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Background: Gabapentin is most commonly prescribed for chronic pain, but acute perioperative effects, including preemptive analgesia and hemodynamic stabilization, have been reported. Adrenal chromaffin cells are a widely used model to investigate neurosecretion, and adrenal catecholamines play important physiologic roles and contribute to the acute stress response. However, the effects of gabapentin on adrenal catecholamine release have never been tested.Methods: Primary cultures of bovine adrenal chromaffin cells were treated with gabapentin or vehicle for 18-24 h. The authors quantified catecholamine secretion from dishes of cells using high-performance liquid chromatography and resolved exocytosis of individual secretory vesicles from single cells using carbon fiber amperometry. Voltage-gated calcium channel currents were recorded using patch clamp electrophysiology and intracellular [Ca2+] using fluorescent imaging.Results: Gabapentin produced statistically significant reductions in catecholamine secretion evoked by cholinergic agonists (24 ± 3%, n = 12) or KCl (16 ± 4%, n = 8) (mean ± SEM) but did not inhibit Ca2+ entry or calcium channel currents. Amperometry (n = 51 cells) revealed that gabapentin inhibited the number of vesicles released upon stimulation, with no change in quantal size or kinetics of these unitary events.Conclusions: The authors show Ca2+ entry was not inhibited by gabapentin but was less effective at triggering vesicle fusion. The work also demonstrates that chromaffin cells are a useful model for additional investigation of the cellular mechanism(s) by which gabapentin controls neurosecretion. In addition, it identifies altered adrenal catecholamine release as a potential contributor to some of the beneficial perioperative effects of gabapentin. [ABSTRACT FROM AUTHOR]

BACKGROUND: Genetic influences have been shown to play a major role in determining the risk of attention-deficit hyperactivity disorder (ADHD). In addition, prenatal exposure to nicotine and/or alcohol has also been suggested to increase risk of the disorder. Little attention, however, has been directed to investigating the roles of genetic transmission and prenatal exposure simultaneously. METHOD: Diagnostic telephone interview data from parents of Missouri adolescent female twin pairs born during 1975-1985 were analyzed. Logistic regression models were fitted to interview data from a total of 1936 twin pairs (1091 MZ and 845 DZ pairs) to determine the relative contributions of parental smoking and drinking behavior (both during and outside of pregnancy) as risk factors for DSM-IV ADHD. Structural equation models were fitted to determine the extent of residual genetic and environmental influences on ADHD risk while controlling for effects of prenatal and parental predictors on risk. RESULTS: ADHD was more likely to be diagnosed in girls whose mothers or fathers were alcohol dependent, whose mothers reported heavy alcohol use during pregnancy, and in those with low birth weight. Controlling for other risk factors, risk was not significantly increased in those whose mothers smoked during pregnancy. After allowing for effects of prenatal and childhood predictors, 86% of the residual variance in ADHD risk was attributable to genetic effects and 14% to non-shared environmental influences. CONCLUSIONS: Prenatal and parental risk factors may not be important mediators of influences on risk with much of the association between these variables and ADHD appearing to be indirect. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that among affected sib pairs with autism there is an increase in the frequency of twins over what would be expected in comparison to the prevalence of twins in the general population. In this study we sought to determine whethersub-thresholdautistic traits were more pronounced in twins than in non-twins. The Social Responsiveness Scale (SRS) was administered in an epidemiologic twin sample (n=802) and in a separate population-based sample of non-twins ascertained from a local school district (n=255). For males (but not females), the mean SRS score was significantly higher among twins than among non-twins. As has been suggested for autism, twin status may incur increased liability to sub-threshold autistic symptomatology, particularly in males. [ABSTRACT FROM AUTHOR]

