Barbara Heude

A genome-wide association study identifies novel risk loci for type 2 diabetes

Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case–control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing β-cells, and two linkage disequilibrium blocks that contain genes potentially involved in β-cell development or function (IDE–KIF11–HHEX and EXT2–ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.

Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations.

We analyzed genome-wide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls. Thirty-eight markers showing strong association were further evaluated in 14,186 European subjects. In addition to FTO and MC4R, we detected significant association of obesity with three new risk loci in NPC1 (endosomal/lysosomal Niemann-Pick C1 gene, P = 2.9 × 10−7), near MAF (encoding the transcription factor c-MAF, P = 3.8 × 10−13) and near PTER (phosphotriesterase-related gene, P = 2.1 × 10−7).

A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk

In genome-wide association (GWA) data from 2,151 nondiabetic French subjects, we identified rs1387153, near MTNR1B (which encodes the melatonin receptor 2 (MT2)), as a modulator of fasting plasma glucose (FPG; P = 1.3 × 10−7). In European populations, the rs1387153 T allele is associated with increased FPG (β = 0.06 mmol/l, P = 7.6 × 10−29, N = 16,094), type 2 diabetes (T2D) risk (odds ratio (OR) = 1.15, 95% CI = 1.08–1.22, P = 6.3 × 10−5, cases N = 6,332) and risk of developing hyperglycemia or diabetes over a 9-year period (hazard ratio (HR) = 1.20, 95% CI = 1.06–1.36, P = 0.005, incident cases N = 515). RT-PCR analyses confirm the presence of MT2 transcripts in neural tissues and show MT2 expression in human pancreatic islets and beta cells. Our data suggest a possible link between circadian rhythm regulation and glucose homeostasis through the melatonin signaling pathway.

Two new Loci for body-weight regulation identified in a joint analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85×10−8 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84×10−7), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ∼1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.

Common nonsynonymous variants in PCSK1 confer risk of obesity.

Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 × 10−8 and P = 2.31 × 10−12, respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.

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 <2500 g at birth after 37 weeks of gestation). Mean concentrations of particulate matter with an aerodynamic diameter of less than 2·5 μm (PM2·5), less than 10 μm (PM10), and between 2·5 μm and 10 μm 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 (NO2) 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 μg/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 μg/m(3) (OR for 5 μg/m(3) increase in participants exposed to concentrations of less than 20 μg/m(3) 1·41, 95% CI 1·20-1·65). PM10 (OR for 10 μg/m(3) increase 1·16, 95% CI 1·00-1·35), NO2 (OR for 10 μg/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 μg/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. FUNDING The European Union.

Time trend in height, weight, and obesity prevalence in school children from Northern France, 1992–2000

OBJECTIVE The aim of this study was to evaluate the changes in height, weight and in the prevalence of overweight and obesity between 1992 and 2000 in children living in two towns of northern France. METHODS Two cross-sectional studies were performed in every pre-school (last section) and primary schools of the two towns in 1992 (383 girls and 421 boys enrolled) and 2000 (296 girls and 305 boys). Children were 5 to 12 year old in both studies. MEASUREMENTS Body height and weight were measured, and BMI was calculated (weight/height(2)). Prevalence of overweight and obesity was determined according to the gender- and age- specific cut-offs of the new international reference (IOTF). We also used the 90(th) and the 97(th) percentiles of the French reference gender- and age-specific BMI curves to define two grades of overweight. RESULTS After adjustment for age, boys were on average 1.5 cm taller in 2000 than in 1992 (p<0.001), and the same trend was observed in girls (+ 0.9 cm, p<0.075). Height-adjusted or age-adjusted weight and BMI were significantly higher in 2000 than in 1992. In girls, obesity defined by IOTF criteria increased from 1.6 to 4.4% (p<0.03) and overweight from 14.1 to 18.6% (p<0.11). In boys, the change in prevalences was significant only when the less stringent criteria (i.e. the 90(th) percentile of French references) was used (13.8% in 1992 vs 20% in 2000, p=0.03). CONCLUSION Over an 8 years period, there was an increase in height and BMI in both boys and girls. These results show that the increase in the prevalence of obesity is accompanied by a global trend of accelerated growth.

Pregnancy and Birth Cohort Resources in Europe: a Large Opportunity for Aetiological Child Health Research

BACKGROUND During the past 25 years, many pregnancy and birth cohorts have been established. Each cohort provides unique opportunities for examining associations of early-life exposures with child development and health. However, to fully exploit the large amount of available resources and to facilitate cross-cohort collaboration, it is necessary to have accessible information on each cohort and its individual characteristics. The aim of this work was to provide an overview of European pregnancy and birth cohorts registered in a freely accessible database located at http://www.birthcohorts.net. METHODS European pregnancy and birth cohorts initiated in 1980 or later with at least 300 mother-child pairs enrolled during pregnancy or at birth, and with postnatal data, were eligible for inclusion. Eligible cohorts were invited to provide information on the data and biological samples collected, as well as the timing of data collection. RESULTS In total, 70 cohorts were identified. Of these, 56 fulfilled the inclusion criteria encompassing a total of more than 500,000 live-born European children. The cohorts represented 19 countries with the majority of cohorts located in Northern and Western Europe. Some cohorts were general with multiple aims, whilst others focused on specific health or exposure-related research questions. CONCLUSION This work demonstrates a great potential for cross-cohort collaboration addressing important aspects of child health. The web site, http://www.birthcohorts.net, proved to be a useful tool for accessing information on European pregnancy and birth cohorts and their characteristics.

Evolution of obesity prevalence in France: an age-period-cohort analysis.

Background: A rapid increase in the prevalence of obesity has been reported in France since 1990. We investigated the impact of birth cohort on the changes in obesity prevalence after taking into account age and survey period. Methods: We analyzed data from 4 national surveys in 1997, 2000, 2003, and 2006. For each survey, self-reported data on weight and height were recorded on mailed questionnaires sent to a sample of 20,000 households, representative of the French population. Obesity was defined according to World Health Organization criteria as body mass index ≥30 kg/m2. We modeled the prevalence of obesity using logistic regression with age, cohort, and period as explanatory variables. As these variables are linearly dependent, only nonlinear effects can be estimated uniquely and interpreted, after including specific chosen constraints in the models. Results: There was a progressive increase in the prevalence of obesity between 1997 and 2006, attributable either to a period effect or to a cohort effect. There was a substantial departure from a linear trend for the cohort effect only, which seemed to be stronger in women: there was an acceleration in the prevalence of obesity with birth cohort for individuals born after the mid-1960s, in both sexes. Conclusions: Our results are consistent with previous studies in other countries. Compared with older generations, men and women born in the late 1960s may have been subject to early exposures that increased their lifelong susceptibility to obesity.

Cohort Profile: The EDEN mother-child cohort on the prenatal and early postnatal determinants of child health and development

The overall objective of the EDEN study was to examine the relations and potential interactions between maternal exposures and health status during pregnancy, fetal development, health status of the infant at birth and the childs health and development.