[Show abstract][Hide abstract] ABSTRACT: Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10-8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.
Full-text · Article · Dec 2015 · Nature Communications
[Show abstract][Hide abstract] ABSTRACT: A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index
are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex-
and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873
children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10−8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05
SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining
all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10−10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in
childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index
and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass
Full-text · Article · Nov 2015 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma.
OBJECTIVE: We sought to assess the hypothesis that these associations are explained by reduced airway patency.
METHODS: We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma.
RESULTS: Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma.
CONCLUSIONS: Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent.
Full-text · Article · Nov 2015 · Journal of Allergy and Clinical Immunology
[Show abstract][Hide abstract] ABSTRACT: Understanding changes in dietary intake during puberty could aid the mapping of dietary interventions for primary prevention. The present study describes dietary changes from childhood to adolescence, and their associations with parental education, family income, child education, body mass index (BMI), pubertal onset and screen-time sedentary behaviour.
Dietary data (n = 1232) were obtained from food frequency questionnaires at the 10- and 15-year follow-ups of the GINIplus birth cohort study. Intakes of 17 food groups, macronutrients and antioxidant vitamins, were described by a) paired Wilcoxon rank sum tests, comparing average intakes at each time-point, and b) Cohen's kappa "tracking" coefficients, measuring stability of intakes (maintenance of relative tertile positions across time). Further, associations of changes (tertile position increase or decrease vs. tracking) with parental education, family income, child education, pubertal onset, BMI, and screen-time, were assessed by logistic regression and multinomial logistic regression models stratified by baseline intake tertile.
Both sexes increased average intakes of water and decreased starchy vegetables, margarine and dairy. Females decreased meat and retinol intakes and increased vegetables, grains, oils and tea. Males decreased fruit and carbohydrates and increased average intakes of meat, caloric drinks, water, protein, fat, polyunsaturated fatty acids (PUFAs), vitamin C and alpha-tocopherol. Both sexes presented mainly "fair" tracking levels [κw = 0.21-0.40]. Females with high (vs. low) parental education were more likely to increase their nut intake [OR = 3.8; 95 % CI = (1.7;8.8)], and less likely to decrease vitamin C intakes [0.2 (0.1;0.5)], while males were less likely to increase egg consumption [0.2 (0.1;0.5)] and n3 PUFAs [0.2 (0.1;0.5)]. Females with a higher (vs. low) family income were more likely to maintain medium wholegrain intakes [0.2 (0.1;0.7) for decrease vs. tracking, and 0.1 (0.0;0.5) for increase vs. tracking], and were less likely to decrease vitamin C intakes [0.2 (0.1;0.6)]. Males with high education were less likely to increase sugar-sweetened foods [0.1 (0.1;0.4)]. Finally, BMI in females was negatively associated with decreasing protein intakes [0.7 (0.6;0.9)]. In males BMI was positively associated with increasing margarine [1.4 (1.1;1.6)] and vitamin C intakes [1.4 (1.1;1.6)], and negatively associated with increasing n3 PUFA.
Average dietary intakes changed significantly, despite fair tracking levels, suggesting the presence of trends in dietary behaviour during puberty. Family income and parental education predominantly influenced intake changes. Our results support the rationale for dietary interventions targeting children, and suggest that sex-specific subpopulations, e.g. low socio-economic status, should be considered for added impact.
