Molecular Genetic Basis of Opposite Gene by Environment Interactions in Reading Disability and Attention Deficit/Hyperactivity Disorder

The goal of this study is to better understand the genetic basis of Reading Disability (RD) and Attention Deficit Hyperactivity Disorder (ADHD) by examining molecular G x E interactions with parental education for each disorder. Research indicates that despite sharing genetic risk factors, RD and ADHD are influenced by different types of G x E interactions with parental education - a diathesis stress interaction in the case of ADHD and a bioecological interaction in RD. In order to resolve this apparent paradox, we conducted a preliminary study using behavioral genetic methods to test for G x E interactions in RD and the inattentive subtype of ADHD (ADHD-I) in the same sample of monozygotic and dizygotic Colorado Learning Disabilities Research Center same-sex twin pairs (DeFries et al., 1997), and our findings were consistent with the literature. We posited a genetic hypothesis for this opposite pattern of interactions, which suggests that only genes specific to each disorder enter into these opposite interactions, not the shared genes underlying their comorbidity. This study sought to further investigate this paradox using molecular genetics methods. We examined multiple candidate genes identified for RD or related language phenotypes and those identified for ADHD for G x E interactions with parental education. The specific aims of this study were as follows: 1) partition known risk alleles for RD and/or related language phenotypes and ADHD-I into those which are pleiotropic and non-pleiotropic by testing each risk allele for association with both RD and ADHD-I, 2) explore the main effects of parental education on both RD and ADHD-I, 3) address G-E correlations, and 4) conduct exploratory G x E interaction analyses in order to test the genetic hypothesis. Analyses suggested a number of pleiotropic genes that influence both RD and ADHD; however, results did not remain after correcting for multiple comparisons. Although exploratory G x E interaction findings were not significant after multiple comparison correction, results suggested a G x E interaction in the bioecological direction with KIAA0319, parental education, and ADHD-I. Given the limited power in the current study, replication of these findings with larger samples is necessary.

Relationship Maintenance in Couples with a Partner Who Has Attention Deficit Hyperactivity Disorder

The body of research on the relationship functioning of adults with attention deficit hyperactivity disorder (ADHD) is relatively small; the aim of the present study is to advance our understanding of this topic. It has been estimated that three to ten percent of children and one to five percent of adults have impairing symptoms of ADHD, which is a total of 4 million children and 4-5 million adults in the U.S. (Wender, 2000). A recent prevalence study found that approximately 4.4% of adults in the U.S. meet the criteria for a diagnosis of ADHD (Kessler et al., 2006). Children with ADHD show innate temperamental characteristics, usually inattentiveness, distractibility, impulsivity, restlessness, demandingness, hyperreactivity, low tolerance for frustration, temperoutbursts, bossiness and stubbornness, and mood lability, along with an innate proclivity for academic underachievement. It has been estimated that one- to two-thirds of children with ADHD have symptoms that continue into adulthood, and for 40-50% of these adults, these symptoms are serious enough to cause impairment in functioning (Everett & Everett, 1999; Wender, 2000). Research suggests that the majority of cases are transmitted genetically, but some may be due to exposure to environmental toxins such as lead. Consumption of excess sugar or allergies to food may exacerbate or mimic ADHD symptoms in some children, but they are not a cause of ADHD (Wender, 2000). One hypothesized cause of the symptoms associated with ADHD is a deficit in the brain's executive functioning (Barkley & Gordon, 2002). Executive functioning can be conceptualized as the ability to inhibit, organize, and plan behaviors. Barkley and Gordon (2002) define it as the abilityto self-direct and regulate behaviors toward future goals, including social behaviors and goals. Other research suggests that executive functioning consists of inhibition, control of interference, verbal and nonverbal working memory, emotional regulation, attention, verbal fluency, visual scanning, and processing speed. Studies have shown impairments in these areas among adults with ADHD (Barkley & Gordon, 2002; Barkley, Murphy & Kwasnik, 1996; Goldstein, 2002).

Making and Keeping Friends: A social skills game that promotes parental involvement to more effectively address social deficits in children with ADHD

The social deficits of children with attention-deficit/hyperactivity disorder (ADHD) have great impact on overall functioning and life satisfaction; however, ways of addressing these deficits to promote positive interpersonal functioning have been limited. The following paper explores the literature that highlights these social deficits, identifies skills that are proposed to target these impairments, discusses child and parent factors that are relevant to positive therapeutic change, and describes the development of a therapeutic game that incorporates variables important to treatment success of these interpersonal difficulties.

