A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways.

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.

Air Pollution Exposure During Pregnancy and Symptoms of Attention Deficit and Hyperactivity Disorder in Children in Europe.

BACKGROUND: Exposure to air pollution during pregnancy may increase attention-deficit/hyperactivity disorder (ADHD) symptoms in children, but findings have been inconsistent. We aimed to study this association in a collaborative study of eight European population-based birth/child cohorts, including 29,127 mother-child pairs. METHODS: Air pollution concentrations (nitrogen dioxide [NO2] and particulate matter [PM]) were estimated at the birth address by land-use regression models based on monitoring campaigns performed between 2008 and 2011. We extrapolated concentrations back in time to exact pregnancy periods. Teachers or parents assessed ADHD symptoms at 3-10 years of age. We classified children as having ADHD symptoms within the borderline/clinical range and within the clinical range using validated cutoffs. We combined all adjusted area-specific effect estimates using random-effects meta-analysis and multiple imputations and applied inverse probability-weighting methods to correct for loss to follow-up. RESULTS: We classified a total of 2,801 children as having ADHD symptoms within the borderline/clinical range, and 1,590 within the clinical range. Exposure to air pollution during pregnancy was not associated with a higher odds of ADHD symptoms within the borderline/clinical range (e.g., adjusted odds ratio [OR] for ADHD symptoms of 0.95, 95% confidence interval [CI] = 0.89, 1.01 per 10 µg/m increase in NO2 and 0.98, 95% CI = 0.80, 1.19 per 5 µg/m increase in PM2.5). We observed similar associations for ADHD within the clinical range. CONCLUSIONS: There was no evidence for an increase in risk of ADHD symptoms with increasing prenatal air pollution levels in children aged 3-10 years. See video abstract at, http://links.lww.com/EDE/B379.

Genome-Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up.

RATIONALE: The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors. OBJECTIVES: To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels. METHODS: We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns. MEASUREMENTS AND MAIN RESULTS: In the European cohorts, 186 SNPs had an interaction P < 1 × 10-4 and a look-up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P < 0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P = 4.50 × 10-4). One other SNP with P < 0.05 for interaction in CHS, rs686237, strongly influenced UDP-Gal:betaGlcNAc ß-1,4-galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P = 1.18 × 10-17). Air pollution exposure was associated with differential discs, large homolog 2 (DLG2) methylation and expression. CONCLUSIONS: Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.

Shared genetic variants suggest common pathways in allergy and autoimmune diseases.

BACKGROUND: The relationship between allergy and autoimmune disorders is complex and poorly understood. OBJECTIVE: We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. METHODS: We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases. RESULTS: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases. CONCLUSION: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.

A genome-wide approach to children's aggressive behavior: The EAGLE consortium.

Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. © 2015 Wiley Periodicals, Inc.

Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

Exposure to visible mould or dampness at home and sleep problems in children: Results from the LISAplus study.

BACKGROUND: Exposure to mould or dampness at home has been associated with adverse respiratory effects in all age groups. This exposure has also been related to insomnia in adults. We aimed to investigate the association between exposure to visible mould or dampness at home and sleep problems in children. METHODS: The study population consisted of 1719 10-year-old children from the German population-based birth cohort LISAplus with available data on current mould or dampness at home and sleep problems. The presence of visible mould or dampness at home was assessed by questionnaire. Parent-reported sleep problems of their child were analysed by four binary variables: presence of any sleep problems, problems to fall asleep, problems sleeping through the night and a 24h sleep time of less than 9h. Logistic regression models adjusted for study centre, sex, age and level of parental education were applied to examine the association between visible mould or dampness at home and sleep problems. Sensitivity analyses included a further adjustment for bedroom sharing and subgroup analyses in children without current allergic diseases. RESULTS: Thirteen percent of parents reported visible mould or dampness at home. We observed increased risks for all four sleep problem variables for children exposed to visible mould or dampness at home. Results were significant for any sleep problems (odds ratio (OR)=1.77 (95%-confidence interval (CI): 1.21-2.60), problems sleeping through the night (OR=2.52(1.27-5.00) and a short sleep time (OR=1.68(1.09-2.61)). While a further adjustment for bedroom sharing and the exclusion of children with asthma or eczema led to similar results, only the association with a short sleep time was still present in children without allergic rhinoconjunctivitis. CONCLUSION: Our data suggests that visible mould or dampness at home might negatively influence sleep in children. The influence of allergic rhinoconjunctivitis on this association needs to be investigated in future studies.

