LPHN3 and attention-deficit/hyperactivity disorder: interaction with maternal stress during pregnancy.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous behavioral disorder, complex both in etiology and clinical expression. Both genetic and environmental factors have been implicated, and it has been suggested that gene-environment interactions may play a pivotal role in the disorder. Recently, a significant association was reported between ADHD and LPHN3 (which codes for latrophilin 3), and replicated in independent samples. METHODS: We have examined the association between tag single nucleotide polymorphisms (SNPs) in LPHN3 within the region previously implicated in ADHD. Family based association tests (FBAT) were conducted (n = 380 families) with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, and response to treatment (given a fixed dose of methylphenidate, 0.5 mg/day). Stratified FBAT analyses, based on maternal smoking and stress during pregnancy, was conducted. RESULTS: Whereas limited association was observed in the total sample, highly significant interaction between four LPHN3 tag SNPs (rs6551665, rs1947274, rs6858066, rs2345039) and maternal stress during pregnancy was noted. Analysis conducted in the sub-group of mothers exposed to minimal stress during pregnancy showed significant associations with ADHD, behavioral and cognitive dimensions related to ADHD, as well as treatment response. Although extensive association was observed with the candidate SNPs, the findings are partially inconsistent with previously published results with the opposite alleles over-transmitted in these studies. CONCLUSIONS: 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.

Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype.

BACKGROUND: Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD. METHODS: Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT. RESULTS: A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5' region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplo-type block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2. LIMITATIONS: The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype. CONCLUSION: The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples.

Dopamine transporter 3'UTR VNTR genotype is a marker of performance on executive function tasks in children with ADHD.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous disorder from both clinical and pathogenic viewpoints. Executive function deficits are considered among the most important pathogenic pathways leading to ADHD and may index part of the heterogeneity in this disorder. METHODS: To investigate the relationship between the dopamine transporter gene (SLC6A3) 3'-UTR VNTR genotypes and executive function in children with ADHD, 196 children diagnosed with ADHD were sequentially recruited, genotyped, and tested using a battery of three neuropsychological tests aimed at assessing the different aspects of executive functioning. RESULTS: Taking into account a correction for multiple comparisons, the main finding of this study is a significant genotype effect on performances on the Tower of London (F = 6.902, p = 0.009) and on the Wechsler Intelligence Scale for Children, Third Edition (WISC-III) Freedom From Distractibility Index (F = 7.125, p = 0.008), as well as strong trends on Self Ordered Pointing Task error scores (F = 4,996 p = 0.026) and WISC-III Digit Span performance (F = 6.28, p = 0.023). Children with the 9/10 genotype exhibited, on average, a poorer performance on all four measures compared to children with the 10/10 genotype. No effect of genotype on Wisconsin Card Sorting Test measures of performance was detected. CONCLUSION: Results are compatible with the view that SLC6A3 genotype may modulate components of executive function performance in children with ADHD.

Performance on the continuous performance test in children with ADHD is associated with sleep efficiency.

STUDY OBJECTIVE: To examine whether the level of sleep efficiency of children diagnosed with ADHD moderates their performance on the Continuous Performance Test (CPT) while receiving a placebo and while receiving methylphenidate (MPH). DESIGN: Nightly sleep actigraphic assessment during a double-blind, placebo-controlled, crossover clinical study (1 week of 0.5 mg/kg MPH; 1 week of placebo) were obtained on 37 children between 6 and 12 years of age with a DSM-IV diagnosis of ADHD. Subjects were divided into 2 groups based on the mean sleep efficiency score during the placebo condition, with subjects above and below the mean placed in the Poor Sleep Group (PSG) and Good Sleep Group (GSG), respectively. SETTING: Vigilance testing was conducted in the laboratory; sleep was assessed in the home. MEASUREMENTS: Sleep was monitored using actigraphy for 2 weeks. In addition, parents were asked to complete nightly sleep logs and a sleep questionnaire. The Conners' Continuous Performance Test (CPT) was used to assess vigilance. RESULTS: Significant interaction of Sleep Group with Medication was found on 1 CPT factor. CONCLUSIONS: The findings of the present study support the hypothesis that sleep moderates performance on CPT in children with ADHD while receiving placebo or MPH.

