Russell Schachar

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis

BACKGROUND: Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. METHODS: We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. FINDINGS: SNPs at four loci surpassed the cutoff for genome-wide significance (p<5x10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers. INTERPRETATION: Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause. FUNDING: National Institute of Mental Health.BACKGROUND Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. METHODS We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. FINDINGS SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers. INTERPRETATION Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause. FUNDING National Institute of Mental Health.

Impulsivity and Inhibitory Control

We report an experiment testing the hypothesis that impulsive behavior reflects a deficit in the ability to inhibit prepotent responses Specifically, we examined whether impulsive people respond more slowly to signals to inhibit (stop signals) than non-impulsive people In this experiment, 136 undergraduate students completed an impulsivity questionnaire and then participated in a stop-signal experiment, in which they performed a choice reaction time (go) task and were asked to inhibit their responses to the go task when they heard a stop signal The delay between the go signal and the stop signal was determined by a tracking procedure designed to allow subjects to inhibit on 50% of the stop-signal trials Reaction time to the go signal did not vary with impulsivity, but estimated stop-signal reaction time was longer in more impulsive subjects, consistent with the hypothesis and consistent with results from populations with pathological problems with impulse control

Development of inhibitory control across the life span.

The stop-signal procedure was used to examine the development of inhibitory control. A group of 275 participants, 6 to 81 years of age, performed a visual choice reaction time (go) task and attempted to inhibit their responses to the go task when they heard a stop signal. Reaction times to the stop and go signals were used to assess performance in inhibition and response execution, respectively. Results indicated the speed of stopping becomes faster with increasing age throughout childhood, with limited evidence of slowing across adulthood. By contrast, strong evidence was obtained for age-related speeding of go-signal reaction time throughout childhood, followed by marked slowing throughout adulthood. Hierarchical regression confirmed that the age-related change in inhibitory control could not be explained by general speeding or slowing of responses. Findings are discussed in regard to the contrast between the development of inhibition and response execution and the utility of the stop-signal procedure.

Why IQ is not a covariate in cognitive studies of neurodevelopmental disorders

IQ scores are volatile indices of global functional outcome, the final common path of an individuals genes, biology, cognition, education, and experiences. In studying neurocognitive outcomes in children with neurodevelopmental disorders, it is commonly assumed that IQ can and should be partialed out of statistical relations or used as a covariate for specific measures of cognitive outcome. We propose that it is misguided and generally unjustified to attempt to control for IQ differences by matching procedures or, more commonly, by using IQ scores as covariates. We offer logical, statistical, and methodological arguments, with examples from three neurodevelopmental disorders (spina bifida meningomyelocele, learning disabilities, and attention deficit hyperactivity disorder) that: (1) a historical reification of general intelligence, g, as a causal construct that measures aptitude and potential rather than achievement and performance has fostered the idea that IQ has special status and that in studying neurocognitive function in neurodevelopmental disorders; (2) IQ does not meet the requirements for a covariate; and (3) using IQ as a matching variable or covariate has produced overcorrected, anomalous, and counterintuitive findings about neurocognitive function.

The ecological validity of delay aversion and response inhibition as measures of impulsivity in AD/HD: a supplement to the NIMH multimodal treatment study of AD/HD

Impulsivity is a primary symptom of the combined type of Attention Deficit/Hyperactivity Disorder (AD/HD). The Stop Signal Paradigm is premised upon a primary deficit in inhibitory control in AD/HD, whereas the Delay Aversion Hypothesis, by contrast, conceptualizes impulsivity in AD/HD, not as an inability to inhibit a response, but rather as a choice to avoid delay. This study compared the ecological validity of the Stop Signal Task (SST) and Choice-Delay Task (C-DT) measure of delay aversion, with respect to their relative utility in discriminating AD/HD children from normal control participants, and their correlations with classroom observations and with ratings of impulsivity and other core AD/HD symptoms on the Conners and SNAP-IV checklists. The tasks exhibited modest discriminant validity when used individually and excellent discriminant validity when used in combination. The C-DT correlated with teacher ratings of impulsivity, hyperactivity, and conduct problems, and with observations of gross motor activity, physical aggression, and an AD/HD composite score. The SST correlated with the observations only. These results suggest that delay aversion is associated with a broad range of AD/HD characteristics whereas inhibitory failure seems to tap a more discrete dimension of executive control

Impulsivity and Inhibitory Control in Normal Development and Childhood Psychopathology

