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1.  Tracking of fetal growth characteristics during different trimesters and the risks of adverse birth outcomes 
Background: Fetal growth characteristics are used to identify influences of several maternal characteristics and to identify individuals at increased risk of adverse outcomes. The extent to which fetal growth characteristics track in different trimesters is not known.
Methods: In a population-based prospective cohort study among 8636 pregnant women, we examined the extent to which fetal growth characteristics track, are influenced by maternal socio-demographic and lifestyle related determinants and are associated with birth outcomes. Fetal growth was assessed in each trimester and at birth.
Results: Correlation coefficient between first-trimester crown-rump length and birthweight was r = 0.12 (P-value < 0.05). Correlation coefficients for fetal-head circumference, (femur) length and (estimated) fetal weight ranged from r = 0.16 to r = 0.30 (all P-values < 0.05) between second trimester and birth and from r = 0.36 to r = 0.58 (all P-values < 0.05) between third trimester and birth, and were highest for (estimated) fetal weight. Correlation coefficients for (estimated) fetal weight tended to be lower among overweight mothers, as compared with normal weight mothers, but were not influenced by other maternal characteristics. First, second and third-trimester fetal growth characteristics were associated with risks of preterm birth and small size for gestational age at birth,with the strongest associations present in third trimester.
Conclusion: Fetal growth characteristics track moderately throughout gestation, with stronger tracking coefficients present in later pregnancy. Tracking coefficients were not materially influenced by maternal socio-demographic and lifestyle characteristics. First, second and third trimester fetal growth characteristics were associated with the risk of adverse birth outcomes.
PMCID: PMC4258770  PMID: 24603318
Fetal growth; tracking; preterm birth; small size for gestational age; cohort study
2.  Fractional exhaled nitric oxide in childhood is associated with 17q11.2-q12 and 17q12-q21 variants 
The fractional concentration of nitric oxide in exhaled air (FeNO) is a biomarker of eosinophilic airway inflammation and associated with childhood asthma. Identification of common genetic variants associated with childhood FeNO may help to define biological mechanisms related to specific asthma phenotypes.
To identify genetic variants associated with childhood FeNO, and their relation with asthma.
FeNO was measured in children aged 5 to 15 years. In 14 genome-wide association (GWA) studies (N = 8,858), we examined the associations of ~2.5 million single nucleotide polymorphisms (SNPs) with FeNO. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci (eQTLs) in genome-wide expression datasets of lymphoblastoid cell lines (N = 1,830), and were related with asthma in a previously published GWA dataset (cases: n=10,365; controls: n=16,110).
We identified 3 SNPs associated with FeNO: rs3751972 in LYR motif containing 9 (LYRM9) (P = 1.97×10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2) (P = 1.28×10−9) both located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB) (P = 1.88×10−8) at 17q12-q21. We found a cis eQTL for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. Rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. Rs8069176 at 17q12-q21, and not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.
This study identified 3 variants associated with FeNO, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight in the regulation of FeNO. This study highlights that both shared and distinct genetic factors affect FeNO and childhood asthma.
PMCID: PMC4334587  PMID: 24315451
airway inflammation; asthma phenotypes; biomarker; genetics; genome-wide association study
3.  Common variation near ROBO2 is associated with expressive vocabulary in infancy 
Nature communications  2014;5:4831.
Twin studies suggest that expressive vocabulary at ~24 months is modestly heritable. However, the genes influencing this early linguistic phenotype are unknown. Here we conduct a genome-wide screen and follow-up study of expressive vocabulary in toddlers of European descent from up to four studies of the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, analysing an early (15-18 months, ‘one-word stage’, NTotal=8,889) and a later (24-30 months, ‘two-word stage’, NTotal=10,819) phase of language acquisition. For the early phase, one SNP (rs7642482) at 3p12.3 near ROBO2, encoding a conserved axon binding receptor, reaches the genome-wide significance level (p=1.3×10−8) in the combined sample. This association links language-related common genetic variation in the general population to a potential autism susceptibility locus and a linkage region for dyslexia, speech-sound disorder and reading. The contribution of common genetic influences is, although modest, supported by Genome-wide Complex Trait Analysis (meta-GCTA h215-18-months=0.13, meta-GCTA h224-30-months=0.14) and in concordance with additional twin analysis (5,733 pairs of European descent, h224-months=0.20).