COMT Val108/158Met gene variant, birth weight, and conduct disorder in children with ADHD.

OBJECTIVE: In a recent study, Thapar and colleagues reported that COMT "gene variant and birth weight predict early-onset antisocial behavior in children" with attention-deficit/hyperactivity disorder. We have attempted to replicate these findings in a group of ADHD children using a similar research design. METHOD: Children (n=191) between 6 and 12 years of age who were diagnosed with ADHD were included in the study. Conduct disorder was diagnosed according to DSM-IV criteria based on clinical evaluation and a structured interview (Diagnostic Interview Schedule for Children-IV). The mother's report on the child's birth weight was used in the analysis. Logistic regression analysis, with genotype and birth weight as independent variables and DSM-IV conduct disorder as the dependent variable, was conducted. RESULTS: No significant main effects of genotype and birth weight or interaction effects on conduct disorder were observed. CONCLUSION: In this sample of children diagnosed with ADHD, we find no association between the COMT ValMet gene variant, birth weight, and conduct disorder. Further investigations are required before using birth weight and COMT genotype as predictors of conduct disorder in children with attention-deficit/hyperactivity disorder, especially given the societal and legal ramifications of conduct disorder.

COMT Val108/158Met polymorphism and the modulation of task-oriented behavior in children with ADHD.

It has been suggested that the symptoms of attention-deficit/hyperactivity disorder (ADHD), including inattention and/or hyperactivity/impulsivity, translate into deficits in task-oriented behavior or problem-focused activity. The frontosubcortical dopamine pathway has been implicated in ADHD. One of the key modulators of extracellular dopamine levels in the prefrontal cortex is catechol-O-methyltransferase (COMT). The objective of this study was to examine the association of the COMT Val(108/158)Met polymorphism with (1) task-oriented behavior in children with ADHD, and (2) response of this behavior given methylphenidate (MPH) treatment. Children of Caucasian ethnicity, having ADHD (n=188), were assessed using the Restricted Academic Situation Scale (RASS). The RASS uses a simulated academic environment within the research clinic, to assess the child's ability for independent, sustained orientation to an assignment of math problems. Each child was administered placebo and MPH (0.5 mg/kg in a divided b.i.d. dose), each for a 1-week period, in a randomized, double-blind, crossover trial. On day 3 of the respective treatment week, the child was administered placebo/MPH in the clinic, and the acute change in behavior (before and 1 h after treatment) was evaluated on the RASS. Analysis was carried out using mixed model analysis of variance. Significant main effects of COMT genotype (F(2,184)=5.12, p=0.007) and treatment (F(1,184)=44.26, p<0.001) on task-oriented behavior were observed. However, no genotype by treatment interaction was observed. These results suggest that the COMT Val(108/158)Met polymorphism modulates task-oriented behavior, but it does not modulate the response of this behavior with MPH treatment.

Sensitivity of tests to assess improvement in ADHD symptomatology.

OBJECTIVE: To assess which measurements best predict improvement on ADHD symptomatology after medication is given. METHODS: 147 children aged 6 to 12 years, diagnosed with ADHD, participated in a double-blind placebo controlled twoweek crossover trial of methylphenidate. RESULTS: There were statistically significant differences on all measures between placebo and medication. Effect size for the overall group was 0.33 (CGI-P), 0.80 (CGI-T), 1.33 (CGI), 0.56 (CPT), 0.82 (RASS). CONCLUSIONS: Acute behavioural response measures, where children are observed by clinicians (RASS and CGI), were overall more reliable than parent reports in detecting improvement on ADHD symptomatology. Teacher reports were also very important, especially in the 9 to 12 year old group.