Studies of the broader autism phenotype, and of subtle changes in autism symptoms over time, have been compromised by a lack of established quantitative assessment tools. The Social Responsiveness Scale (SRS-formerly known as the Social Reciprocity Scale) is a new instrument that can be completed by parents and/or teachers in 15-20 minutes. We compared the SRS with the Autism Diagnostic Interview-Revised (ADI-R) in 61 child psychiatric patients. Correlations between SRS scores and ADI-R algorithm scores for DSM-IV criterion sets were on the order of 0.7. SRS scores were unrelated to I.Q. and exhibited inter-rater reliability on the order of 0.8. The SRS is a valid quantitative measure of autistic traits, feasible for use in clinical settings and for large-scale research studies of autism spectrum conditions. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relation between parent reports of motor problems and clinically significant autistic symptoms in children with and without attention-deficit/hyperactivity disorder (ADHD).Method: Subjects were male (n = 521) and female (n = 330) twins from an epidemiological study of ADHD, ages 7 to 19 years at assessment using the Child Behavior Checklist and semistructured psychiatric diagnostic interviews. Parent-rated Social Responsiveness Scale questionnaires were returned for 62% of 1,647 individuals who participated in interviews. After exclusion of subjects with incomplete data or evidence of mental retardation, 851 subjects (52%) were available for the present study analysis. Each subject was classified by DSM-IV ADHD subtype and assigned to one of seven population-defined ADHD subtypes based on latent class analysis of DSM-IV ADHD symptoms. Within each ADHD subtype, we examined the relation between Child Behavior Checklist motor problem endorsement and elevated autistic symptoms on the Social Responsiveness Scale.Results: Motor problems and high levels of autistic traits were most common in individuals with combined-type ADHD. Within each of the clinically relevant DSM-IV and latent class ADHD subtypes, individuals with the combination of motor problems and ADHD were more likely to have high levels of autistic traits than those with ADHD alone.Conclusions: Children with the combination of ADHD and parent-reported motor coordination deficits have elevated levels of autistic symptoms. Targeted treatment and prevention interventions may be warranted. The exclusion criteria for DSM-IV ADHD should be revised to reflect these population-based findings. [ABSTRACT FROM AUTHOR]

Objective: Evidence is steadily accumulating that a preventable environmental hazard, child maltreatment, exerts causal influences on the development of long-standing patterns of antisocial behavior in humans. The relationship between child maltreatment and antisocial outcome, however, has never previously been tested in a large-scale study in which official reports (rather than family member reports) of child abuse and neglect were incorporated, and genetic influences comprehensively controlled for.Method: We cross-referenced official report data on child maltreatment from the Missouri Division of Social Services (DSS) with behavioral data from 4,432 epidemiologically ascertained Missouri twins from the Missouri Twin Registry (MOTWIN). We performed a similar procedure for a clinically ascertained sample of singleton children ascertained from families affected by alcohol dependence participating in the Collaborative Study on the Genetics of Alcoholism (COGA; n = 428) to determine whether associations observed in the general population held true in an "enriched" sample at combined inherited and environmental risk for antisocial development.Results: For both the twin and clinical samples, the additive effects (not interactive effects) of maltreatment and inherited liability on antisocial development were confirmed and were highly statistically significant.Conclusions: Child maltreatment exhibited causal influence on antisocial outcome when controlling for inherited liability in both the general population and in a clinically ascertained sample. Official report maltreatment data represents a critical resource for resolving competing hypotheses on genetic and environmental causation of child psychopathology, and for assessing intervention outcomes in efforts to prevent antisocial development. [ABSTRACT FROM AUTHOR]

Objective: Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of DSM-IV-TR ADHD.Method: Families were ascertained at Massachusetts General Hospital (MGH; N = 309 trios), Washington University at St. Louis (WASH-U; N = 272 trios), and University of California at Los Angeles (UCLA; N = 156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families.Results: Our smallest p value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08), but one of the 20 most significant associations was located in a candidate gene of interest for ADHD (SLC9A9, rs9810857, p = 6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9.Conclusions: We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders. [ABSTRACT FROM AUTHOR]