Re-Examining the Stop-Signal Task to Test Competing Theories of AD/HD

The current study tested two competing models of Attention-Deficit/Hyperactivity Disorder (AD/HD), the inhibition and state regulation theories, by conducting fine-grained analyses of the Stop-Signal Task and another putative measure of behavioral inhibition, the Gordon Continuous Performance Test (G-CPT), in a large sample of children and adolescents. The inhibition theory posits that performance on these tasks reflects increased difficulties for AD/HD participants to inhibit prepotent responses. The model predicts that putative stop-signal reaction time (SSRT) group differences on the Stop-Signal Task will be primarily related to AD/HD participants requiring more warning than control participants to inhibit to the stop-signal and emphasizes the relative importance of commission errors, particularly "impulsive" type commissions, over other error types on the G-CPT. The state regulation theory, on the other hand, proposes response variability due to difficulties maintaining an optimal state of arousal as the primary deficit in AD/HD. This model predicts that SSRT differences will be more attributable to slower and/or more variable reaction time (RT) in the AD/HD group, as opposed to reflecting inhibitory deficits. State regulation assumptions also emphasize the relative importance of omission errors and "slow processing" type commissions over other error types on the G-CPT. Overall, results of Stop-Signal Task analyses were more supportive of state regulation predictions and showed that greater response variability (i.e., SDRT) in the AD/HD group was not reducible to slow mean reaction time (MRT) and that response variability made a larger contribution to increased SSRT in the AD/HD group than inhibitory processes. Examined further, ex-Gaussian analyses of Stop-Signal Task go-trial RT distributions revealed that increased variability in the AD/HD group was not due solely to a few excessively long RTs in the tail of the AD/HD distribution (i.e., tau), but rather indicated the importance of response variability throughout AD/HD group performance on the Stop-Signal Task, as well as the notable sensitivity of ex-Gaussian analyses to variability in data screening procedures. Results of G-CPT analyses indicated some support for the inhibition model, although error type analyses failed to further differentiate the theories. Finally, inclusion of primary variables of interest in exploratory factor analysis with other neurocognitive predictors of AD/HD indicated response variability as a separable construct and further supported its role in Stop-Signal Task performance. Response variability did not, however, make a unique contribution to the prediction of AD/HD symptoms beyond measures of motor processing speed in multiple deficit regression analyses. Results have implications for the interpretation of the processes reflected in widely-used variables in the AD/HD literature, as well as for the theoretical understanding of AD/HD.

Examining the relationship among genes, attention bias to emotion, and depression in youth

The investigation of biologically initiated pathways to psychological disorder is critical to advance our understanding of mental illness. Research has suggested that attention bias to emotion may be an intermediate trait for depression associated with biologically plausible candidate genes, such as the serotonin transporter (5-HTTLPR) and catechol-o-methyl-transferase (COMT) genes, yet there have been mixed findings in regards to the precise direction of effects. The experience of recent stressful life events (SLEs) may be an important, yet currently unstudied, moderator of the relationship between genes and attention bias as SLEs have been associated with both gene expression and attention to emotion. Additionally, although attention biases to emotion have been studied as a possible intermediate trait associated with depression, no study has examined whether attention biases within the context of measured genetic risk lead to increased risk for clinical depressive episodes over time. Therefore, this research investigated both whether SLEs moderate the link between genetic risk (5-HTTLPR and COMT) and attention bias to emotion and whether 5-HTTLPR and COMT moderated the relationship between attention biases to emotional faces and clinical depression onset prospectively across 18 months within a large community sample of youth (n= 467). Analyses revealed a differential effect of gene. Youth who were homozygous for the low expressing allele of 5-HTTLPR (S/S) and had experienced more recent SLEs within the last three months demonstrated preferential attention toward negative emotional faces (angry and sad). However, youth who were homozygous for the high expressing COMT genotype (Val/Val) and had experienced more recent SLEs showed attentional avoidance of positive facial expressions (happy). Additionally, youth who avoided negative emotion (i.e., anger) and were homozygous for the S allele of the 5-HTTLPR gene were at greater risk for prospective depressive episode onset. Increased risk for depression onset was specific to the 5-HTTLPR gene and was not found when examining moderation by COMT. These findings highlight the importance of examining risk for depression across multiple levels of analysis, such as combined genetic, environmental, and cognitive risk, and is the first study to demonstrate clear evidence of attention biases to emotion functioning as an intermediate trait predicting depression.