Air pollution during pregnancy and childhood cognitive and psychomotor development: six European birth cohorts.

BACKGROUND: Accumulating evidence from laboratory animal and human studies suggests that air pollution exposure during pregnancy affects cognitive and psychomotor development in childhood. METHODS: We analyzed data from 6 European population-based birth cohorts-GENERATION R (The Netherlands), DUISBURG (Germany), EDEN (France), GASPII (Italy), RHEA (Greece), and INMA (Spain)-that recruited mother-infant pairs from 1997 to 2008. Air pollution levels-nitrogen oxides (NO2, NOx) in all regions and particulate matter (PM) with diameters of <2.5, <10, and 2.5-10 µm (PM2.5, PM10, and PMcoarse, respectively) and PM2.5 absorbance in a subgroup-at birth addresses were estimated by land-use regression models, based on monitoring campaigns performed primarily between 2008 and 2011. Levels were back-extrapolated to exact pregnancy periods using background monitoring sites. Cognitive and psychomotor development was assessed between 1 and 6 years of age. Adjusted region-specific effect estimates were combined using random-effects meta-analysis. RESULTS: A total of 9482 children were included. Air pollution exposure during pregnancy, particularly NO2, was associated with reduced psychomotor development (global psychomotor development score decreased by 0.68 points [95% confidence interval = -1.25 to -0.11] per increase of 10 µg/m in NO2). Similar trends were observed in most regions. No associations were found between any air pollutant and cognitive development. CONCLUSIONS: Air pollution exposure during pregnancy, particularly NO2 (for which motorized traffic is a major source), was associated with delayed psychomotor development during childhood. Due to the widespread nature of air pollution exposure, the public health impact of the small changes observed at an individual level could be considerable.

Prenatal nicotine exposure and child behavioural problems.

In utero exposure to tobacco smoke has been related to numerous adverse health effects in new-borns, infants, children, adolescents and adults. The aim of this review was to summarise findings on prenatal nicotine exposure and its relationship with behavioural problems in the offspring. The majority of studies, and especially several recent epidemiological studies, observed a higher likelihood for attention-deficit/hyperactivity disorder (ADHD) or ADHD symptoms in exposed subjects. However, both human and animal studies have failed to provide clear evidence on causality. Existing literature on studies investigating the association between prenatal nicotine exposure and conduct or externalising problems in the offspring suggests a causal effect. The establishment of a final conclusion concerning the relationship between prenatal nicotine exposure and internalising problems in the offspring is complicated by insufficient data and mixed results in epidemiological studies. Prenatal nicotine exposure has been associated with altered brain structure and function in human offspring, and a proposed biological mechanism is related to nicotine's adverse influence on neurotransmitter systems during brain development. In conclusion, establishing a statement on the causality of the relationship between prenatal nicotine exposure and behavioural problems in children remains a challenging task. Nevertheless, considering the results of an increasing number of studies which link prenatal exposure to nicotine to externalising problems applying different methodologies to account for confounding and in view of other adverse health effects known to be caused by this exposure, parents should consider smoking cessation.

Healthcare use and costs associated with children's behavior problems.

