2010 › Trails



Genetic studies: Influence of common variants near INSIG2, in FTO, and near MC4R genes on overweight and the metabolic profile in adolescence: the TRAILS (TRacking Adolescents’ Individual Lives Survey) Study

Authors: Liem ET, Vonk JM, Sauer PJJ, Van der Steege G, Oosterom E, Stolk RP, Snieder H

Background: Overweight is a complex trait in which both environmental and genetic factors play a role. Objective: We aimed to evaluate the influence of common genetic variants identified by genome-wide association studies on overweight and the metabolic profile in adolescence. Design: In a population-based cohort of 663 girls and 612 boys aged 16 y, weight, height, skinfold thicknesses, percentage body fat, waist circumference, blood pressure, glucose, insulin, lipid profile, and DNA were obtained. We defined overweight according to international criteria. We performed multiple linear and logistic regression analyses to assess the influence of candidate single nucleotide polymorphisms near the INSIG2, in the FTO, and near the MC4R genes and repeated-measures analyses of available body mass index (BMI) and skinfold thickness data across 3 visits at ages 11, 13.5, and 16 y. Results: A total of 15.1% of participants were overweight or obese at age 16 y. No associations with INSIG2 were found. Common variation in the FTO gene was associated with sex-specific z scores of BMI (B: 0.11; 95% CI: 0.03, 0.19), sum of skinfold thicknesses (B: 0.12; 95% CI: 0.04, 0.20), percentage body fat (B: 0.11; 95% CI: 0.03, 0.19), waist circumference (B: 0.11; 95% CI: 0.03, 0.19), fasting glucose (B: 0.10; 95% CI: 0.00, 0.20), and overweight (odds ratio: 1.34; 95% CI: 1.06, 1.69) at age 16 y. Repeated-measures analyses confirmed the associations for BMI and sum of skinfold thicknesses, and physical activity did not modify these associations. Common variation near the MC4R gene was associated with BMI in cross-sectional (B: 0.11; 95% CI: 0.02, 0.20) and repeated-measures (B: 0.12; 95% CI: 0.03, 0.20) analyses. Conclusions: Common variation in the FTO gene is associated with overall and abdominal adiposity. Variation near the MC4R gene is associated with BMI. These findings in adolescents strengthen and extend the results from previous research.

Genetic studies: Evidence for plasticity genotypes in a gene-gene-environment interaction: The TRAILS study

Authors: Nederhof E, Bouma EMC, Riese H, Laceulle OM, Ormel J, Oldehinkel AJ

The purpose was to study how functional polymorphisms in the brain derived neurotrophic factor gene (BDNF val66met) and the serotonin transporter gene linked promotor region (5-HTTLPR) interact with childhood adversities in predicting Effortful Control. Effortful Control refers to the ability to regulate behaviour in a goal directed manner and is an interesting endophenotype for psychopathology because of its heritability and the association of low Effortful Control with both internalizing and externalizing problems. In a longitudinal population-based study Effortful Control was assessed with the parent version of the Early Adolescent Temperament Questionnaire at age 11. Pregnancy and delivery adversities and childhood events were assessed in a parent interview at age 11. Long term difficulties until age 11 were assessed with a parent questionnaire at age 13.5. Blood or buccal cells were collected at age 16 for genotyping the rs6265 and rs25531 SNPs and the 5-HTTLPR length polymorphism. The study included 1032 complete data sets. Effortful Control was significantly predicted by the interaction between BDNF val66met, 5-HTTLPR and childhood events. The BDNF val66met val/val - 5-HTTLPR l’/l’ genotype was unaffected by childhood events, while having either at least one BDNF val66met met or 5-HTTLPR s’ allele (l’/l’-met-carrier; l’/s’-val/val; s’/s’-val/val) made children sensitive to childhood events. Predictions of Effortful Control by pregnancy and delivery adversities and long term difficulties were largely independent of genotype. We concluded that the l’/l’-met-carrier, l’/s’-val/val and the s’/s’-val/val genotypes showed greatest plasticity while the l’/l’-val/val genotype was unaffected by childhood events.

Genetic studies: Perinatal Risk Factors Interacting With Catechol O-Methyltransferase and the Serotonin Transporter Gene Predict ASD symptoms in Children With ADHD

Authors: Nijmeijer JS, Hartman CA, Rommelse NNJ, Altink ME, Buschgens CJM, Fliers EA, Franke B, et al.

Background: Symptoms of Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) often co-occur. Given the previously found familiality of ASD symptoms in children with ADHD, addressing these symptoms may be useful for genetic association studies, especially for candidate gene findings that have not been consistently replicated for ADHD. Methods: We studied the association of the catechol o-methyltransferase (COMT) Val158Met polymorphism and the serotonin transporter (SLC6A4/SERT/5-HTT) 5-HTTLPR insertion/deletion polymorphism with ASD symptoms in children with ADHD, and whether these polymorphisms would interact with pre- and perinatal risk factors, i.e., maternal smoking during pregnancy and low birth weight. Analyses were performed using linear regression in 207 Dutch participants with combined type ADHD of the International Multicenter ADHD Genetics (IMAGE) study, and repeated in an independent ADHD sample (n = 439) selected from the TRracking Adolescents’ Individual Lives Survey (TRAILS). Dependent variables were the total and subscale scores of the Children’s Social Behavior Questionnaire (CSBQ). Results: No significant main effects of COMT Val158Met, 5-HTTLPR, maternal smoking during pregnancy and low birth weight on ASD symptoms were found. However, the COMT Val/Val genotype interacted with maternal smoking during pregnancy in increasing stereotyped behavior in the IMAGE sample (p = 0.008); this interaction reached significance in the TRAILS sample after correction for confounders (p = 0.02). In the IMAGE sample, the 5-HTTLPR S/S genotype interacted with maternal smoking during pregnancy, increasing problems in social interaction (p = 0.02), and also interacted with low birth weight, increasing rigid behavior (p = 0.03). Findings for 5-HTTLPR in the TRAILS sample were similar, albeit for related CSBQ subscales. Conclusions: These findings suggest gene-environment interaction effects on ASD symptoms in children with ADHD.