Objective: To examine gender and age differences in attention-deficit/hyperactivity disorder (ADHD) symptom endorsement in a large community-based sample.Method: Families with four or more full siblings ascertained from Missouri birth records completed telephone interviews regarding lifetime DSM-IV ADHD symptoms and the Strengths and Weaknesses of ADHD-Symptoms and Normal-behavior (SWAN) questionnaire for current ADHD symptoms. Complete data were available for 9,380 subjects aged 7 through 29 years. Lifetime and current DSM-IV-like ADHD diagnoses were assigned by the DSM-IV symptom criteria. Linear regression was used to examine sex and age effects on SWAN ADHD symptom scores. Logistic regression was used to examine sex and age effects on specific ADHD diagnoses. Fractional polynomial graphs were used to examine ADHD symptom count variations across age.Results: Overall prevalence of current DSM-IV-like ADHD was 9.2% with a male:female ratio of 2.28:1. The prevalence of DSM-IV-like ADHD was highest in children. Gender differences in DSM-IV-like ADHD subtype prevalences were highest in adolescents. On average, individuals with lifetime DSM-IV-like ADHD diagnoses had elevated current ADHD symptoms even as adolescents or adults.Conclusions: Lower male:female ratios than reported in some clinic-based studies suggest that females are underdiagnosed in the community. Although they may no longer meet the full symptom criteria, young adults with a history of lifetime DSM-IV-like ADHD maintain higher levels of ADHD symptoms compared with the general population. The use of age-specific diagnostic criteria should be considered for DSM-V and ICD-11. [ABSTRACT FROM AUTHOR]

It has been demonstrated that shape differences in cortical structures may be manifested in neuropsychiatric disorders. Such morphometric differences can be measured by labeled cortical distance mapping (LCDM) which characterizes the morphometry of the laminar cortical mantle of cortical structures. LCDM data consist of signed/labeled distances of gray matter (GM) voxels with respect to GM/white matter (WM) surface. Volumes and other summary measures for each subject and the pooled distances can help determine the morphometric differences between diagnostic groups, however they do not reveal all the morphometric information contained in LCDM distances. To extract more information from LCDM data, censoring of the pooled distances is introduced for each diagnostic group where the range of LCDM distances is partitioned at a fixed increment size; and at each censoring step, the distances not exceeding the censoring distance are kept. Censored LCDM distances inherit the advantages of the pooled distances but also provide information about the location of morphometric differences which cannot be obtained from the pooled distances. However, at each step, the censored distances aggregate, which might confound the results. The influence of data aggregation is investigated with an extensive Monte Carlo simulation analysis and it is demonstrated that this influence is negligible. As an illustrative example, GM of ventral medial prefrontal cortices (VMPFCs) of subjects with major depressive disorder (MDD), subjects at high risk (HR) of MDD, and healthy control (Ctrl) subjects are used. A significant reduction in laminar thickness of the VMPFC in MDD and HR subjects is observed compared to Ctrl subjects. Moreover, the GM LCDM distances (i.e., locations with respect to the GM/WM surface) for which these differences start to occur are determined. The methodology is also applicable to LCDM-based morphometric measures of other cortical structures affected by disease.

Objective: Intrathecal (IT) drug delivery systems for patients with chronic non-malignant pain are intended to improve pain and quality of life and reduce side effects of systemic use. A subset of patients may have escalating pain, functional decline, and/or intolerable side effects even as IT opioid doses are increased. Discontinuation of IT medications may represent a viable treatment option but strategies to accomplish this are needed., Subjects and Interventions: Three patients with intrathecal drug delivery systems (IDDS), inadequate pain control, and declining functionality underwent abrupt IT opioid cessation. This was accomplished through a standardized protocol with symptom-triggered administration of clonidine and buprenorphine, monitored using the clinical opiate withdrawal scale., Results: Symptoms of IT withdrawal were similar in all patients and included diuresis, agitation, hyperalgesia, mild diarrhea, yawning, and taste and smell aversion. Hypertension and tachycardia were effectively controlled by clonidine administration. Classic symptoms of withdrawal, such as piloerection, chills, severe diarrhea, nausea, vomiting, diaphoresis, myoclonus, and mydriasis, were not noted. At 2 to 3 months follow-up, patients reported decreased, but ongoing pain, with improvements in functional capacity and quality of life., Conclusions: This preliminary work demonstrates the safety of abrupt IT opioid cessation utilizing standardized inpatient withdrawal protocols. To our knowledge, these are among the first reported cases of intentional, controlled IT opioid cessation without initiation of an opioid bridge: self-reported pain scores, functional capacity, and quality of life improved. The IT opioid withdrawal syndrome is characterized based upon our observations and a review of the literature., (© 2012 The Authors. Pain Practice © 2012 World Institute of Pain.)

