GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.</p

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values Author summary Although twin studies have shown that body mass index (BMI) is highly heritable, many common genetic variants involved in the development of BMI have not yet been identified, especially in children. We studied associations of more than 40 million genetic variants with childhood BMI in 61,111 children aged between 2 and 10 years. We identified 25 genetic variants that were associated with childhood BMI. Two of these have not been implicated for BMI previously, located close to the genesNEDD4LandSLC45A3. We also show that the genetic background of childhood BMI overlaps with that of birth weight, adult BMI, waist-to-hip-ratio, diastolic blood pressure, type 2 diabetes, and age at menarche. Our results suggest that the biological processes underlying childhood BMI largely overlap with those underlying adult BMI. However, the overlap is not complete. Additionally, the genetic backgrounds of childhood BMI and other cardio-metabolic phenotypes are overlapping. This may mean that the associations of childhood BMI and later cardio-metabolic outcomes are partially explained by shared genetics, but it could also be explained by the strong association of childhood BMI with adult BMI.Peer reviewe

Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

ObjectiveProinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.Research design and methodsWe have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.ResultsNine SNPs at eight loci were associated with proinsulin levels (P &lt; 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.ConclusionsWe have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (ndiscovery=52654 and nreplication=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined=1.8x10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined=1.5x10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined=1.2x10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.</p

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood

Ambient air pollution and low birthweight: a European cohort study (ESCAPE)

Background Ambient air pollution has been associated with restricted fetal growth, which is linked with adverse respiratory health in childhood. We assessed the effect of maternal exposure to low concentrations of ambient air pollution on birthweight. Methods We pooled data from 14 population-based mother-child cohort studies in 12 European countries. Overall, the study population included 74 178 women who had singleton deliveries between Feb 11, 1994, and June 2, 2011, and for whom information about infant birthweight, gestational age, and sex was available. The primary outcome of interest was low birthweight at term (weight &lt;2500 g at birth after 37 weeks of gestation). Mean concentrations of particulate matter with an aerodynamic diameter of less than 2.5 mu m (PM2.5), less than 10 mu m (PM10), and between 2.5 mu m and 10 mu m during pregnancy were estimated at maternal home addresses with temporally adjusted land-use regression models, as was PM2.5 absorbance and concentrations of nitrogen dioxide (NO 2) and nitrogen oxides. We also investigated traffic density on the nearest road and total traffic load. We calculated pooled effect estimates with random-effects models. Findings A 5 mu g/m(3) increase in concentration of PM2.5 during pregnancy was associated with an increased risk of low birthweight at term (adjusted odds ratio [OR] 1.18, 95% CI 1.06-1.33). An increased risk was also recorded for pregnancy concentrations lower than the present European Union annual PM2.5 limit of 25 mu g/m(3) (OR for 5 mu g/m(3) increase in participants exposed to concentrations of less than 20 mu g/m(3) 1.41, 95% CI 1.20-1.65). PM10 (OR for 10 mu g/m(3) increase 1.16, 95% CI 1.00-1.35), NO2 (OR for 10 mu g/m(3) increase 1.09, 1.00-1.19), and traffic density on nearest street (OR for increase of 5000 vehicles per day 1.06, 1.01-1.11) were also associated with increased risk of low birthweight at term. The population attributable risk estimated for a reduction in PM2.5 concentration to 10 mu g/m(3) during pregnancy corresponded to a decrease of 22% (95% CI 8-33%) in cases of low birthweight at term. Interpretation Exposure to ambient air pollutants and traffic during pregnancy is associated with restricted fetal growth. A substantial proportion of cases of low birthweight at term could be prevented in Europe if urban air pollution was reduced

Epidemiological studies with environmental relevance in Germany

Unsere Umwelt beeinflusst Gesundheit und Wohlbefinden des Menschen, von der Geburt bis ins hohe Alter. In diesem Überblick werden die wichtigsten epidemiologischen Studien und Gesundheitsmonitoringsysteme in Deutschland erläutert, die unter anderem auch Umwelteinflüsse in verschiedenen Bevölkerungsgruppen untersuchen und Gesundheitseffekte abschätzen. Die darin jeweils untersuchten Umweltfaktoren werden beschrieben. Diese Studien an Kindern und Erwachsenen schaffen eine Basis für Vorhersagen und präventive Maßnahmen. Die hohe Anzahl der erfassten umweltbezogenen Faktoren und die Intensität ihrer Untersuchung unterscheiden sich in den Studien, ebenso wie die (phänotypische) Charakterisierung der Studienteilnehmenden. Dennoch bilden die gewonnenen Daten eine Grundlage für die zukünftige Forschungsarbeit. Hierzu ist allerdings eine flächendeckende dauerhafte Erfassung der Daten zu den verschiedenen Umweltfaktoren notwendig. Da der Anteil der in städtischen Gebieten lebenden Bevölkerung in Zukunft weiter steigen wird, werden Umweltfaktoren wie Luftverschmutzung, Lufttemperatur, Lärm, aber auch soziale Ungerechtigkeit zukünftig die Gesundheit und Lebensqualität der Bevölkerung maßgeblich beeinflussen. Die Herausforderung einer alternden Gesellschaft, aber auch die mögliche Adaptation der Bevölkerung an diverse Umweltstimuli machen einen multidisziplinären Ansatz erforderlich. Gerade aus umweltepidemiologischer Sicht sind hier die gesammelten Daten der in diesem Artikel aufgezeigten Kohortenstudien in Deutschland ein wertvoller Schatz, denn nur damit können Zusammenhänge zwischen Umwelteinflüssen und Gesundheit erforscht und public-health-relevante präventive Maßnahmen identifiziert werden. Die NAKO-Gesundheitsstudie, die in den kommenden Jahrzehnten die größte verfügbare Ressource für Gesundheitsdaten sein wird, sollte in zukünftige Aktivitäten zur Erforschung von Umwelteinflüssen eingebunden werden.Our environment is a major factor in determining health and well-being throughout life, from conception into old age. This overview illustrates the most important epidemiological studies and health monitoring systems in Germany, which investigate environmental influences in various population subgroups and estimate related health effects. Environmental factors examined in each study are described. The mentioned studies in children and adults build the basis for predictions and preventive measures. The number of the assessed environmental factors, the depth of the examinations as well as the (phenotypical) characterization of the study participants differ. Still, the obtained data build a base for important future research. However, for this, a permanent and Germany-wide assessment of environmental factors is necessary. The proportion of the European population living in urban areas is projected to increase in the future. Therefore, environmental factors such as air pollution, air temperature, and noise, but also social inequality, are likely to have a negative effect on health and quality of life of the population. The challenge of the aging population as well as potential adaptation processes to the diverse environmental stimuli requires multidisciplinary approaches. From an environmental epidemiology view, the collected data from the described studies are of immense value because only with this data can associations between environment and health be investigated and public health-relevant preventive measures be identified. The NAKO health study will be the largest resource of health data and should therefore be included in future activities related to the investigation of environmental health effects in Germany.Peer Reviewe