PMCID: PMC4175587  PMID: 25226531
4.  Sedentary behaviors, physical activity behaviors, and body fat in 6-year-old children: the Generation R Study 
Childhood overweight and obesity is a major public health concern. Knowledge on modifiable risk factors is needed to design effective intervention programs. This study aimed to assess associations of children’s sedentary behaviors (television viewing and computer game use) and physical activity behaviors (sports participation, outdoor play, and active transport to/from school) with three indicators of body fat, i.e., percent fat mass, body mass index (BMI) standard deviation scores, and weight status (normal weight, overweight).
Cross-sectional data from 5913 6-year-old ethnically diverse children were analyzed. Children’s weight and height were objectively measured and converted to BMI. Weight status was defined according to age- and sex-specific cut-off points of the International Obesity Task Force. BMI standard deviation scores were created, based on Dutch reference growth curves. Fat mass was measured my dual-energy X-ray absorptiometry (DXA). Sedentary and physical activity behaviors were assessed by parent-reported questionnaires. Series of logistic and linear regression analyses were performed, controlling for confounders (i.e., socio-demographic factors, family lifestyle factors, and other sedentary behaviors and physical activity behaviors).
Sports participation was inversely associated with fat mass (p < 0.001), even after adjustment for socio-demographic factors, family lifestyle factors, and other sedentary behaviors and physical activity behaviors. No other independent associations were observed.
The results of this study indicate that sports participation is inversely associated with percent body fat among ethnically diverse 6-year-old children. More research in varied populations including objective measurements and longitudinal designs are needed to confirm these current results.
PMCID: PMC4145220  PMID: 25124336
Body fat; Overweight; Lifestyle; Physical activity; Sedentary; Children
5.  The role of early life factors in the development of ethnic differences in growth and overweight in preschool children: a prospective birth cohort 
BMC Public Health  2014;14:722.
Ethnic differences in childhood and adulthood are known, but ethnic differences in preschool overweight and associated factors are less studied. We assessed ethnic differences in pre-school age overweight, and studied the mediating role of early life factors in this association. Furthermore, we assessed body mass index (BMI) z-score development from birth to age 4 years to study ethnic-specific differences in BMI z-score trajectory.
We used data on 4581 children participating in a birth cohort who were born between 2002 and 2006 in Rotterdam, the Netherlands. Child’s ethnicity was defined according to country of birth of the parents. Weight and length/height was repeatedly measured between 1 and 45 months of age. Overweight at age 4 years was defined according to cut-off points for BMI from the international obesity task force. We performed logistic regression to obtain independent estimates of the association between ethnicity and preschool-age overweight, and to assess the mediating role of early life risk factors. Mixed models were used to describe BMI-z development for each ethnic group from birth to preschool age.
Relative to native Dutch children, non-Dutch children were more likely to be overweight at age 4 years, except for Surinamese-Hindustani children. Socio-demographic factors, parental BMI, and infant weight change in the first 6 months after birth reduced associations. After full adjustment, Turkish (OR: 2.02, 95% CI: 1.34-3.04) and Antillean/Surinamese Creole (OR: 1.78, 95% CI: 1.06-3.02) children were still more likely to be overweight at age 4 years.
Ethnic differences on the prevalence of overweight in preschool children can be partially explained by maternal educational level, parental overweight and early infant weight change. These may be possible targets to reduce ethnic inequalities in preschool age overweight.
PMCID: PMC4227130  PMID: 25022314
Ethnicity; Preschool; Overweight; Epidemiology; Infant weight gain; Socio-economic status; Breastfeeding; BMI
6.  Television viewing through ages 2-5 years and bullying involvement in early elementary school 
BMC Public Health  2014;14:157.
High television exposure time at young age has been described as a potential risk factor for developing behavioral problems. However, less is known about the effects of preschool television on subsequent bullying involvement. We examined the association between television viewing time through ages 2-5 and bullying involvement in the first grades of elementary school. We hypothesized that high television exposure increases the risk of bullying involvement.