A 52-year-old female presented with idiopathic stocking-glove neuropathy. She underwent a series of right and left stellate ganglion blocks with ropivacaine and clonidine, followed by lumbar sympathetic blocks. This resulted in complete symptom relief for two weeks. These procedures were repeated after a two-month interval; at that time she was still experiencing partial relief from the first series. She again remained completely pain free for several weeks following the injections. As the pain partially returned, daily oral clonidine was initiated and resulted in almost complete cessation of her symptoms, which persisted at a three-month follow-up examination.

Three experiments explored attention to eye gaze, which is incompletely understood in typical development and is hypothesized to be disrupted in autism. Experiment 1 (n = 26 typical adults) involved covert orienting to box, arrow, and gaze cues at two probabilities and cue-target times to test whether reorienting for gaze is endogenous, exogenous, or unique; experiment 2 (total n = 80: male and female children and adults) studied age and sex effects on gaze cueing. Gaze cueing appears endogenous and may strengthen in typical development. Experiment 3 tested exogenous, endogenous, and gaze-based orienting in 25 typical and 27 Autistic Spectrum Disorder (ASD) children. ASD children made more saccades, slowing their reaction times; however, exogenous and endogenous orienting, including gaze cueing, appear intact in ASD.

Neuropsychiatric disorders have been demonstrated to manifest shape differences in cortical structures. Labeled Cortical Distance Mapping (LCDM) is a powerful tool in quantifying such morphometric differences and characterizes the morphometry of the laminar cortical mantle of cortical structures. Specifically, LCDM data are distances of labeled gray matter (GM) voxels with respect to the gray/white matter cortical surface. Volumes and descriptive measures (such as means and variances for each subject) based on LCDM distances provide descriptive summary information on some of the shape characteristics. However, additional morphometrics are contained in the data and their analysis may provide additional clues to underlying differences in cortical characteristics. To use more of this information, we pool (merge) LCDM distances from subjects in the same group. These pooled distances can help detect morphometric differences between groups, but do not provide information about the locations of such differences in the tissue in question. In this article, we check for the influence of the assumption violations on the analysis of pooled LCDM distances. We demonstrate that the classical parametric tests are robust to the non-normality and within sample dependence of LCDM distances and nonparametric tests are robust to within sample dependence of LCDM distances. We specify the types of alternatives for which the tests are more sensitive. We also show that the pooled LCDM distances provide powerful results for group differences in distribution of LCDM distances. As an illustrative example, we use GM in the ventral medial prefrontal cortex (VMPFC) in subjects with major depressive disorder (MDD), subjects at high risk (HR) of MDD, and healthy subjects. Significant morphometric differences were found in VMPFC due to MDD or being at HR. In particular, the analysis indicated that distances in left and right VMPFCs tend to decrease due to MDD or being at HR, possibly as a result of thinning. The methodology can also be applied to other cortical structures.

Background: Variations in the alleles for the alcohol-metabolizing enzymes have been shown to influence risk for alcohol dependence. One variant, ADH1B*3, is observed almost exclusively in populations of African ancestry and has been shown to be associated with reduced rates of alcohol dependence. We conducted an alcohol challenge study to test whether ADH1B*3 is associated with differences in subjective and physiological response to alcohol., Method: We administered a moderate dose of alcohol (0.72 g/kg for males, 0.65 g/kg for females) to a sample of African-American young adults (n = 91; ages 21 to 26). Participants were genotyped for ADH1B, as well as additional polymorphisms that might contribute to alcohol response. Breath alcohol concentration, self-reported sedation and stimulation, and pulse rate were assessed prior to alcohol administration and for 2.5 hours following administration., Results: ADH1B*3 was associated with higher levels of sedation and a sharper increase in pulse rate immediately following alcohol consumption., Conclusions: These findings suggest that the lower rates of alcohol dependence in those with ADH1B*3 alleles may be because of differences in alcohol response, particularly increased sedation.