The objective of the study was to investigate associations between severity of behavior problems, specific symptom domains with healthcare use and costs in school-aged children. A cross-sectional study using data from the 10-year follow-up of two population-based birth cohorts was conducted on four rural and urban communities in Germany. There were 3,579 participants [1,834 boys (51%), 1,745 girls (49%)] on average aged 10.4 years. The severity levels (normal, at risk, abnormal) and symptom domains of behavioral problems were assessed by parent-reported strengths and difficulties questionnaire (SDQ).The outcomes were medical use categories (physicians, therapists, hospital, and rehabilitation), medical costs categories and total direct medical use and costs (calculated from parent-reported utilization of healthcare services during the last 12 months). Total direct medical costs showed a graded relationship with severity level (adjusted p < 0.0001). Average annual cost difference in total direct medical costs between at risk and normal total difficulties was Euro () 271 (SD 858), and 1,237 (SD 2,528) between abnormal and normal total difficulties. A significant increase in physician costs showed between children with normal and at risk total difficulties (1.30), and between normal and abnormal total difficulties (1.29; p < 0.0001). Between specific symptom domains, children with emotional symptoms showed highest costs for physicians, psychotherapist, and hospitalization as well as total direct medical costs. Children with hyperactivity/inattention showed highest costs for therapists and emergency room costs. Healthcare use and costs are related to the severity of child behavior problems. In general, children's costs for psychotherapy treatments have been low relative to general medical treatments which may indicate that some children with behavioral problems did not get appropriate care. To some degree, medical conditions may be attributable to some of the high hospitalization costs found in children with emotional symptom.

Genome-wide association study (GWAS) for molar-incisor hypomineralization (MIH).

OBJECTIVES: This genome-wide association study (GWAS) investigated the relationship between molar-incisor hypomineralization (MIH) and possible genetic loci. Clinical and genetic data from the 10-year follow-up of 668 children from the Munich GINI-plus and LISA-plus birth cohort studies were analyzed. MATERIAL AND METHODS: The dental examinations included the diagnosis of MIH according to the criteria of the European Academy of Paediatric Dentistry (EAPD). Children with MIH were categorized as those with a minimum of one hypomineralized first permanent molar. A GWAS was implemented following a quality-control step and an additive genetic effect was assumed. RESULTS: A total of 2,013,491 single-nucleotide polymorphisms (SNPs) were available for analysis. Rs13058467, which is located near the SCUBE1 gene on chromosome 22 (p < 3.72E-7), was identified as a possible locus linked to MIH when using a threshold of p value <1E-6. CONCLUSIONS: After considering the limitations of the present study (e.g., limited sample size and lack of an independent replication sample), it can be concluded that (1) replication analyses in an independent cohort study are strongly recommended and (2) large-scale and well-powered studies are needed to investigate a possible genetic link to MIH.

Childhood allergic rhinitis, traffic-related air pollution, and variability in the GSTP1, TNF, TLR2, and TLR4 genes: results from the TAG Study.

BACKGROUND: Associations between traffic-related air pollution (TRAP) and allergic rhinitis remain inconsistent, possibly because of unexplored gene-environment interactions. OBJECTIVE: In a pooled analysis of 6 birth cohorts (Ntotal = 15,299), we examined whether TRAP and genetic polymorphisms related to inflammation and oxidative stress predict allergic rhinitis and sensitization. METHODS: Allergic rhinitis was defined with a doctor diagnosis or reported symptoms at age 7 or 8 years. Associations between nitrogen dioxide, particulate matter 2.5 (PM2.5) mass, PM2.5 absorbance, and ozone, estimated for each child at the year of birth, and single nucleotide polymorphisms within the GSTP1, TNF, TLR2, or TLR4 genes with allergic rhinitis and aeroallergen sensitization were examined with logistic regression. Models were stratified by genotype and interaction terms tested for gene-environment associations. RESULTS: Point estimates for associations between nitrogen dioxide, PM2.5 mass, and PM2.5 absorbance with allergic rhinitis were elevated, but only that for PM2.5 mass was statistically significant (1.37 [1.01, 1.86] per 5 µg/m(3)). This result was not robust to single-cohort exclusions. Carriers of at least 1 minor rs1800629 (TNF) or rs1927911 (TLR4) allele were consistently at an increased risk of developing allergic rhinitis (1.19 [1.00, 1.41] and 1.24 [1.01, 1.53], respectively), regardless of TRAP exposure. No evidence of gene-environment interactions was observed. CONCLUSION: The generally null effect of TRAP on allergic rhinitis and aeroallergen sensitization was not modified by the studied variants in the GSTP1, TNF, TLR2, or TLR4 genes. Children carrying a minor rs1800629 (TNF) or rs1927911 (TLR4) allele may be at a higher risk of allergic rhinitis.