TV viewing time was assessed repeatedly in early childhood using parental report. To combine these repeated assessments we used latent class analysis. Four exposure classes were identified and labeled “low”, “mid-low”, “mid-high” and “high”. Bullying involvement was assessed by teacher questionnaire (n = 3423, mean age 6.8 years). Additionally, peer/self-report of bullying involvement was obtained using a peer nomination procedure (n = 1176, mean age 7.6 years). We examined child risk of being a bully, victim or a bully-victim (compared to being uninvolved in bullying).
High television exposure class was associated with elevated risks of bullying and victimization. Also, in both teacher- and child-reported data, children in the high television exposure class were more likely to be a bully-victim (OR = 2.11, 95% CI: 1.42-3.13 and OR = 3.68, 95% CI: 1.75-7.74 respectively). However, all univariate effect estimates attenuated and were no longer statistically significant once adjusted for maternal and child covariates.
The association between television viewing time through ages 2-5 and bullying involvement in early elementary school is confounded by maternal and child socio-demographic characteristics.
PMCID: PMC3944918  PMID: 24520886
Television; Bullying; Aggression; Children
7.  Toward an operative diagnosis of fussy/picky eating: a latent profile approach in a population-based cohort 
Definitions and assessment methods of fussy/picky eating are heterogeneous and remain unclear.
We aimed to identify an eating behavior profile reflecting fussy/picky eating in children and to describe characteristics of fussy eaters.
Eating behavior was assessed with the Child Eating Behavior Questionnaire (CEBQ) in 4914 4-year olds in a population-based birth cohort study. Latent Profile Analysis (LPA) was used to identify eating behavior profiles based on CEBQ subscales.
Results and discussion
We found a “fussy” eating behavior profile (5.6% of children) characterized by high food fussiness, slowness in eating, and satiety responsiveness in combination with low enjoyment of food and food responsiveness. Fussy eaters were more often from families with low household income than non-fussy eaters (42% vs. 31.8% respectively; Χ 2 (1) = 9.97, p < .01). When they were 14 months old, fussy eaters had a lower intake of vegetables (t [3008] = 2.42, p < .05) and fish (t [169.77] = 2.40, p < .05) but higher intake of savory snacks (t [153.69] = -2.03, p < .05) and sweets (t [3008] = -2.30, p < .05) compared to non-fussy eaters. Also, fussy eaters were more likely to be underweight at 4 years of age (19.3%) than non-fussy eaters (12.3%; Χ 2 (1) = 7.71, p < .01).
A distinct fussy eating behavior profile was identified by LPA, which was related to family and child characteristics, food intake, and BMI. This behavior profile might be used in future research and the development of interventions.
PMCID: PMC3922255  PMID: 24512388
Fussy eating; Children; Latent profile analysis; Population-based cohort study; Dietary intake; BMI; Child and family characteristics
8.  Variation in the Glucocorticoid Receptor Gene at rs41423247 Moderates the Effect of Prenatal Maternal Psychological Symptoms on Child Cortisol Reactivity and Behavior 
Neuropsychopharmacology  2012;37(11):2541-2549.
Prenatal maternal psychopathology affects child development, but some children seem more vulnerable than others. Genetic variance in hypothalamic–pituitary–adrenal axis genes may influence the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems. This hypothesis was tested in the Generation R Study, a population-based cohort from fetal life onward. In total, 1727 children of Northern European descent and their mothers participated in this study and were genotyped for variants in the glucocorticoid receptor (GR) gene (rs6189/rs6190, rs10052957, rs41423247, rs6195, and rs6198) and the FK506-binding protein 5 (FKBP5) gene (rs1360780). Prenatal maternal psychological symptoms were assessed at 20 weeks pregnancy and child behavior was assessed by both parents at 3 years. In a subsample of 331 children, data about cortisol reactivity were available. Based on power calculations, only those genetic variants with sufficient minor allele frequencies (rs41423247, rs10052957, and rs1360780) were included in the interaction analyses. We found that variation in GR at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems (beta 0.41, SE 0.16, p=0.009). This prenatal interaction effect was independent of mother's genotype and maternal postnatal psychopathology, and not found for prenatal psychological symptoms of the father. Moreover, the interaction between rs41423247 and prenatal psychological symptoms was also associated with decreased child cortisol reactivity (beta −2.30, p-value 0.05). These findings emphasize the potential effect of prenatal gene–environment interaction, and give insight in possible mechanisms accounting for children's individual vulnerability to develop emotional and behavioral problems.