Full-text · Article · Sep 2015 · BMC Public Health
[Show abstract][Hide abstract] ABSTRACT: Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N=28,459). We identified 7 independent top SNPs (P<1x10(-6)) for birth length, of which 3 were novel and 4 were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The 3 novel SNPs were followed-up in 9 replication studies (Stage 2; N=11,995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1+2; ß=0.046, S.E.=0.008, P=2.46x10(-8), explained variance=0.05%). Rs905938 was also associated with infant length (N=28,228; P=5.54x10(-4)) and adult height (N=127,513; P=1.45x10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
No preview · Article · Oct 2014 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Negative associations between bone turnover markers and bone mineral density have been reported. In order to study the association between ambient air pollution and bone turnover markers, as indicators of bone loss, we investigated associations between land-use regression modeled air pollution (NO2, PM2.5 mass, PM2.5-10 [coarse particles], PM10 mass and PM2.5 absorbance) and bone turnover markers in 2264 children aged 10 years. Serum osteocalcin and C-terminal telopeptide of type I collagen (CTx), measured by Modular-System (Roche), were the two bone turnover markers considered in this analysis. In total population, NO2, PM2.5-10 and PM10 mass exposure were positively and significantly associated with both osteocalcin and CTx. A 2.5 (95% CI: 0.6, 4.4) ng/ml increase in osteocalcin and a 24.0 (95% CI: 6.7, 41.3) ng/L increase in CTx were observed per IQR (6.7 μg/m3) increase in NO2, independent of socioeconomic status, sex, age, pubertal status, fasting status and total physical activity. The estimated coefficients were 3.0 (95% CI: 0.1, 5.8) for osteocalcin and 32.3 (95% CI: 6.1, 58.5) for CTx with PM2.5-10; 3.2 (95% CI: 0.0, 6.4) for osteocalcin and 30.7 (95% CI: 1.7, 59.7) for CTx with PM10. Children living close to a major road (≤ 350 m) had higher levels of both osteocalcin (1.4 [-1.2, 4.0] ng/ml) and CTx (16.2 [-7.4, 39.8] ng/L). The adverse impact of ambient air pollution on bone turnover rates observed in one of the study areas showed stimulation of more such studies.
Full-text · Article · Aug 2014 · International Journal of Hygiene and Environmental Health
[Show abstract][Hide abstract] ABSTRACT: Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 x 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
[Show abstract][Hide abstract] ABSTRACT: Objective:
To investigate the cross-sectional association between food intake and overweight in children.
Height and weight were measured in 2,565 school-aged children. Intakes of 11 food groups were categorized (low, medium and high) using specific tertile cutoffs. Multivariate energy partition models were applied. Adjustment included energy intake from other food groups, city, family income, parental education and 'screen' time. Possible underreporters were identified and used in sensitivity analyses.
Compared to low intake, high intakes of meat, fish, beverages and bakery products were associated with greater BMI z-scores [β (95% CI) = 0.32 (0.21, 0.42), 0.13 (0.03, 0.24), 0.23 (0.11, 0.35) and 0.10 (-0.01, 0.20)] and increased risk of being overweight [odds ratio (OR) (95% CI) = 2.08 (1.58, 2.73), 1.39 (1.08, 1.80), 1.36 (1.01, 1.84) and 1.62 (1.24, 2.11)]. Conversely, medium and high intakes of confectionery were associated with smaller BMI z-scores [β = -0.18 (-0.28, -0.07) and -0.22 (-0.33, -0.12)] and decreased risk of being overweight [OR = 0.64 (0.50, 0.83) and 0.53 (0.40, 0.68)]. These associations were robust to sensitivity analyses.
Intakes of meat, fish, beverages and bakery products correlate with body weight status.
No preview · Article · May 2014 · Annals of Nutrition and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Background/Objectives:
Mother's body mass index (BMI) is a strong predictor of child BMI. Whether mother's BMI correlates with child's food intake is unclear. We investigated associations between mother's BMI/overweight and child's food intake using data from two German birth cohorts.
Food intakes from 3230 participants were derived from parent-completed food frequency questionnaires. Intakes of 11 food groups were categorized into three levels using group- and sex-specific tertile cutoffs. Mother's BMI and overweight were calculated on the basis of questionnaire data. Multinomial regression models assessed associations between a child's food intake and mother's BMI/overweight. Linear regression models assessed associations between a child's total energy intake and mother's BMI. Models were adjusted for study region, maternal education, child's age, sex, pubertal status and energy intake and the BMIs of the child and father.
