Methylation of BDNF in women with bulimic eating syndromes: associations with childhood abuse and borderline personality disorder.

DNA methylation allows for the environmental regulation of gene expression and is believed to link environmental stressors to such mental-illness phenotypes as eating disorders. Numerous studies have shown an association between bulimia nervosa (BN) and variations in brain-derived neurotrophic factor (BDNF). BDNF has also been linked to borderline personality disorder (BPD) and to such traits as reward dependence. We examined the extent to which BDNF methylation corresponded to bulimic or normal-eater status, and also to the presence of comorbid borderline personality disorder (BPD) and childhood abuse. Our sample consisted of 64 women with BN and 32 normal-eater (NE) control women. Participants were assessed for eating-disorder symptoms, comorbid psychopathology, and childhood trauma, and then they were required to provide blood samples for methylation analyses. We observed a significant site×group (BN vs. NE) interaction indicating that women with BN showed increases in methylation at specific regions of the BDNF promoter. Furthermore, examining effects of childhood abuse and BPD, we observed significant site×group interactions such that groups composed of individuals with childhood abuse or BPD had particularly high levels of methylation at selected CpG sites. Our findings suggest that BN, especially when co-occurring with childhood abuse or BPD, is associated with a propensity towards elevated methylation at specific BDNF promoter region sites. These findings imply that hypermethylation of the BDNF gene may be related to eating disorder status, developmental stress exposure, and comorbid psychopathology.

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.

Relevance of the 5-HTTLPR polymorphism and childhood abuse to increased psychiatric comorbidity in women with bulimia-spectrum disorders.

OBJECTIVE: Individuals with bulimia nervosa have been shown to display heterogeneous profiles of comorbid psychiatric disturbance, possibly due to varying degrees of genetic and environmental vulnerability. Using information about comorbid psychiatric disturbances, we developed an empirically based classification of individuals with bulimia-spectrum disorders, and then explored whether or not the resulting phenotypes corresponded to variations in the serotonin transporter promoter polymorphism (5-HTTLPR) and exposure to childhood abuse. METHOD: Eighty-nine women aged 17 to 49 years with DSM-IV bulimia-spectrum disorders completed questionnaires assessing eating and general psychopathologic symptoms, participated in interviews assessing Axis I disorders and childhood abuse, and provided blood samples for genotyping. Data on lifetime Axis I disorders were analyzed using latent class analysis, and resulting classes were compared on eating and psychopathologic symptoms, 5-HTTLPR genotype, and childhood abuse. The study was conducted from June 2002 to October 2006. RESULTS: The analysis yielded a model with 2 classes: a first class labeled low comorbidity (N = 59, 66%), characterized by a high likelihood of major depressive disorder, and another class labeled high comorbidity (N = 30, 34%), characterized by a high likelihood of major depressive disorder, anxiety disorder, and substance-use disorders. The high-comorbidity class displayed significantly higher dieting preoccupations and conduct problems, and showed a greater likelihood of carrying the 5-HTTLPR S allele and of childhood abuse than did the low-comorbidity class. CONCLUSIONS: The present results are consistent with previous findings identifying a subgroup of individuals with bulimia characterized by high psychiatric comorbidity and suggest that the 5-HTTLPR polymorphism and childhood trauma may both be pertinent to explaining the presence of greater psychiatric comorbidity in bulimia-spectrum disorders.

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.

Schizotypy, attention deficit hyperactivity disorder, and dopamine genes.

Previous research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of Schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features.

Sleep and COMT polymorphism in ADHD children: preliminary actigraphic data.

OBJECTIVE: To examine whether COMT (catechol-O-methyltransferase) polymorphism modulates aspects of sleep in children diagnosed with attention-deficit/hyperactivity disorder (ADHD). METHOD: Nightly sleep actigraphic recordings during a double-blind, placebo-controlled, crossover clinical study (1 week of 0.5 mg/kg MPH; 1 week of placebo) were obtained for 34 children, 7.4 to 12 years old, diagnosed with ADHD (DSM-IV). Diagnosis was generated by the Diagnostic Interview Schedule for Children and was confirmed by multidisciplinary consensus. RESULTS: Children who were Val allele carriers had poorer sleep continuity compared with children with the Met-Met genotype while receiving a placebo and while receiving methylphenidate. CONCLUSIONS: The findings of the present study support the hypothesis that sleep disturbances in children with ADHD are related to the underlying pathophysiology of the disorder.