Traffic, asthma and genetics: combining international birth cohort data to examine genetics as a mediator of traffic-related air pollution's impact on childhood asthma.

Associations between traffic-related air pollution and incident childhood asthma can be strengthened by analysis of gene-environment interactions, but studies have typically been limited by lack of study power. We combined data from six birth cohorts on: asthma, eczema and allergic rhinitis to 7/8 years, and candidate genes. Individual-level assessment of traffic-related air pollution exposure was estimated using land use regression or dispersion modeling. A total of 11,760 children were included in the Traffic, Asthma and Genetics (TAG) Study; 6.3 % reported physician-diagnosed asthma at school-age, 16.0 % had asthma at anytime during childhood, 14.1 % had allergic rhinitis at school-age, 10.0 % had eczema at school-age and 33.1 % were sensitized to any allergen. For GSTP1 rs1138272, the prevalence of heterozygosity was 16 % (range amongst individual cohorts, 11-17 %) and homozygosity for the minor allele was 1 % (0-2 %). For GSTP1 rs1695, the prevalence of heterozygosity was 45 % (40-48 %) and homozygosity for the minor allele, 12 % (10-12 %). For TNF rs1800629, the prevalence of heterozygosity was 29 % (25-32 %) and homozygosity for the minor allele, 3 % (1-3 %). TAG comprises a rich database, the largest of its kind, for investigating the effect of genotype on the association between air pollution and childhood allergic disease.

Exposure to road traffic noise and children's behavioural problems and sleep disturbance: results from the GINIplus and LISAplus studies.

BACKGROUND: Exposure to transportation noise showed negative health effects in children and adults. Studies in children mainly focussed on aircraft noise at school. OBJECTIVES: We aimed to investigate road traffic noise exposure at home and children's behavioural problems and sleeping problems. METHODS: 872 10-year-old children from Munich from two German population-based, birth-cohort studies with data on modelled façade noise levels at home and behavioural problems were included. Noise was assessed by the day-evening-night noise indicator Lden and the night noise indicator Lnight. Behavioural problems were assessed by the Strengths and Difficulties Questionnaire (SDQ). A subgroup (N=287) had information on sleeping problems. Continuation ratio models (logistic regression models) adjusted for various covariates were applied to investigate the association between interquartile range increases in noise and SDQ scales (sleeping problems). RESULTS: Noise measured by Lden at the most exposed façade of the building was related to more hyperactivity/inattention (continuation odds ratio (cOR)=1.28(95%-confidence interval(CI):1.03-1.58). Noise at the least exposed façade increased the relative odds for having borderline or abnormal values on the emotional symptoms scale, especially the relative odds to have abnormal values for a subject with at least borderline values (Lden:cOR=2.19(95% CI:1.32-3.64). Results for Lnight were similar. Nocturnal noise at the least exposed façade was associated with any sleeping problems (odds ratio (OR)=1.79(95% CI=1.10-2.92)). CONCLUSIONS: Road traffic noise exposure at home may be related to increased hyperactivity and more emotional symptoms in children. Future longitudinal studies are required to explore noise exposure and behavioural problems in more detail, especially the role of sleep disturbances.

The association between road traffic noise exposure and blood pressure among children in Germany: the GINIplus and LISAplus studies.

Studies examining the association between road traffic noise and blood pressure in children are scarce. Nighttime noise levels and window orientations have not been considered in most previous studies. Investigate the association between road traffic noise exposure and blood pressure among children, and investigate the impact of bedroom window direction on this association. We measured blood pressure in 605 children aged 10 years from two Munich cohorts. Demographic and health information was collected by parent completed questionnaires. Road traffic noise levels were assessed by day-evening-night noise indicator "Lden" and night noise indicator "Lnight". Minimum and maximum levels within a 50 m buffer around child's home address were derived. Generalized additive models were applied to explore effect of noise levels on systolic and diastolic blood pressure (SBP and DBP). The orientation of child's bedroom window was considered in sensitivity analyses. DBP was significantly associated with the minimum level of noise during 24 h (Lden_min) and nightime (Lnight_min). Specifically, DBP increased by 0.67 and 0.89 mmHg for every 5 A-weighted decibels increase in Lden_min and Lnight_min. After adjusting for Lden_min (Lnight_min), DBP of children whose bedroom window faced the street was 1.37 (1.28) mmHg higher than those whose bedroom window did not, these children showed statistically significant increased SBP for Lden_min (3.05 mmHg) and Lnight_min (3.27 mmHg) compared to children whose bedroom window did not face the street. Higher minimum levels of weighted day-evening-night noise and nighttime noise around the home residence may increase a child's blood pressure.