Mothers' BMI was associated with high meat intake in children (adjusted relative risk ratio (RRR (95% confidence interval))=1.06 (1.03; 1.09)). Mothers' overweight was associated with the meat intake (medium versus low RRR=1.30 (1.07; 1.59); high versus low RRR=1.50 (1.19; 1.89)) and egg intake (medium versus low RRR=1.24 (1.02; 1.50); high versus low RRR=1.30 (1.07; 1.60)) of children. There were no consistent associations for rest of the food groups. For every one-unit increase in mothers' BMI, the total energy intake in children increased by 9.2 kcal (3.7; 14.7). However, this effect was not significant after adjusting for children's BMI.
Our results suggest that mother's BMI and mother's overweight are important correlates of a child's intake of energy, meat and eggs.
Full-text · Article · May 2014 · European Journal of Clinical Nutrition
[Show abstract][Hide abstract] ABSTRACT: Objective
To investigate whether birth by cesarean delivery rather than vaginal delivery is a risk factor for later childhood obesity.
Healthy, full-term infants were recruited. Overweight and obesity were defined using measured weight and height according to World Health Organization reference data. Associations between cesarean delivery and being overweight or obese were investigated at age 2, 6, and 10 years (n = 1734, 1244, and 1170, respectively) by multivariate logistic regression models adjusted for socioeconomic status, child characteristics, and maternal prepregnancy characteristics.
Mothers who gave birth by cesarean delivery (∼17%) had a higher mean prepregnancy body mass index (23.7 kg/m2 vs 22.5 kg/m2), greater mean gestational weight gain (15.3 kg vs 14.5 kg), and shorter mean duration of exclusive breastfeeding (3.4 months vs 3.8 months) compared with those who delivered vaginally. The proportion of obese children was greater in the cesarean delivery group compared with the vaginal delivery group at age 2 years (13.6% vs 8.3%), but not at older ages. Regression analyses revealed a greater likelihood of obesity at age 2 years in the cesarean delivery group compared with the vaginal delivery group at age 2 years (aOR, 1.68; 95% CI, 1.10-2.58), but not at age 6 years (aOR, 1.49; 95% CI, 0.55-4.05) or age 10 years (aOR, 1.16; 95% CI, 0.59-2.29).
Cesarean delivery may increase the risk of obesity in early childhood. Our results do not support the hypothesis that an increasing rate of cesarean delivery contributes to obesity in childhood.
Full-text · Article · May 2014 · The Journal of pediatrics
[Show abstract][Hide abstract] ABSTRACT: Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11,000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of MKL2 (P=8.9 x 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P=4.6 x 10(-5)) and short adult stature (P=1.1 x 10(-11)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes.Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, BMI-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes, and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
Full-text · Article · Apr 2014 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: When evaluating the causal link between obesity and the development of asthma in children, prospective cohort studies are essential. The results of the most recently published birth cohort studies from Sweden, Germany, Brazil, Belarus, and California, USA, as well as from a joint analysis of eight European birth cohorts of the Global Allergy and Asthma European Network are evaluated. Moreover, the results of two meta-analyses are presented.
Most recent prospective cohort studies found a dose-response association between overweight or obesity and asthma. The evidence of effect modification by sex, ethnicity, and age was inconsistent. Both meta-analyses also showed that overweight children were at an increased risk of incident asthma compared with nonoverweight children and that the relationship was further elevated for obesity.
Prospective cohort studies and two recently published meta-analyses found an association between overweight (and especially obesity) and asthma in the appropriate temporal sequence and in a dose-response manner. Children with a pronounced weight gain slope in early life were particularly at risk for asthma within the first 6 years of life. The gain in BMI over time during infancy may be an even more important predictor for asthma in childhood than excess weight at any specific age.
Full-text · Article · Feb 2014 · Current Opinion in Allergy and Clinical Immunology
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. OBJECTIVE: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). RESULTS: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 x 10-10) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 x 10-9), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 x 10-8) at 17q12-q21. We found a cis expression quantitative trait locus 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, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. CONCLUSION: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma.
No preview · Article · Dec 2013 · Journal of Allergy and Clinical Immunology