role of omega and polyunsaturated fatty acids levels in delaying age at menopause. CONCLUSIONS: Our study suggests that metabolites from the glycerophosphocholine and fatty acid families play a causal role in the timing of both menarche and menopause. This underscores the significance of specific metabolic pathways in the biology of female reproductive longevity.

Depressive symptoms in adolescence and adult educational and employment outcomes: a structured life course analysis.

BACKGROUND: Depression is a common mental health disorder that often starts during adolescence, with potentially important future consequences including 'Not in Education, Employment or Training' (NEET) status. METHODS: We took a structured life course modeling approach to examine how depressive symptoms during adolescence might be associated with later NEET status, using a high-quality longitudinal data resource. We considered four plausible life course models: (1) an early adolescent sensitive period model where depressive symptoms in early adolescence are more associated with later NEET status relative to exposure at other stages; (2) a mid adolescent sensitive period model where depressive symptoms during the transition from compulsory education to adult life might be more deleterious regarding NEET status; (3) a late adolescent sensitive period model, meaning that depressive symptoms around the time when most adults have completed their education and started their careers are the most strongly associated with NEET status; and (4) an accumulation of risk model which highlights the importance of chronicity of symptoms. RESULTS: Our analysis sample included participants with full information on NEET status (N = 3951), and the results supported the accumulation of risk model, showing that the odds of NEET increase by 1.015 (95% CI 1.012-1.019) for an increase of 1 unit in depression at any age between 11 and 24 years. CONCLUSIONS: Given the adverse implications of NEET status, our results emphasize the importance of supporting mental health during adolescence and early adulthood, as well as considering specific needs of young people with re-occurring depressed mood.

Shorter night-time sleep duration and later sleep timing from infancy to adolescence.

BACKGROUND: Here, we (a) examined the trajectories of night-time sleep duration, bedtime and midpoint of night-time sleep (MPS) from infancy to adolescence, and (b) explored perinatal risk factors for persistent poor sleep health. METHODS: This study used data from 12,962 participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Parent or self-reported night-time sleep duration, bedtime and wake-up time were collected from questionnaires at 6, 18 and 30 months, and at 3.5, 4-5, 5-6, 6-7, 9, 11 and 15-16 years. Child's sex, birth weight, gestational age, health and temperament, together with mother's family adversity index (FAI), age at birth, prenatal socioeconomic status and postnatal anxiety and depression, were included as risk factors for persistent poor sleep health. Latent class growth analyses were applied first to detect trajectories of night-time sleep duration, bedtime and MPS, and we then applied logistic regressions for the longitudinal associations between risk factors and persistent poor sleep health domains. RESULTS: We obtained four trajectories for each of the three sleep domains. In particular, we identified a trajectory characterized by persistent shorter sleep, a trajectory of persistent later bedtime and a trajectory of persistent later MPS. Two risk factors were associated with the three poor sleep health domains: higher FAI with increased risk of persistent shorter sleep (OR = 1.20, 95% CI = 1.11-1.30, p < .001), persistent later bedtime (OR = 1.28, 95% CI = 1.19-1.39, p < .001) and persistent later MPS (OR = 1.30, 95% CI = 1.22-1.38, p < .001); and higher maternal socioeconomic status with reduced risk of persistent shorter sleep (OR = 0.99, 95% CI = 0.98-1.00, p = .048), persistent later bedtime (OR = 0.98, 95% CI = 0.97-0.99, p < .001) and persistent later MPS (OR = 0.99, 95% CI = 0.98-0.99, p < .001). CONCLUSIONS: We detected trajectories of persistent poor sleep health (i.e. shorter sleep duration, later bedtime and later MPS) from infancy to adolescence, and specific perinatal risk factors linked to persistent poor sleep health domains.

Demographic, socioeconomic and life-course risk factors for internalized weight stigma in adulthood: evidence from an English birth cohort study.

Background: Obesity is highly stigmatized, with negative obesity-related stereotypes widespread across society. Internalized weight stigma (IWS) is linked to negative outcomes including poor mental health and disordered eating. Previous evidence examining population groups at higher risk of experiencing IWS comes from small, nonrepresentative samples. Here, we re-assess previously reported associations of IWS with demographic, socioeconomic, and wider social factors in a large general population birth cohort study for the first time. Methods: In the Avon Longitudinal Study of Parents and Children (ALSPAC), we explored differences in IWS at age 31 years by sex, ethnicity, socioeconomic factors, sexual orientation, and family and wider social influences, using confounder-adjusted multivariable regression. Findings: In models adjusted for potential confounders and BMI in childhood, adolescence, and adulthood (N = 4060), IWS was higher for females (standardized beta: 0.56, 95% CI: 0.50, 0.61), sexual minorities (0.17 S.D. higher, 95% CI: 0.09, 0.24), and less socioeconomically advantaged individuals (e.g., 0.16 S.D. higher (95% CI: 0.08, 0.24) for participants whose mothers had minimum or no qualifications, compared to a university degree). The social environment during adolescence and young adulthood was important: IWS was higher for people who at age 13 years felt pressure to lose weight from family (by 0.13 S.D., 95% CI: 0.03, 0.23), and the media (by 0.17, 95% CI: 0.10, 0.25), or had experienced bullying (e.g., 0.25 S.D., 95% CI: 0.17, 0.33 for bullying at age 23 years). Interpretation: Internalized weight stigma differs substantially between demographic groups. Risk is elevated for females, sexual minorities, and socioeconomically disadvantaged adults, and this is not explained by differences in BMI. Pressure to lose weight from family and the media in adolescence may have long-lasting effects on IWS. Funding: The ESRC, MRC, NIHR, and Wellcome Trust.

Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts.

Chronic inflammation is a hallmark of age-related disease states. The effectiveness of inflammatory proteins including C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. We show that inter-individual differences in DNAm capture 50% of the variance in circulating CRP (N = 17,936, Generation Scotland). We develop a series of DNAm predictors of CRP using state-of-the-art algorithms. An elastic-net-regression-based predictor outperformed competing methods and explained 18% of phenotypic variance in the Lothian Birth Cohort of 1936 (LBC1936) cohort, doubling that of existing DNAm predictors. DNAm predictors performed comparably in four additional test cohorts (Avon Longitudinal Study of Parents and Children, Health for Life in Singapore, Southall and Brent Revisited, and LBC1921), including for individuals of diverse genetic ancestry and different age groups. The best-performing predictor surpassed assay-measured CRP and a genetic score in its associations with 26 health outcomes. Our findings forge new avenues for assessing chronic low-grade inflammation in diverse populations.

Emotional problems across development: examining measurement invariance across childhood, adolescence and early adulthood.

Emotional problems (anxiety, depression) are prevalent in children, adolescents and young adults with varying ages at onset. Studying developmental changes in emotional problems requires repeated assessments using the same or equivalent measures. The parent-rated Strengths and Difficulties Questionnaire is commonly used to assess emotional problems in childhood and adolescence, but there is limited research about whether it captures a similar construct across these developmental periods. Our study addressed this by investigating measurement invariance in the scales' emotional problems subscale (SDQ-EP) across childhood, adolescence and early adulthood. Data from two UK population cohorts were utilised: the Millennium Cohort Study (ages 3-17 years) and the Avon Longitudinal Study of Parents and Children (4-25 years). In both samples we observed weak (metric) measurement invariance by age, suggesting that the parent-rated SDQ-EP items contribute to the underlying construct of emotional problems similarly across age. This supports the validity of using the subscale to rank participants on their levels of emotional problems in childhood, adolescence and early adulthood. However strong (scalar) measurement invariance was not observed, suggesting that the same score may correspond to different levels of emotional problems across developmental periods. Comparisons of mean parent-rated SDQ-EP scores across age may therefore not be valid.

The association between sexual orientation and psychotic like experiences during adolescence: a prospective cohort study.

PURPOSE: Psychotic like experiences (PLEs) are relatively common during adolescence and associated with a range of negative outcomes. There is evidence that sexual minorities are at increased risk of mental health problems including depression, anxiety, self-harm and suicidality. However, no study has investigated the association between sexual orientation and psychotic experiences during adolescence. We compared trajectories of PLEs in sexual minority and heterosexual adolescents from 12 to 24 years of age. METHODS: We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants provided data on sexual orientation at age 16 and PLEs at ages 12, 17 and 24. We used multi-level logistic regression models to test associations between sexual orientation and PLEs, before and after adjusting for covariates. We investigated whether the association differed according to time-point and sex using interaction terms. RESULTS: We found evidence that the odds of PLEs were 2.35 times (95% Confidence Interval 1.79-3.06, p < 0.0001) higher among sexual minority compared with heterosexual adolescents, across all ages, after adjusting for covariates. There was no evidence that the association between sexual orientation and PLEs differed according to time-point (p = 0.50) or sex (p = 0.29). CONCLUSION: We found an increased risk of psychosis in sexual minorities compared with heterosexuals, which was present from around 12 years of age and persisted until age 24. Early interventions to prevent this mental health inequality could include universal interventions to promote inclusivity and acceptance of diverse sexual orientations.

Smoking during pregnancy and its effect on placental weight: a Mendelian randomization study.

BACKGROUND: The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery. METHODS: We used one-sample Mendelian randomization, drawing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (N = 690 to 804) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (N = 4267 to 4606). The sample size depends on the smoking definition used for different analyses. The analysis was performed in pre-pregnancy smokers only, due to the specific role of the single-nucleotide polymorphism (SNP) rs1051730 (CHRNA5 - CHRNA3 - CHRNB4) in affecting smoking cessation but not initiation. RESULTS: Fixed effect meta-analysis showed a 182 g [95%CI: 29,335] higher placental weight for pre-pregnancy smoking mothers who continued smoking at the beginning of pregnancy, compared with those who stopped smoking. Using the number of cigarettes smoked per day in the first trimester as the exposure, the causal effect on placental weight was 11 g [95%CI: 1,21] per cigarette per day. Similarly, smoking at the end of pregnancy was causally associated with higher placental weight. Using the residuals of birth weight regressed on placental weight as the outcome, we showed evidence of lower offspring birth weight relative to the placental weight, both for continuing smoking at the start of pregnancy as well as continuing smoking throughout pregnancy (change in z-score birth weight adjusted for z-score placental weight: -0.8 [95%CI: -1.6,-0.1]). CONCLUSION: Our results suggest that continued smoking during pregnancy causes higher placental weights.