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.

Passive smoking and behavioural problems in children: results from the LISAplus prospective birth cohort study.

OBJECTIVE: To analyse the association between pre- and postnatal exposure to tobacco smoke and child behavioural problems and to further investigate the influence of trimester-specific exposure to maternal smoking and the impact of paternal smoking at home on the same outcome. METHODS: Data of 3097 German children recruited at birth for a population-based, prospective study were used. Detailed information on children's tobacco smoke exposure was collected by self-administered questionnaires at each follow-up. Behavioural outcomes were measured by the Strengths and Difficulties Questionnaire applied at 10-year follow-up. RESULTS: Children exposed to environmental tobacco smoke at home showed increased risks of hyperactivity/inattention problems. Only smoking during the entire pregnancy increased the risk for conduct and hyperactivity/inattention problems (proportional odds ratio (pOR)=1.58, 95% confidence interval (CI)=1.06-2.37 and pOR=1.67, CI=1.03-2.72). Pre- and postnatal exposure to paternal smoking was associated with hyperactivity/inattention problems in children of non-smoking mothers (pOR=1.97, CI=1.06-3.65). Effect estimates were adjusted for study centre, sex, parental educational level, mother's age at birth, having a single parent and time spent in front of a screen. CONCLUSIONS: Not only maternal smoking during pregnancy but also paternal smoking at home should be considered as a risk for hyperactivity/inattention problems in children.

Association of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study.

Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures: Type 2 diabetes and glycemic traits. Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (ß = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

Traffic-related air pollution and hyperactivity/inattention, dyslexia and dyscalculia in adolescents of the German GINIplus and LISAplus birth cohorts.

BACKGROUND: Few studies have examined the link between air pollution exposure and behavioural problems and learning disorders during late childhood and adolescence. OBJECTIVES: To determine whether traffic-related air pollution exposure is associated with hyperactivity/inattention, dyslexia and dyscalculia up to age 15years using the German GINIplus and LISAplus birth cohorts (recruitment 1995-1999). METHODS: Hyperactivity/inattention was assessed using the German parent-completed (10years) and self-completed (15years) Strengths and Difficulties Questionnaire. Responses were categorized into normal versus borderline/abnormal. Parent-reported dyslexia and dyscalculia (yes/no) at age 10 and 15years were defined using parent-completed questionnaires. Individual-level annual average estimates of nitrogen dioxide (NO2), particulate matter (PM)10 mass, PM2.5 mass and PM2.5 absorbance concentrations were assigned to each participant's birth, 10year and 15year home address. Longitudinal associations between the air pollutants and the neurodevelopmental outcomes were assessed using generalized estimation equations, separately for both study areas, and combined in a random-effects meta-analysis. Odds ratios and 95% confidence intervals are given per interquartile range increase in pollutant concentration. RESULTS: The prevalence of abnormal/borderline hyperactivity/inattention scores and parental-reported dyslexia and dyscalculia at 15years of age was 12.9%, 10.5% and 3.4%, respectively, in the combined population (N=4745). In the meta- analysis, hyperactivity/inattention was associated with PM2.5 mass estimated to the 10 and 15year addresses (1.12 [1.01, 1.23] and 1.11 [1.01, 1.22]) and PM2.5 absorbance estimated to the 10 and 15year addresses (1.14 [1.05, 1.25] and 1.13 [1.04, 1.23], respectively). CONCLUSIONS: We report associations suggesting a potential link between air pollution exposure and hyperactivity/inattention scores, although these findings require replication.