Parental psychopathology in families of children with attention-deficit/hyperactivity disorder and exposed to maternal smoking during pregnancy.

BACKGROUND: Both genetic and environmental factors have been implicated in the etiology of attention-deficit/hyperactivity disorder (ADHD). We had previously suggested that exposure to maternal smoking during pregnancy (MSDP) may be a valid basis for delineating a distinct subtype of ADHD, where children exposed to MSDP present with a more severe clinical picture. Here, we examine the psychopathology of parents in this group, to better understand the etiology of ADHD. METHODS: Using the Family Interview for Genetic Studies in a sample of 514 families of children with ADHD, we collected data pertaining to lifetime parental psychopathology. Families were stratified based on maternal smoking during the complete gestational period. The frequency of different disorders was compared using the χ2 statistic. RESULTS: In the group where mothers smoked during pregnancy, both parents were significantly more likely to have antisocial personality disorder, and problems with alcohol and drug abuse. Mothers had a significantly higher frequency of major depressive disorder (MDD), while fathers showed a trend for both MDD and bipolar disorder. CONCLUSIONS: Based on the pattern of psychopathology in parents of children exposed to MSDP, as well as earlier reports of the severe clinical, behavioral, and cognitive phenotype in these children, combined with the large body of epidemiological evidence, we propose that these children present a distinct subtype of ADHD with comorbid conduct disorder. Furthermore, we propose that MSDP may be a proxy measure to help delineate this subtype.

Association between obesity-related gene FTO and 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 genome-wide 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.

Selected rapporteur summaries from the XX World Congress of Psychiatric Genetics, Hamburg, Germany, October 14-18, 2012.

The XXth World Congress of Psychiatric Genetics (WCPG), sponsored by The International Society of Psychiatric Genetics (ISPG) took place in Hamburg, Germany on October 14-18, 2012. Approximately 600 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned sessions as rapporteurs. This manuscript represents topics covered in most, but not all, oral presentations during the conference, and some of the major notable new findings reported at this 2012 WCPG.

Maternal smoking during pregnancy and ADHD: a comprehensive clinical and neurocognitive characterization.

INTRODUCTION: Evidence from epidemiological studies has consistently shown an association between maternal smoking during pregnancy (MSDP) and attention-deficit/hyperactivity disorder (ADHD). The objective of this study is to test the hypothesis that children with ADHD exposed to MSDP show a distinctive clinical and neurocognitive profile when compared with unexposed children. METHODS: Four hundred and thirty-six children diagnosed with ADHD were stratified by exposure to MSDP and compared with regard to severity of illness, comorbidity, IQ, and executive function as assessed by a battery of neuropsychological tests. All comparisons were adjusted for socioeconomic status, ethnicity, mother's age at child's birth, and maternal alcohol consumption during pregnancy. RESULTS: Exposed children had more severe behavioral problems with greater externalizing symptoms and more conduct and oppositional defiant disorder items, lower verbal IQ, and a sluggish cognitive profile on the Continuous Performance Test (CPT). Linear regression analyses revealed a dose-response relationship between the average number of cigarettes smoked per day during pregnancy and verbal IQ, CPT omission errors T score and several other clinical variables. CONCLUSIONS: 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.

Comprehensive phenotype/genotype analyses of the norepinephrine transporter gene (SLC6A2) in ADHD: relation to maternal smoking during pregnancy.

OBJECTIVE: Despite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD. METHODS: Children (6-12 years old) diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH) using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT), including categorical and quantitative trait analyses, were conducted in 377 nuclear families. RESULTS: A highly significant association was observed with rs36021 (and linked SNPs) in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z=3.74, P=0.0002), behavioral assessments by parents (CBCL, P=0.00008), as well as restless-impulsive subscale scores on Conners'-teachers (P=0.006) and parents (P=0.006). In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z=3.28, P=0.001), parents (Z=2.62, P=0.009), as well as evaluation in the simulated academic environment (Z=3.58, P=0.0003). CONCLUSIONS: By using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment. Clinical trial registration information - Clinical and Pharmacogenetic Study of Attention Deficit with Hyperactivity Disorder (ADHD); www.clinicaltrials.gov; NCT00483106.

Family-based association study of ADHD and genes increasing the risk for smoking behaviours.

OBJECTIVE: To investigate five top single nucleotide polymorphisms (SNPs) located in different genes and loci (CHRNA3, BDNF, DBH and LOC100188947) that were highly associated with different dimensions of smoking behaviour, in relation to attention-deficit hyperactivity disorder (ADHD). DESIGN: Cohort study consisting of a clinical sample of children with ADHD. SETTING: Douglas Institute ADHD Clinic, Montreal, Canada. PATIENTS: Families of 454 children with ADHD aged 6-12 years old. INTERVENTIONS: Family-based association tests used to study the transmission of risk alleles within these five genetic markers. MAIN OUTCOME MEASURES: Clinical diagnosis of ADHD, and a number of behavioural and neurocognitive phenotypes relevant to the disorder. RESULTS: One SNP (rs1329650) from a non-coding RNA (LOC100188947) was significantly associated with overall ADHD diagnosis with the C* risk allele being over-transmitted from parents to children with ADHD (p=0.02). It was also over-transmitted to children with higher scores on Conners' Parents (p=0.01) and Conners' Teacher (p=0.002) index scores, and Child Behaviour Checklist withdrawn (p=0.001) and aggressive (p=0.007) behaviours. Children with poorer performances on executive and attention tasks were more likely to inherit the risk allele. CONCLUSIONS: The C* allele of rs1329650 may be increasing the risk for ADHD and smoking behaviour through a common mechanism, possibly externalising behaviours and specific cognitive deficits that manifest as ADHD in childhood and are the gateway to smoking behaviour later in life. This exploratory study illustrates the use of comorbid disorders to investigate ADHD genetics. In spite of its relatively large sample size, replication in future studies is warranted.

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.

Symptom persistence and memory performance in posttraumatic stress disorder: a gene x environment pilot stud.

The FKBP5 gene, a glucocorticoid receptor (GR)-regulating co-chaperone of stress proteins, is of special interest because of its role in hypothalamic-pituitary-adrenal (HPA)-axis regulation. However, studies finding a genetic relationship between posttraumatic stress disorder (PTSD) and the FKBP5 gene have failed to distinguish between the development and persistence of PTSD, thereby limiting the prognostic usefulness of such a finding. The present study sought to longitudinally explore this question by examining the association between four single-nucleotide polymorphisms (SNPs) in the FKBP5 gene (rs3800373, rs9470080, rs1360780, and rs9296158), the persistence of PTSD (severity and diagnostic status), and memory performance among twenty-two treatment-seekers diagnosed with acute PTSD. Results showed that the four SNPs significantly interacted with improvement in PTSD symptoms as well as PTSD diagnostic status. Individuals homozygous for the dominant allele and having experienced higher levels of peritraumatic responses subsequently showed more memory dysfunction. The results of this study suggest that SNPs in the FKBP5 gene are associated with symptom persistence and memory dysfunction in acute PTSD.

The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD.

BACKGROUND: Animal 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. METHODS: Patients 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 x treatment interaction effects. RESULTS: Mixed model analysis of variance revealed a gene x 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. CONCLUSIONS: A 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 REGISTRATION: ClinicalTrials.gov NCT00483106.

Development and persistence of posttraumatic stress disorder and the 5-HTTLPR polymorphism.

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.