Background: We have previously identified suggestive linkage for alcohol consumption in a community-based sample of Australian adults. In this companion paper, we explore the strength of genetic linkage signals for alcohol dependence symptoms., Methods: An alcohol dependence symptom score, based on DSM-IIIR and DSM-IV criteria, was examined. Twins and their nontwin siblings (1,654 males, 2,518 females), aged 21 to 81 years, were interviewed, with 803 individuals interviewed on 2 occasions, approximately 10 years apart. Linkage analyses were conducted on datasets compiled to maximize data collected at either the younger or the older age. In addition, linkage was compared between full samples and truncated samples that excluded the lightest drinkers (approximately 10% of the sample)., Results: Suggestive peaks on chromosome 5p (LODs >2.2) were found in a region previously identified in alcohol linkage studies using clinical populations. Linkage signal strength was found to vary between full and truncated samples and when samples differed only on the collection age for a sample subset., Conclusions: The results support the finding that large community samples can be informative in the study of alcohol-related traits.

Recent research has suggested that autistic social impairment (ASI) is continuously distributed in nature and that subtle autistic-like social impairments aggregate in the family members of children with pervasive developmental disorders (PDDs). This study examined the longitudinal course of quantitatively characterized ASI in 3- to 18-year-old boys with and without PDD. We obtained assessments of 95 epidemiologically ascertained male-male twin pairs and a clinical sample of 95 affected children using the Social Responsiveness Scale (SRS), at two time points, spaced 1-5 years apart. Longitudinal course was examined as a function of age, familial loading for PDD, and autistic severity at baseline. Interindividual variation in SRS scores was highly preserved over time, with test-retest correlation of 0.90 for the entire sample. SRS scores exhibited modest general improvement over the study period; individual trajectories varied as a function of severity at baseline and were highly familial. Quantitative measurements of ASI reflect heritable traitlike characteristics. Such measurements can serve as reliable indices of phenotypic severity for genetic and neurobiologic studies, and have potential utility for ascertaining incremental response to intervention.

Attention deficit hyperactivity disorder (ADHD) is to a large extent influenced by genetic factors, but environmental influences are considered important as well. To distinguish between functional brain changes underlying primarily genetically and environmentally mediated ADHD, we used functional magnetic resonance imaging (fMRI) to compare response interference in monozygotic twins highly concordant or discordant for attention problems (AP). AP scores were assessed longitudinally with the Child Behavior Check List attention problem scale (CBCL-AP). Response interference was measured during two executive function paradigms; a color-word Stroop and a flanker task. The neuroimaging results indicated that, across the entire sample, children with high CBCL-AP scores, relative to children with low CBCL-AP scores, showed decreased activation to response interference in dorsolateral prefrontal, parietal and temporal brain regions. Increased activation was noted in the premotor cortex and regions associated with visual selective attention processing, possibly reflecting compensatory mechanisms to maintain task performance. Specific comparisons of high and low scoring concordant twin pairs suggest that AP of genetic origin was characterized by decreased activation of the left dorsolateral prefrontal cortex during the Stroop task and right parietal lobe during the flanker task. In contrast, comparison of twins from discordant monozygotic pairs, suggests that AP of environmental origin was characterized by decreased activation in left and right temporal lobe areas, but only during Stroop interference. The finding of distinct brain activation changes to response interference in inattention/hyperactivity of "genetic" versus "environmental" origin, indicates that genetic and environmental risk factors for attention/hyperactivity problems affect the brain in different ways.

