These results suggest that MSDP is associated with a more severe form of ADHD, characterized by more severe clinical manifestations and poorer neuropsychological performance. This phenotypic signature associated with MSDP may help to identify a more homogenous subgroup of children with ADHD.

Objective: Attention-deficit/hyperactivity disorder (ADHD) is an etiologically complex heterogeneous behavioral disorder. Several studies have reported that ADHD subjects are more likely to be overweight/ obese and that this comorbidity may be due to shared genetic factors. The objective of this study is to explore the association between ADHD and FTO, a gene strongly associated with obesity in genomewide studies. Design and Methods: One tag SNP (single-nucleotide polymorphism, rs8050136, risk allele A) in the FTO gene was selected and its association with ADHD was tested. Family-based association tests (FBATs) were conducted with the categorical diagnosis of ADHD as well as behavioral and cognitive phenotypes related to ADHD. Furthermore, stratified FBAT analyses based on maternal smoking during pregnancy (MSDP) status were conducted. Results: Statistically significant associations were observed between rs8050136 and several of the traits tested in the total sample. These associations were stronger when the analysis was restricted to children who were not exposed to MSDP. Conclusions: These exploratory results suggest the involvement of the FTO SNP rs8050136 in modulating the risk for ADHD, particularly in those children who were not exposed to MSDP. If confirmed, they may explain, at least in part, the complex links between obesity and ADHD.

Association between 5-HTTLPR polymorphism and development of acute and persistence of chronic posttraumatic stress disorder (PTSD) was prospectively investigated. DNA was extracted from 41 motor-vehicle accident victims evaluated for development and persistence of PTSD, 1 and 12 months posttrauma. At Time 1, a nonsignificant trend for higher acute PTSD rate in ll homozygotes (82%) was observed compared to those with ss and sl genotypes (50%). At Time 2, higher chronic PTSD rate was found in ll homozygotes (55%) compared to those with ss and sl genotypes (20%), with an odds ratio of 4.8 (95% CI = 1.09-21.22). Contrary to previous findings, these data are suggestive of a protective role for the s allele of 5-HTTLPR in chronic PTSD.

These results provide evidence for the interaction between a genetic and environmental factor independently shown to be associated with ADHD. If confirmed in independent large studies, they may present a step forward in unraveling the complex etiology of ADHD.

No abstract

Exposure to stressors results in a spectrum of autonomic, endocrine, and behavioral responses. A key pathway in this response to stress is the hypothalamic-pituitary-adrenal (HPA) axis, which results in a transient increase in circulating cortisol, which exerts its effects through the two related ligand-activated transcription factors: the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Genetic polymorphisms in these receptors have been shown to influence HPA axis reactivity, and chronic dysregulation of the HPA axis has been associated with the development of several psychiatric disorders. The objective of the study was to test the association between four functional polymorphisms in NR3C1 (encoding GR: ER22/23EK-rs6189, N363S-rs6195, BclI-rs41423247, A3669G-rs6198) and two in NR3C2 (encoding MR: 215G/C-rs2070951, I180 V-rs5522) with childhood ADHD. Family-based association tests (FBAT) were conducted with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, as well as with treatment response assessed in a 2-week, double-blind, placebo-controlled trial with methylphenidate. A specific haplotype (G:A:G:G; ER22/23EK- N363S- BclI- A3669G) of NR3C1 showed a significant association with behaviors related to ADHD (particularly thought and attention problems, aggressive behavior), comorbidity with oppositional defiant disorder, and executive function domains. An association was also observed with treatment response (assessed by the Conners'-Teachers and Restricted Academic Situation Scale). In contrast, MR gene polymorphisms were not associated with any of the variables tested. To the best of our knowledge, this is the first report showing an association between functional polymorphisms in NR3C1 and ADHD, providing genetic evidence for involvement of the HPA axis in the disorder and treatment response.

No abstract

BackgroundAnimal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. In this study, we have investigated the relationship between the 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) and the response of ADHD relevant behaviors with methylphenidate treatment.MethodsPatients between ages 6-12 (n = 157) were assessed with regard to their behavioral response to methylphenidate (0.5 mg/kg/day) using a 2-week prospective within-subject, placebo-controlled (crossover) trial. The children were then genotyped with regard to the triallelic 5-HTTLPR polymorphism in the SLC6A4 gene. Main outcome measure: Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) at baseline and at the end of each week of treatment with placebo and methylphenidate. For both outcome measurements, we used a mixed model analysis of variance to determine gene, treatment and gene × treatment interaction effects.ResultsMixed model analysis of variance revealed a gene × treatment interaction for CGI-Parents but not for CGI-Teachers. Children homozygous for the lower expressing alleles (s+lG = s') responded well to placebo and did not derive additional improvement with methylphenidate compared to children carrying a higher expressing allele (lA). No genotype main effects on either CGI-Parents or CGI-teachers were observed.ConclusionsA double blind placebo-controlled design was used to assess the behavioral effects of methylphenidate in relation to the triallelic 5-HTTLPR polymorphism of the SLC6A4 gene in children with ADHD. This polymorphism appears to modulate the behavioral response to methylphenidate in children with ADHD as assessed in the home environment by parents. Further investigation is needed to assess the clinical implications of this finding.Trial RegistrationClinicalTrials.gov NCT00483106