PMCID: PMC3442349  PMID: 22781842
glucocorticoid receptor gene; prenatal psychological symptom; gene–environment interaction; cortisol reactivity; child emotional and behavioral problem; biological psychiatry; child emotional and behavioral problems; cortisol reactivity; epidemiology; gene–environment interaction; glucocorticoid receptor gene; neuroendocrinology; prenatal psychological symptoms; psychiatry and behavioral sciences
9.  Differences in problem behaviour among ethnic minority and majority preschoolers in the Netherlands and the role of family functioning and parenting factors as mediators: the Generation R Study 
BMC Public Health  2012;12:1092.
Studies have shown that, compared to native counterparts, preschoolers from ethnic minorities are at an increased risk of problem behaviour. Socio-economic factors only partly explain this increased risk. This study aimed to further unravel the differences in problem behaviour among ethnic minority and native preschoolers by examining the mediating role of family functioning and parenting factors.
We included 4,282 preschoolers participating in the Generation R Study, an ethnically-diverse cohort study with inclusion in early pregnancy. At child age 3 years, parents completed the Child Behavior Checklist (CBCL/1,5-5); information on demographics, socio-economic status and measures of family functioning (maternal psychopathology; general family functioning) and parenting (parenting stress; harsh parenting) were retrieved from questionnaires. CBCL Total Problems scores in each ethnic subgroup were compared with scores in the Dutch reference population. Mediation was evaluated using multivariate regression models.
After adjustment for confounders, preschoolers from ethnic minorities were more likely to present problem behaviour than the Dutch subgroup (e.g. CBCL Total Problems Turkish subgroup (OR 7.0 (95% CI 4.9; 10.1)). When considering generational status, children of first generation immigrants were worse off than the second generation (P<0.01). Adjustment for socio-economic factors mediated the association between the ethnic minority status and child problem behaviour (e.g. attenuation in OR by 54.4% (P<0.05) from OR 5.1 (95% CI 2.8; 9.4) to OR 2.9 (95% CI 1.5; 5.6) in Cape Verdean subgroup). However, associations remained significant in most ethnic subgroups. A final adjustment for family functioning and parenting factors further attenuated the association (e.g. attenuation in OR by 55.5% (P<0.05) from OR 2.2 (95% CI 1.3; 4.4) to OR 1.5 (95% CI 1.0; 2.4) in European other subgroup).
This study showed that preschoolers from ethnic minorities and particularly children of first generation immigrants are at an increased risk of problem behaviour compared to children born to a Dutch mother. Although socio-economic factors were found to partly explain the association between the ethnic minority status and child problem behaviour, a similar part was explained by family functioning and parenting factors. Considering these findings, it is important for health care workers to also be attentive to symptoms of parental psychopathology (e.g. depression), poor family functioning, high levels of parenting stress or harsh parenting in first and second generation immigrants with young children.
PMCID: PMC3577476  PMID: 23253397
Ethnicity; Migration; Paediatric; Psychosocial factors; Mental Health
10.  Air pollution, fetal and infant tobacco smoke exposure, and wheezing in preschool children: a population-based prospective birth cohort 
Environmental Health  2012;11:91.
Air pollution is associated with asthma exacerbations. We examined the associations of exposure to ambient particulate matter (PM10) and nitrogen dioxide (NO2) with the risk of wheezing in preschool children, and assessed whether these associations were modified by tobacco smoke exposure.
This study was embedded in the Generation R Study, a population-based prospective cohort study among 4,634 children. PM10 and NO2 levels were estimated for the home addresses using dispersion modeling. Annual parental reports of wheezing until the age of 3 years and fetal and infant tobacco smoke exposure was obtained by questionnaires.
