DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

Agreement between self-reported and registry-based use of sleep medications and tranquilizers.

PURPOSE: The purpose of the present study was to assess the agreement between self-reported use of sleep medications and tranquilizers and dispensed hypnotics and anxiolytics. METHODS: Self-reported medication use was obtained from the population-based survey Health and Environment in Oslo (HELMILO) (2009-2010) (n = 13 019). Data on dispensed hypnotics and anxiolytics were obtained from the Norwegian Prescription Database (NorPD). As measures of validity, we calculated sensitivity and specificity using both self-reports and prescription records as the reference standard. Furthermore, we calculated Cohen's kappa. Current self-reported medication use was compared with prescription data in time windows of both 100 and 200 days preceding questionnaire completion. RESULTS: The highest sensitivity was observed for current sleep medication use in the 100-day time window (sensitivity = 0.76, 95% confidence interval [CI]: 0.74, 0.79) when using prescription records as the reference standard. Sensitivity was generally lower for tranquilizers compared with sleep medications. Cohen's kappa showed the highest agreement for the 200-day time window with substantial agreement for sleep medications (kappa = 0.64; 95% CI: 0.62, 0.67) and moderate agreement for tranquilizers (kappa = 0.45; 95% CI: 0.41, 0.48). CONCLUSIONS: The present study suggests moderate to substantial agreement between self-reported use of sleep medications and tranquilizers and dispensed drugs in a general adult population. The magnitude of agreement varied according to drug category and time window. Since self-reported and registry-based use of these drug classes does not match each other accurately, limitations of each data source should be considered when such medications are applied as the exposure or outcome in epidemiologic studies.

Road traffic noise and registry based use of sleep medication.

BACKGROUND: Road traffic noise has been associated with adverse health effects including sleep disturbances. Use of sleep medication as an indicator of sleeping problems has rarely been explored in studies of the effects of traffic noise. Furthermore, using registry data on sleep medications provides an opportunity to study the effects of noise on sleep where attribution of sleep problems to noise is not possible. METHODS: We used questionnaire data from the population-based study Health and Environment in Oslo (HELMILO) (2009-10) (n = 13,019). Individual data on sleep medications was obtained from the Norwegian Prescription Database (NorPD). Noise levels (L night) were modeled for the most exposed façade of the building at each participant's home address. Logistic regression models adjusted for potential confounders were used to analyze the association between traffic noise and sleep medication use both for one whole year and for the summer season. The results were reported as changes in the effect estimate per 5 decibel (dB) increase in noise level. RESULTS: We observed no association between traffic noise and sleep medication use during one year [odds ratio (OR) = 1.00; 95% confidence interval (CI): 0.96, 1.04]. For sleep medication use in the summer season, there was a positive, however non-significant association (OR = 1.04; 95% CI: 0.99, 1.10). Among individuals sleeping with the bedroom window open, the association increased slightly and was borderline statistically significant (OR = 1.06; 95% CI: 1.00, 1.12). CONCLUSIONS: We found no evidence of an association between traffic noise and sleep medication use during one year. However, for the summer season, there was some suggestive evidence of an association. These findings indicate that season may play a role in the association between traffic noise and sleep, possibly because indoor traffic noise levels are likely to be higher during summer due to more frequent window opening. More studies are, however, necessary in order to confirm this.

Availability, accessibility, and use of green spaces and cognitive development in primary school children.

Green spaces may have beneficial impacts on children's cognition. However, few studies explored the exposure to green spaces beyond residential areas, and their availability, accessibility and uses at the same time. The aim of the present study was to describe patterns of availability, accessibility, and uses of green spaces among primary school children and to explore how these exposure dimensions are associated with cognitive development. Exposures to green space near home, school, commuting route, and other daily activity locations were assessed for 1607 children aged 6-11 years from six birth cohorts across Europe, and included variables related to: availability (NDVI buffers: 100, 300, 500 m), potential accessibility (proximity to a major green space: linear distance; within 300 m), and use (play time in green spaces: hours/year), and the number of visits to green spaces (times/previous week). Cognition measured as fluid intelligence, inattention, and working memory was assessed by computerized tests. We performed multiple linear regression analyses on pooled and imputed data adjusted for individual and area-level confounders. Availability, accessibility, and uses of green spaces showed a social gradient that was unfavorable in more vulnerable socioeconomic groups. NDVI was associated with more playing time in green spaces, but proximity to a major green space was not. Associations between green space exposures and cognitive function outcomes were not statistically significant in our overall study population. Stratification by socioeconomic variables showed that living within 300 m of a major green space was associated with improved working memory only in children in less deprived residential areas (ß = 0.30, CI: 0.09,0.51), and that more time playing in green spaces was associated with better working memory only in children of highly educated mothers (ß per IQR increase in hour/year = 0.10; 95% CI: 0.01, 0.19). However, studying within 300 m of a major green space increased inattention scores in children in more deprived areas (ß = 15.45, 95% CI: 3.50, 27.40).