Background: Previous research has reported a significant genetic correlation between heaviness of alcohol consumption and alcohol dependence (AD), but this association might be driven by the influence of AD on consumption rather than the reverse. We test the genetic overlap between AD symptoms and a heaviness of consumption measure among individuals who do not have AD. A high genetic correlation between these measures would suggest that a continuous measure of consumption may have a useful role in the discovery of genes contributing to dependence risk., Methods: Factor analysis of five alcohol use measures was used to create a measure of heaviness of alcohol consumption. Quantitative genetic analyses of interview data from the 1989 Australian Twin Panel (n = 6257 individuals; M = 29.9 years) assessed the genetic overlap between heaviness of consumption, DSM-IV AD symptoms, DSM-IV AD symptom clustering, and DSM-IV alcohol abuse., Results: Genetic influences accounted for 30%-51% of the variance in the alcohol measures and genetic correlations were .90 or higher for all measures, with the correlation between consumption and dependence symptoms among nondependent individuals estimated at .97 (95% confidence interval: .80-1.00)., Conclusions: Heaviness of consumption and AD symptoms have a high degree of genetic overlap even among nondependent individuals in the general population, implying that genetic influences on dependence risk in the general population are acting to a considerable degree through heaviness of use and that quantitative measures of consumption will likely have a useful role in the identification of genes contributing to AD.

Nicotine withdrawal (NW) is both an important contributor to difficulty quitting cigarettes and because of mood-related withdrawal symptoms a problem of particular relevance to psychiatry. Twin-studies suggest that genetic factors influence NW (heritability = 45%). Only one previous linkage study has published findings on NW [Swan et al. (2006); Am J Med Genet Part B 141B:354-360; LOD = 2.7; Chr. 6 at 159 cM]. As part of an international consortium, genome-wide scans (using over 360 autosomal microsatellite markers) and telephone diagnostic interviews were conducted on 289 Australian (AUS) and 161 Finnish (FIN, combined (COMB) N = 450 families) families ascertained from twin registries through index-cases with a lifetime history of cigarette smoking. The statistical approach used an affected-sib-pair design (at least two adult full siblings reported a history of DSM-IV NW) and conducted the linkage analyses using MERLIN. Linkage signals with LOD scores >1.5 were found on two chromosomes: 6 (FIN: LOD = 1.93 at 75 cM) and 11 at two different locations (FIN: LOD = 3.55 at 17 cM, and AUS: LOD = 1.68 with a COMB: LOD = 2.30 at 123 cM). The multipoint LOD score of 3.55 on chromosome 11p15 in FIN met genomewide significance (P = 0.013 with 1,000 simulations). At least four strong candidate genes lie within or near this peak on chromosome 11: DRD4, TPH, TH, and CHRNA10. Other studies have reported that chromosome 11 may harbor genes associated with various aspects of smoking behavior. This study adds to that literature by highlighting evidence for NW., ((c) 2009 Wiley-Liss, Inc.)

Recent research has suggested that the mode of inheritance for simplex autism (SA, one individual in the family affected) may be distinct from that for multiplex autism (MA, two or more individuals affected). Since sub clinical autistic traits have been observed in "unaffected" relatives of children with autism, we explored whether the distributions of such traits in families supported differential modes of genetic transmission for SA and MA autism. We measured patterns of familial aggregation of quantitative autistic traits (QAT) in children and parents in 80 SA families and 210 MA families, using the Social Responsiveness Scale. When considering all SA and MA siblings who scored below a uniform quantitative (clinical-level) severity threshold, MA brothers exhibited a distinct pathological shift in the distribution, compared to SA brothers (P < 0.0001). Such aggregation of QAT was also observed in fathers but not among females in MA families. Significant spousal correlations for QAT-suggestive of assortative mating-were observed in both SA and MA families, but neither group was characterized by a greater-than-chance level of concordant elevation among spousal pairs in this volunteer sample. Among male first degree relatives, there exist distinct patterns of QAT manifestation for simplex versus multiplex autism. These findings are consistent with the results of molecular genetic studies that have suggested differential modes of intergenerational transmission for SA and MA. Characterization of QAT and other endophenotypes among close relatives may be useful for reducing sample heterogeneity in future genetic and neurobiologic studies of autism., ((c) 2008 Wiley-Liss, Inc.)