Average annual PM10 or NO2 exposure levels per year were not associated with wheezing in the same year. Longitudinal analyses revealed non-significant tendencies towards positive associations of PM10 or NO2 exposure levels with wheezing during the first 3 years of life (overall odds ratios (95% confidence interval): 1.21 (0.79, 1.87) and 1.06 (0.92, 1.22)) per 10 μg/m3 increase PM10 and NO2, respectively). Stratified analyses showed that the associations were stronger and only significant among children who were exposed to both fetal and infant tobacco smoke (overall odds ratios 4.54 (1.17, 17.65) and 1.85 (1.15, 2.96)) per 10 μg/m3 increase PM10 and NO2, respectively (p-value for interactions <0.05).
Our results suggest that long term exposure to traffic-related air pollutants is associated with increased risks of wheezing in children exposed to tobacco smoke in fetal life and infancy. Smoke exposure in early life might lead to increased vulnerability of the lungs to air pollution.
PMCID: PMC3533997  PMID: 23231783
Cohort study; Asthma; Pediatrics; Environmental tobacco smoke exposure; Air pollution
11.  Children's eating behavior, feeding practices of parents and weight problems in early childhood: results from the population-based Generation R Study 
Weight problems that arise in the first years of life tend to persist. Behavioral research in this period can provide information on the modifiable etiology of unhealthy weight. The present study aimed to replicate findings from previous small-scale studies by examining whether different aspects of preschooler’s eating behavior and parental feeding practices are associated with body mass index (BMI) and weight status -including underweight, overweight and obesity- in a population sample of preschool children.
Cross-sectional data on the Child Eating Behaviour Questionnaire, Child Feeding Questionnaire and objectively measured BMI was available for 4987 four-year-olds participating in a population-based cohort in the Netherlands.
Thirteen percent of the preschoolers had underweight, 8% overweight, and 2% obesity. Higher levels of children’s Food Responsiveness, Enjoyment of Food and parental Restriction were associated with a higher mean BMI independent of measured confounders. Emotional Undereating, Satiety Responsiveness and Fussiness of children as well as parents’ Pressure to Eat were negatively related with children’s BMI. Similar trends were found with BMI categorized into underweight, normal weight, overweight and obesity. Part of the association between children’s eating behaviors and BMI was accounted for by parental feeding practices (changes in effect estimates: 20-43%), while children’s eating behaviors in turn explained part of the relation between parental feeding and child BMI (changes in effect estimates: 33-47%).
This study provides important information by showing how young children’s eating behaviors and parental feeding patterns differ between children with normal weight, underweight and overweight. The high prevalence of under- and overweight among preschoolers suggest prevention interventions targeting unhealthy weights should start early in life. Although longitudinal studies are necessary to ascertain causal directions, efforts to prevent or treat unhealthy child weight might benefit from a focus on changing the behaviors of both children and their parents.
PMCID: PMC3543222  PMID: 23110748
Overweight; Underweight; BMI; Eating behavior; Feeding; Parenting; Children
12.  Predicting asthma in preschool children with asthma symptoms: study rationale and design 
In well-child care it is difficult to determine whether preschool children with asthma symptoms actually have or will develop asthma at school age. The PIAMA (Prevention and Incidence of Asthma and Mite Allergy) Risk Score has been proposed as an instrument that predicts asthma at school age, using eight easy obtainable parameters, assessed at the time of first asthma symptoms at preschool age. The aim of this study is to present the rationale and design of a study 1) to externally validate and update the PIAMA Risk Score, 2) to develop an Asthma Risk Appraisal Tool to predict asthma at school age in (specific subgroups of) preschool children with asthma symptoms and 3) to test implementation of the Asthma Risk Appraisal Tool in well-child care.
Methods and design
The study will be performed within the framework of Generation R, a prospective multi-ethnic cohort study. In total, consent for postnatal follow-up was obtained from 7893 children, born between 2002 and 2006. At preschool age the PIAMA Risk Score will be assessed and used to predict asthma at school age. Discrimination (C-index) and calibration will be assessed for the external validation. We will study whether the predictive ability of the PIAMA Risk Score can be improved by removing or adding predictors (e.g. preterm birth). The (updated) PIAMA Risk Score will be converted to the Asthma Risk Appraisal Tool- to predict asthma at school age in preschool children with asthma symptoms. Additionally, we will conduct a pilot study to test implementation of the Asthma Risk Appraisal Tool in well-child care.