Two experiments investigated the development and pathology of inhibitory control in children. Inhibitory control was investigated with the stop-signal paradigm, which is based on a formal theory of inhibition and directly measures the mechanism of inhibition. The ability to inhibit developed little after Grade 2, but subjects with attention deficit disorder with hyperactivity (ADDH) showed deficient inhibitory control. Their deficient inhibitory control was attributable to the subgroup of ADDH subjects with pervasive hyperactivity who had a more severe inhibitory deficit than did the situational hyperactive subgroup, the normal group, and the pathological controls. These studies reflect the utility of the stop-signal paradigm as a measure of inhibitory control. The concept of inhibitory control is central in theories of child development and in the definition and explanation of psychopathological disorders of childhood—in particular, of attention deficit disorder with hyperactivity (ADDH; Douglas, 1983; Kogan, 1983; Milich & Kramer, 1984). Inhibitory control is one of several processes that perform the executive functions of the cognitive system. These functions determine how various mental processes (e.g., encoding, recognition, retrieval) will work together in the performance of a task. Children need executive control to choose, construct, execute, and maintain optimal strategies for performing a task, as well as to inhibit strategies that become inappropriate when goals or task demands change or errors occur (Logan, 1985). Deficient inhibitory control is revealed by impulsive behaviors such as responding before the task is understood, answering before sufficient information is available, allowing attention to be captured by irrelevant stimuli (i.e, distractibility), or failing to correct obviously inappropriate responses. Poorly developed inhibitory control might account for impulsive behaviors of younger children and of children with various types of psychopathology. Despite the importance of inhibitory control in theories of child development and psychopathology, no widely accepted

Deficient inhibitory control in attention deficit hyperactivity disorder.

The purpose of this study was to examine two executive control processes — response inhibition and re-engagement of responses after inhibition in children with attention deficit hyperactivity disorder (ADHD). Thirty-three children with ADHD and 22 normal control children of similar age (7 to 11 years) and mean IQ (107) were tested with the change paradigm. ADHD subgroups were defined by the context in which the ADHD symptoms predominated (in the home only; at school only; and in both, i.e., pervasive ADHD). Children with marked oppositional defiant or conduct disorder were excluded. Children with ADHD exhibited deficits in inhibitory control and in response re-engagement. Deficits were greatest in pervasive ADHD and, to a lesser extent, in those with ADHD limited to the school context. ADHD limited to the home context showed the least deficit. These results replicate an earlier study that found deficient inhibitory control in pervasive ADHD and demonstrate that the deficit in ADHD involves a second aspect of executive control.

Confirmation of an Inhibitory Control Deficit in Attention-Deficit/Hyperactivity Disorder

The objective of this study was to determine whether deficient inhibitory control distinguishes children with a diagnosis of attention-deficit/hyperactivity (ADHD) disorder, conduct disorder (CD), and comorbid ADHD + CD from normally developing children. Participants were rigorously diagnosed children (age 7 to 12 years) with ADHD (N = 72), CD (N = 13) or ADHD + CD (N = 47) and 33 control children (NC). We studied inhibitory control using the stop-signal paradigm, a laboratory task that assessed the ability to inhibit an ongoing action. The ADHD group had significantly impaired inhibitory control compared to NC, CD, and ADHD + CD children. These results indicate that children with ADHD have deficient inhibition as measured in the stop-signal paradigm and that ADHD occurring in the presence of ADHD + CD may represent a phenocopy of CD rather than a variant of ADHD.

Differential Effects of Methylphenidate on Working Memory in ADHD Children with and without Comorbid Anxiety

OBJECTIVE To examine the effects of methylphenidate (MPH) on working memory and behavior in anxious and nonanxious children with attention-deficit hyperactivity disorder (ADHD). METHOD A total of 40 ADHD children (22 nonanxious, 18 anxious) completed a randomized, double-blind, placebo-controlled, crossover trial with three doses (0.3, 0.6, 0.9 mg/kg) of MPH. A serial addition task was used to assess working memory; direct observation of motor activity indexed behavior. RESULTS MPH improved working memory in the nonanxious ADHD group but not in the comorbidity anxious group. By contrast, MPH reduced activity level in both groups. The presence of concurrent learning disabilities did not influence stimulant response. CONCLUSIONS The presence of comorbid anxiety in children with ADHD predicts a less robust response to stimulant treatment and suggests that ADHD with anxiety may constitute a distinct and clinically meaningful subtype of ADHD.

The Development of Selective Inhibitory Control Across the Life Span

A modification of the stop-signal task was used to investigate the development of selective inhibitory control. A group of 317 participants, age 6 to 82 years, performed a visual choice reaction time (go) task and attempted to selectively inhibit their response to the go task when hearing one of two randomly presented tones (1000 Hz, 250 Hz), each presented on 20% of trials. Measures of response execution and inhibition were assessed by using reaction times to the go signal (GoRT) and stop signal (SSRT), respectively. Results indicated that SSRT gets faster with increasing age throughout childhood, with pronounced slowing in older adulthood. In addition, strong evidence was obtained for age-related speeding in GoRT throughout childhood, with marked slowing throughout adulthood. Subsequent hierarchical regression analyses illustrated that the age-related changes in selective inhibitory control could not be explained simply by overall slowing or speeding of responses. Findings are discussed in regard to the decay and maturation of selective inhibitory control across the life span.