The Trier Attention-deficit hyperactivity disorder study
A growing body of evidence points to the interplay between genetic vulnerability and psychosocial circumstances in early life (prenatal/postnatal) being involved in the pathogenesis of ADHD. Research is taking place within a framwork of a multicenter collaboration study conducted by three clinical units of child psychiatry (University of Trier, Homburg/Saar, and Wuerzburg). The aim of this research is to establish a DNA and data collection from a large sample of parent-offspring trios and/or affected sib pairs with ADHD to conduct genetic, psychosocial, and behavioral studies, and to define the role of gene-environment interaction in ADHD.
Our research group focuses on stress-impaired pre- and postnatal development in ADHD, with the aim to gain a better insight into the role of gene-environment interaction in ADHD.
Attention-deficit hyperactivity disorder
Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder characterized by age-inappropriate symptoms of inattention, motor activity, and impulsiveness. The symptoms of ADHD appear, on average, between three and six years of age (APA, 1994). The prevalence of ADHD has been estimated to be around 4-7% in all school-aged children (Mirsky & Duncan, 2001). Follow up studies involving ADHD children suggest that 60-70% of the cases have incomplete or full syndrome in adult life (Murphy & Barkley, 1996a). ADHD is, furthermore, highly comorbid with other psychiatric disorders, with studies using clinical samples indicating that around 87% have at least one other disorder and 67% have two or more disorders (Kadesjo & Gillberg, 2001). The most commonly seen comorbidity in ADHD is oppositional defiant disorder (ODD), diagnosed in 50 to 60% of ADHD children (Gillberg et al., 2004). Anxiety disorders are present in around 25% of the cases (see Biderman, et al., 1991 for review) and mood disorders are evident in about 20 to 30% of children with ADHD (Biederman et al., 1992; Cuffe et al, 2001).
Despite numerous studies over the last decades, the etiology of ADHD still eludes us. Findings from neuropsychological studies indicate that ADHD is associated with problems in executive functions, leading to difficulties with planning, working memory, and cognitive flexibility (reviewed in Arnsten et al 1996; Barkley 1997). Results from neuroimaging studies have, furthermore, described reduced blood flow or metabolism ( Rubia et al 1999; Yeo et al 2000) and reductions (Castellanos et al. 1996; Filipek et al., 1997) in prefrontal volume in ADHD individuals.
Findings from family, twin, and adoption studies indicate that the heritability in ADHD is around 0.80 (see Faraone et al. 2005; Smalley 1997; for review). There is, furthermore, converging evidence indicating neurobiological factors among the main mechanisms underlying the symptoms of ADHD, where many genes of small effect contribute to the disease susceptibility (Comings et al. 2000; Fischer et al. 2002).The efficacy of stimulants in the treatment of ADHD supports the notion that imbalance in the catecholamine systems plays a pivotal role in the pathophysiology of ADHD. Among many candidates implicated in the etiology of ADHD are the genes encoding for the dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and serotonin transporter (5-HTT; Faraone et al. 2005; Maher et al. 2002). Another gene that has been implicated in ADHD is Catechol-O-methyltransferase (COMT). The COMT gene has been localized to chromosomal region 22q11.2 in humans (Grossman, Emanuel, & Budarf, 1992), and exists in two forms, soluble (S-COMT) and a membrane bound (MB-COMT; Bertocci et al. 1991). A single nucleotide polymorphisms (SNP), where guanine is substituted by adenine at codon 158 of the MB-COMT, results in 3 to 4-fold difference in COMT activity by coding for the synthesis of the amino acid methionine (Met) instead of valine (Val). Homozygosity for Met leads to a reduction in COMT activity, compared with homozygosity for Val (Lachman et al., 1996). COMT plays a crucial role in the metabolism of catecholamines in the prefrontal cortex (Grossman et al. 1992), which is instrumental in the control of executive functions and guidance of behaviour and effect (Arnsten & Li, 2005). Balance in catecholamine transmission is therefore needed for the optimal function of the frontal lobe, where faulty catecholamine transmission can result in executive dysfunction and impaired behavioral control.