Application of the Asthma Risk Appraisal Tool in well-child care will help to distinguish preschool children at high- and low-risk of developing asthma at school age when asthma symptoms appear.
This study will increase knowledge about the validity of the PIAMA risk score and might improve risk assessment of developing asthma at school age in (specific subgroups of) preschool children, who present with asthma symptoms at well-child care.
PMCID: PMC3515509  PMID: 23067313
Asthma Risk Appraisal Tool; Children; External validation; Prediction; Well-child care
Paternoster, Lavinia | Standl, Marie | Chen, Chih-Mei | Ramasamy, Adaikalavan | Bønnelykke, Klaus | Duijts, Liesbeth | Ferreira, Manuel A | Alves, Alexessander Couto | Thyssen, Jacob P | Albrecht, Eva | Baurecht, Hansjörg | Feenstra, Bjarke | Sleiman, Patrick MA | Hysi, Pirro | Warrington, Nicole M | Curjuric, Ivan | Myhre, Ronny | Curtin, John A | Groen-Blokhuis, Maria M | Kerkhof, Marjan | Sääf, Annika | Franke, Andre | Ellinghaus, David | Fölster-Holst, Regina | Dermitzakis, Emmanouil | Montgomery, Stephen B | Prokisch, Holger | Heim, Katharina | Hartikainen, Anna-Liisa | Pouta, Anneli | Pekkanen, Juha | Blakemore, Alexandra IF | Buxton, Jessica L | Kaakinen, Marika | Duffy, David L | Madden, Pamela A | Heath, Andrew C | Montgomery, Grant W | Thompson, Philip J | Matheson, Melanie C | Le Souëf, Peter | Pourcain, Beate St | Smith, George Davey | Henderson, John | Kemp, John P | Timpson, Nicholas J | Deloukas, Panos | Ring, Susan M | Wichmann, H-Erich | Müller-Nurasyid, Martina | Novak, Natalija | Klopp, Norman | Rodríguez, Elke | McArdle, Wendy | Linneberg, Allan | Menné, Torkil | Nohr, Ellen A | Hofman, Albert | Uitterlinden, André G | van Duijn, Cornélia M | Rivadeneira, Fernando | de Jongste, Johan C | van der Valk, Ralf JP | Wjst, Matthias | Jogi, Rain | Geller, Frank | Boyd, Heather A | Murray, Jeffrey C | Kim, Cecilia | Mentch, Frank | March, Michael | Mangino, Massimo | Spector, Tim D | Bataille, Veronique | Pennell, Craig E | Holt, Patrick G | Sly, Peter | Tiesler, Carla MT | Thiering, Elisabeth | Illig, Thomas | Imboden, Medea | Nystad, Wenche | Simpson, Angela | Hottenga, Jouke-Jan | Postma, Dirkje | Koppelman, Gerard H | Smit, Henriette A | Söderhäll, Cilla | Chawes, Bo | Kreiner-Møller, Eskil | Bisgaard, Hans | Melén, Erik | Boomsma, Dorret I | Custovic, Adnan | Jacobsson, Bo | Probst-Hensch, Nicole M | Palmer, Lyle J | Glass, Daniel | Hakonarson, Hakon | Melbye, Mads | Jarvis, Deborah L | Jaddoe, Vincent WV | Gieger, Christian | Strachan, David P | Martin, Nicholas G | Jarvelin, Marjo-Riitta | Heinrich, Joachim | Evans, David M | Weidinger, Stephan
Nature genetics  2011;44(2):187-192.
Atopic dermatitis (AD) is a common chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing AD are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 cases and 20,565 controls from 16 population-based cohorts and followed up the ten most strongly associated novel markers in a further 5,419 cases and 19,833 controls from 14 studies. Three SNPs met genome-wide significance in the discovery and replication cohorts combined: rs479844 upstream of OVOL1 (OR=0.88, p=1.1×10−13) and rs2164983 near ACTL9 (OR=1.16, p=7.1×10−9), genes which have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster on 5q31.1 (OR=1.11, p=3.8×10−8). We also replicated the FLG locus and two recently identified association signals at 11q13.5 (rs7927894, p=0.008) and 20q13.3 (rs6010620, p=0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in AD pathogenesis.
