Search

Objective: Irritability, which is strongly associated with impairment and negative outcomes, is a common reason for referral to mental health services but is a nosological and treatment challenge. A major issue is how irritability should be conceptualized. The authors used a developmental approach to test the hypothesis that there are several forms of irritability, including a "neurodevelopmental/ADHD-like" type, with onset in childhood, and a "depression/mood" type, with onset in adolescence.Methods: Data were analyzed from the Avon Longitudinal Study of Parents and Children, a prospective U.K. population-based cohort. Irritability trajectory classes were estimated for 7,924 individuals with data at multiple time points across childhood and adolescence (four possible time points from approximately ages 7 to 15). Psychiatric diagnoses were assessed at approximately ages 7 and 15. Psychiatric genetic risk was indexed by polygenic risk scores (PRSs) for attention deficit hyperactivity disorder (ADHD) and depression, derived using large genome-wide association study results.Results: Five irritability trajectory classes were identified: low (81.2%), decreasing (5.6%), increasing (5.5%), late-childhood limited (5.2%), and high-persistent (2.4%). The early-onset high-persistent trajectory was associated with male preponderance, childhood ADHD (odds ratio=108.64, 95% CI=57.45-204.41), and ADHD PRS (odds ratio=1.31, 95% CI=1.09-1.58). The adolescent-onset increasing trajectory was associated with female preponderance, adolescent depression (odds ratio=5.14, 95% CI=2.47-10.73), and depression PRS (odds ratio=1.20, 95% CI=1.05-1.38). Both the early-onset high-persistent and adolescent-onset increasing trajectory classes were associated with adolescent depression diagnosis and ADHD PRS.Conclusions: The developmental context of irritability may be important in its conceptualization: early-onset persistent irritability may be more neurodevelopmental/ADHD-like and later-onset irritability more depression/mood-like. These findings have implications for treatment as well as nosology. [ABSTRACT FROM AUTHOR]

Objective: Association between attention deficit hyperactivity disorder (ADHD) and the 7-repeat allele of a variant (a 48 bp variable number of tandem repeats) in the dopamine D4 receptor gene (DRD4) has been widely documented. A meta-analysis of 21 studies revealed evidence of significant association. In this article the authors examine whether the DRD4 7-repeat allele is associated with performance on a variety of neuropsychological tasks in children with ADHD.Method: The presence or absence of the 7-repeat allele was determined in 133 drug-naive children 6 to 13 years of age who fulfilled diagnostic criteria for ADHD. These children were then assessed on several neuropsychological tests known to be associated with attention, impulse control, and response inhibition (the Continuous Performance Test, Matching Familiar Figures Test, Go/No Go Task, and Stop Task). Activity levels were assessed with an actigraph. Children with and without at least one 7-repeat allele were compared with each other and with children in a previous population-based study.Results: Children who had the 7-repeat allele had significantly more incorrect responses on the Matching Familiar Figures Test (16.1 versus 14.3) than children who did not have the allele. Children with the allele also had shorter mean reaction times for incorrect responses on the Matching Familiar Figures Test (846.1 versus 1103.7 msec) and on the Stop Task (116.6 versus 134.1 msec) than children without the allele. Children with the allele also displayed higher activity levels. The children with and without the allele did not differ significantly in number of ADHD symptoms when the symptoms were split into the areas of inattention and hyperactivity/impulsivity. Both groups of children with ADHD were more neuropsychologically impaired than the nonpatient comparison group.Conclusions: In children with ADHD, possession of the DRD4 7-repeat allele appears to be associated with an inaccurate, impulsive response style on neuropsychological tasks that is not explained by ADHD symptom severity. [ABSTRACT FROM AUTHOR]

Objective: A major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs. Method: The authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD. Results: No SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS. Conclusions: Both common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways. [ABSTRACT FROM AUTHOR]

Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. Method: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. Results: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. Conclusions: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5-3.6), this locus could be an important contributor to ADHD etiology. [ABSTRACT FROM AUTHOR]