Urban environment and health behaviours in children from six European countries.

BACKGROUND: Urban environmental design is increasingly considered influential for health and wellbeing, but evidence is mostly based on adults and single exposure studies. We evaluated the association between a wide range of urban environment characteristics and health behaviours in childhood. METHODS: We estimated exposure to 32 urban environment characteristics (related to the built environment, traffic, and natural spaces) for home and school addresses of 1,581 children aged 6-11 years from six European cohorts. We collected information on health behaviours including total amount of overall moderate-to-vigorous physical activity, physical activity outside school hours, active transport, sedentary behaviours and sleep duration, and developed patterns of behaviours with principal component analysis. We used an exposure-wide association study to screen all exposure-outcome associations, and the deletion-substitution-addition algorithm to build a final multi-exposure model. RESULTS: In multi-exposure models, green spaces (Normalized Difference Vegetation Index, NDVI) were positively associated with active transport, and inversely associated with sedentary time (22.71 min/day less (95 %CI -39.90, -5.51) per interquartile range increase in NDVI). Residence in densely built areas was associated with more physical activity and less sedentary time, and densely populated areas with less physical activity outside school hours and more sedentary time. Presence of a major road was associated with lower sleep duration (-4.80 min/day (95 %CI -9.11, -0.48); compared with no major road). Results for the behavioural patterns were similar. CONCLUSIONS: This multicohort study suggests that areas with more vegetation, more building density, less population density and without major roads are associated with improved health behaviours in childhood.

Early-life environmental exposure determinants of child behavior in Europe: A longitudinal, population-based study.

BACKGROUND: Environmental exposures in early life influence the development of behavioral outcomes in children, but research has not considered multiple exposures. We therefore aimed to investigate the impact of a broad spectrum of pre- and postnatal environmental exposures on child behavior. METHODS AND FINDINGS: We used data from the HELIX (Human Early Life Exposome) project, which was based on six longitudinal population-based birth cohorts in Europe. At 6-11 years, children underwent a follow-up to characterize their exposures and assess behavioral problems. We measured 88 prenatal and 123 childhood environmental factors, including outdoor, indoor, chemical, lifestyle and social exposures. Parent-reported behavioral problems included (1) internalizing, (2) externalizing scores, using the child behavior checklist (CBCL), and (3) the Conner's Attention Deficit Hyperactivity Disorder (ADHD) index, all outcomes being discrete raw counts. We applied LASSO penalized negative binomial regression models to identify which exposures were associated with the outcomes, while adjusting for co-exposures. In the 1287 children (mean age 8.0 years), 7.3% had a neuropsychiatric medical diagnosis according to parent's reports. During pregnancy, smoking and car traffic showing the strongest associations (e.g. smoking with ADHD index, aMR:1.31 [1.09; 1.59]) among the 13 exposures selected by LASSO, for at least one of the outcomes. During childhood, longer sleep duration, healthy diet and higher family social capital were associated with reduced scores whereas higher exposure to lead, copper, indoor air pollution, unhealthy diet were associated with increased scores. Unexpected decreases in behavioral scores were found with polychlorinated biphenyls (PCBs) and organophosphate (OP) pesticides. CONCLUSIONS: Our systematic exposome approach identified several environmental contaminants and healthy lifestyle habits that may influence behavioral problems in children. Modifying environmental exposures early in life may limit lifetime mental health risk.

Early life multiple exposures and child cognitive function: A multi-centric birth cohort study in six European countries.

Epidemiological studies mostly focus on single environmental exposures. This study aims to systematically assess associations between a wide range of prenatal and childhood environmental exposures and cognition. The study sample included data of 1298 mother-child pairs, children were 6-11 years-old, from six European birth cohorts. We measured 87 exposures during pregnancy and 122 cross-sectionally during childhood, including air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals and life styles. The measured cognitive domains were fluid intelligence (Raven's Coloured Progressive Matrices test, CPM), attention (Attention Network Test, ANT) and working memory (N-Back task). We used two statistical approaches to assess associations between exposure and child cognition: the exposome-wide association study (ExWAS) considering each exposure independently, and the deletion-substitution-addition algorithm (DSA) considering all exposures simultaneously to build a final multiexposure model. Based on this multiexposure model that included the exposure variables selected by ExWAS and DSA models, child organic food intake was associated with higher fluid intelligence (CPM) scores (beta = 1.18; 95% CI = 0.50, 1.87) and higher working memory (N-Back) scores (0.23; 0.05, 0.41), and child fast food intake (-1.25; -2.10, -0.40), house crowding (-0.39; -0.62, -0.16), and child environmental tobacco smoke (ETS) (-0.89; -1.42, -0.35), were all associated with lower CPM scores. Indoor PM2.5 exposure was associated with lower N-Back scores (-0.09; -0.16, -0.02). Additional associations in the unexpected direction were found: Higher prenatal mercury levels, maternal alcohol consumption and child higher perfluorooctane sulfonic acid (PFOS) levels were associated with better cognitive performance; and higher green exposure during pregnancy with lower cognitive performance. This first comprehensive and systematic study of many prenatal and childhood environmental risk factors suggests that unfavourable child nutrition, family crowdedness and child indoor air pollution and ETS exposures adversely and cross-sectionally associate with cognitive function. Unexpected associations were also observed and maybe due to confounding and reverse causality.

Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis.

Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p < 0.05) in either of the EWAS were correlated between timepoints (ρ = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p < 1 × 10-7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p < 1 × 10-7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.

Human Early Life Exposome (HELIX) study: a European population-based exposome cohort.

PURPOSE: Essential to exposome research is the collection of data on many environmental exposures from different domains in the same subjects. The aim of the Human Early Life Exposome (HELIX) study was to measure and describe multiple environmental exposures during early life (pregnancy and childhood) in a prospective cohort and associate these exposures with molecular omics signatures and child health outcomes. Here, we describe recruitment, measurements available and baseline data of the HELIX study populations. PARTICIPANTS: The HELIX study represents a collaborative project across six established and ongoing longitudinal population-based birth cohort studies in six European countries (France, Greece, Lithuania, Norway, Spain and the UK). HELIX used a multilevel study design with the entire study population totalling 31 472 mother-child pairs, recruited during pregnancy, in the six existing cohorts (first level); a subcohort of 1301 mother-child pairs where biomarkers, omics signatures and child health outcomes were measured at age 6-11 years (second level) and repeat-sampling panel studies with around 150 children and 150 pregnant women aimed at collecting personal exposure data (third level). FINDINGS TO DATE: Cohort data include urban environment, hazardous substances and lifestyle-related exposures for women during pregnancy and their offspring from birth until 6-11 years. Common, standardised protocols were used to collect biological samples, measure exposure biomarkers and omics signatures and assess child health across the six cohorts. Baseline data of the cohort show substantial variation in health outcomes and determinants between the six countries, for example, in family affluence levels, tobacco smoking, physical activity, dietary habits and prevalence of childhood obesity, asthma, allergies and attention deficit hyperactivity disorder. FUTURE PLANS: HELIX study results will inform on the early life exposome and its association with molecular omics signatures and child health outcomes. Cohort data are accessible for future research involving researchers external to the project.

A Population-Based Study on Nighttime Road Traffic Noise and Insomnia.

Study Objectives: The aims of the present study were to investigate how nighttime road traffic noise relates to self-reported symptoms of insomnia and sleep medication use. Methods: We used questionnaire data from the population-based study Health and Environment in Oslo (HELMILO) (2009-2010; n = 13019). The insomnia symptoms difficulties falling asleep, awakenings during the night, and waking up too early in the morning as well as self-reported sleep medication use were included as outcomes. Modeled noise levels (Lnight) were assigned to each participant's home address. For selecting covariates to the statistical model, we used a directed acyclic graph. The associations between noise and sleep were analyzed using logistic regression models. Results: After adjustment for potential confounders, we found an odds ratio (OR) of 1.05 (95% confidence interval [CI]: 1.01-1.09) for the association between traffic noise and difficulties falling asleep, in the total study population. For the association between traffic noise and awakenings during the night, the OR was 1.04 (95% CI: 1.00-1.08) and for waking up too early, the OR was 1.06 (95% CI: 1.02-1.11). The effect estimates are given per 5-dB increase in traffic noise level (Lnight). Self-reported sleep medication use was not statistically significantly associated with traffic noise exposure. Conclusions: In an adult population from Oslo, traffic noise was associated with difficulties falling asleep and waking up too early. These findings indicate that sleep quantity may be compromised for individuals living in areas highly exposed to nighttime traffic noise.

Nocturnal Road Traffic Noise Exposure and Children's Sleep Duration and Sleep Problems.

Almost half of the European Union (EU)'s population is exposed to road traffic noise above levels that constitute a health risk. Associations between road traffic noise and impaired sleep in adults have consistently been reported. Less is known about effects of noise on children's sleep. The aim of this study was to examine the association between nocturnal road traffic noise exposure and children's parental-reported sleep duration and sleep problems. The present cross-sectional study used data from The Norwegian Mother and Child Cohort Study. Parental report of children's sleep duration and sleep problems at age 7 was linked to modelled levels of residential night-time road traffic noise. The study population included 2665 children from Oslo, Norway. No association was found between road traffic noise and sleep duration in the total study population (odds ratio (OR): 1.05, 95% confidence interval (CI): [0.94, 1.17]), but a statistically significant association was observed in girls (OR: 1.21, 95% CI: [1.04, 1.41]). For sleep problems, the associations were similar (OR: 1.36, 95% CI: [0.85, 2.16]) in girls. The ORs are presented for an increase of 10 dB. The findings suggest there is an association between road traffic noise and sleep for girls, underlining the importance of protecting children against excessive noise levels.