PMCID: PMC3272375  PMID: 22197932
14.  Air pollution exposure estimation using dispersion modelling and continuous monitoring data in a prospective birth cohort study in the Netherlands 
Environmental Health  2012;11:9.
Previous studies suggest that pregnant women and children are particularly vulnerable to the adverse effects of air pollution. A prospective cohort study in pregnant women and their children enables identification of the specific effects and critical periods. This paper describes the design of air pollution exposure assessment for participants of the Generation R Study, a population-based prospective cohort study from early pregnancy onwards in 9778 women in the Netherlands. Individual exposures to PM10 and NO2 levels at the home address were estimated for mothers and children, using a combination of advanced dispersion modelling and continuous monitoring data, taking into account the spatial and temporal variation in air pollution concentrations. Full residential history was considered. We observed substantial spatial and temporal variation in air pollution exposure levels. The Generation R Study provides unique possibilities to examine effects of short- and long-term air pollution exposure on various maternal and childhood outcomes and to identify potential critical windows of exposure.
PMCID: PMC3372438  PMID: 22356901
Air pollution; Dispersion modelling; Particulate matter; Nitrogen dioxide; Cohort study; Pregnant women; Prenatal development; Child health
15.  Early detection and counselling intervention of asthma symptoms in preschool children: study design of a cluster randomised controlled trial 
BMC Public Health  2010;10:555.
Prevention of childhood asthma is an important public health objective. This study evaluates the effectiveness of early detection of preschool children with asthma symptoms, followed by a counselling intervention at preventive child health centres. Early detection and counselling is expected to reduce the prevalence of asthma symptoms and improve health-related quality of life at age 6 years.
This cluster randomised controlled trial was embedded within the Rotterdam population-based prospective cohort study Generation R in which 7893 children (born between April 2002 and January 2006) participated in the postnatal phase. Sixteen child health centres are involved, randomised into 8 intervention and 8 control centres. Since June 2005, an early detection tool has been applied at age 14, 24, 36 and 45 months at the intervention centres. Children who met the intervention criteria received counselling intervention (personal advice to parents to prevent smoke exposure of the child, and/or referral to the general practitioner or asthma nurse). The primary outcome was asthma diagnosis at age 6 years. Secondary outcomes included frequency and severity of asthma symptoms, health-related quality of life, fractional exhaled nitric oxide and airway resistance at age 6 years. Analysis was according to the intention-to-treat principle. Data collection will be completed end 2011.
This study among preschool children provides insight into the effectiveness of early detection of asthma symptoms followed by a counselling intervention at preventive child health centres.
Trial registration
Current Controlled Trials ISRCTN15790308.
PMCID: PMC2944378  PMID: 20843313
16.  Glucocorticoid receptor gene polymorphisms do not affect growth in fetal and early postnatal life. The Generation R Study 
BMC Medical Genetics  2010;11:39.
Glucocorticoids have an important role in early growth and development. Glucocorticoid receptor gene polymorphisms have been identified that contribute to the variability in glucocorticoid sensitivity. We examined whether these glucocorticoid receptor gene polymorphisms are associated with growth in fetal and early postnatal life.
This study was embedded in a population-based prospective cohort study from fetal life onwards. The studied glucocorticoid receptor gene polymorphisms included BclI (rs41423247), TthIIII (rs10052957), GR-9β (rs6198), N363S (rs6195) and R23K (rs6789 and6190). Fetal growth was assessed by ultrasounds in second and third trimester of pregnancy. Anthropometric measurements in early childhood were performed at birth and at the ages of 6, 14 and 24 months postnatally. Analyses focused on weight, length and head circumference. Analyses were based on 2,414 healthy, Caucasian children.
Glucocorticoid receptor gene polymorphisms were not associated with fetal weight, birth weight and early postnatal weight. Also, no associations were found with length and head circumference. Neither were these polymorphisms associated with the risks of low birth weight or growth acceleration from birth to 24 months of age.
We found in a large population-based cohort no evidence for an effect of known glucocorticoid receptor gene polymorphisms on fetal and early postnatal growth characteristics. Further systematic searches for common genetic variants by means of genome-wide association studies will enable us to obtain a more complete understanding of what genes and polymorphisms are involved in growth in fetal life and infancy.
PMCID: PMC2846902  PMID: 20199670
17.  Residential traffic exposure and pregnancy-related outcomes: a prospective birth cohort study 
Environmental Health  2009;8:59.
The effects of ambient air pollution on pregnancy outcomes are under debate. Previous studies have used different air pollution exposure assessment methods. The considerable traffic-related intra-urban spatial variation needs to be considered in exposure assessment. Residential proximity to traffic is a proxy for traffic-related exposures that takes into account within-city contrasts.
We investigated the association between residential proximity to traffic and various birth and pregnancy outcomes in 7,339 pregnant women and their children participating in a population-based cohort study. Residential proximity to traffic was defined as 1) distance-weighted traffic density in a 150 meter radius, and 2) proximity to a major road. We estimated associations of these exposures with birth weight, and with the risks of preterm birth and small size for gestational age at birth. Additionally, we examined associations with pregnancy-induced hypertension, (pre)eclampsia, and gestational diabetes.
There was considerable variation in distance-weighted traffic density. Almost fifteen percent of the participants lived within 50 m of a major road. Residential proximity to traffic was not associated with birth and pregnancy outcomes in the main analysis and in various sensitivity analyses.
Mothers exposed to residential traffic had no higher risk of adverse birth outcomes or pregnancy complications in this study. Future studies may be refined by taking both temporal and spatial variation in air pollution exposure into account.
PMCID: PMC2811104  PMID: 20028508
18.  Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies 
BMC Medical Genetics  2009;10:67.
An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy.
This study was performed in two independent birth cohort studies, one prospective population-based (Generation R), and one of subjects born small-for-gestational-age (SGA cohort). Fetal growth was assessed by ultrasounds in second and third trimesters of pregnancy in Generation R. Growth in infancy was assessed in both cohorts at birth and at 6, 12 and 24 months postnatally. TCF7L2 genotype was determined in 3,419 subjects in Generation R and in 566 subjects in the SGA cohort.
Minor allele frequency did not differ significantly (p = 0.47) between Generation R (T-allele: 28.7%) and the SGA cohort (T-allele: 29.8%). No differences at birth were found in gestational age or size (head circumference, length, weight) between the genotypes in either cohort. TCF7L2 genotype was also not associated with any pre- or postnatal growth characteristic in either Generation R or the SGA cohort.
We found no evidence for an association between TCF7L2 genotype and fetal and early postnatal growth. Furthermore, this TCF7L2 polymorphism was not associated with an increased risk of SGA.
PMCID: PMC2722586  PMID: 19615048
19.  Genome-wide association study of height-adjusted BMI in childhood identifies functional variant in ADCY3 
Obesity (Silver Spring, Md.)  2014;22(10):2252-2259.
Genome-wide association studies (GWAS) of BMI are mostly undertaken under the assumption that “kg/m2” is an index of weight fully adjusted for height, but in general this is not true. The aim here was to assess the contribution of common genetic variation to a adjusted version of that phenotype which appropriately accounts for covariation in height in children.
A GWAS of height-adjusted BMI (BMI[x] = weight/heightx), calculated to be uncorrelated with height, in 5809 participants (mean age 9.9 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC) was performed.
GWAS based on BMI[x] yielded marked differences in genomewide results profile. SNPs in ADCY3 (adenylate cyclase 3) were associated at genome-wide significance level (rs11676272 (0.28 kg/m3.1 change per allele G (0.19, 0.38), P = 6 × 10−9). In contrast, they showed marginal evidence of association with conventional BMI [rs11676272 (0.25 kg/m2 (0.15, 0.35), P = 6 × 10−7)]. Results were replicated in an independent sample, the Generation R study.
Analysis of BMI[x] showed differences to that of conventional BMI. The association signal at ADCY3 appeared to be driven by a missense variant and it was strongly correlated with expression of this gene. Our work highlights the importance of well understood phenotype use (and the danger of convention) in characterising genetic contributions to complex traits.
PMCID: PMC4265207  PMID: 25044758

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