Objective: New attention-deficit/hyperactivity disorder (ADHD) subtypes identified through latent class analysis have been recently proposed. Here, we assess the accuracy of simple rules based on symptom counts for the assignment of youths to clinically relevant population-derived ADHD subtypes: severe inattentive (SI) and severe combined (SC)., Method: Data from 9,675 twins and siblings from Missouri and Australia aged 7 to 19 years were analyzed using continuous and categorical models of ADHD symptoms using principal components analysis and subtyping by DSM-IV and by latent class criteria. Cut points were derived for classifying SI and SC subtypes by positive predictive value, negative predictive value, percent positive agreement, and Matthew coefficient of agreement., Results: Principal components analysis suggested two underlying factors: total number of symptoms and symptom type, with SI and SC latent class subtypes clearly mapping to distinct areas on a plot of these factors. Having six or more total symptoms and fewer than three hyperactive-impulsive symptoms accurately predicts the latent class SI subtype. The latent class SC subtype was best identified by 11 or more total symptoms and 4 or more hyperactive-impulsive. The DSM-IV ADHD subtype criteria accurately identified the SC subtype but only poorly for the SI subtype., Conclusions: Symptom counts criteria allow the simple and accurate identification of subjects with severe ADHD subtypes defined by latent class analysis. Such simple symptom counts corresponding to screening cut points selected latent class-derived SI subtype subjects with greater precision than DSM-IV criteria.

Background: Previous studies have identified evidence of genetic influence on alcohol use in samples selected to be informative for alcoholism research. However, there are a growing number of genome-wide association studies (GWAS) using samples unselected for alcohol consumption (i.e., selected on other traits and forms of psychopathology), which nevertheless assess consumption as a risk factor. Is it reasonable to expect that genes contributing to variation in alcohol consumption can be identified in such samples?, Methods: An exploratory approach was taken to determine whether linkage analyses for heaviness of alcohol consumption, using a sample collected for heterogeneous purposes, could replicate previous findings. Quantity and frequency measures of consumption were collected in telephone interviews from community samples. These measures, and genotyping, were available for 5,441 individuals (5,067 quasi-independent sibling pairs). For 1,533 of these individuals, data were collected on 2 occasions, about 8.2 years apart, providing 2 datasets that maximize data collected at either a younger or an older age. Analyses were conducted to address the question of whether age and heavier levels of alcohol consumption effects outcome. Linkage results were compared in the younger and older full samples, and with samples in which approximately 10, 20, and 40 of drinkers from the lower end of the distribution of alcohol consumption were dropped., Results: Linkage peaks varied for the age differentiated samples and for percentage of light drinkers retained. Larger peaks (LOD scores >2.0) were typically found in regions previously identified in linkage studies and/or containing proposed candidate genes for alcoholism including AGT, CARTPT, OPRD1, PIK3R1, and PDYN., Conclusions: The results suggest that GWAS assessing alcohol consumption as a covariate for other conditions will have some success in identifying genes contributing to consumption-related variation. However, sample characteristics, such as participant age, and trait distribution, may have substantial effects on the strength of the genetic signal. These results can inform forthcoming GWAS where the same restrictions apply.

Objective: The purpose of this study was to develop a quantitative measure of alcohol consumption for gene-mapping studies., Method: Using a sample of 3,787 young-adult twin women and an independent sample of 489 men and women from a college drinking study, we developed an alcohol-consumption factor score indexed by (1) maximum typical consumption (log-transformed quantity frequency [LQNTFRQ]), (2) maximum drinks in a 24-hours period (LMAXALC), (3) frequency of drinking five or more drinks per day (FIVE), and (4) frequency of drinking to intoxication (INTOX). We tested (1) for factorial and psychometric equivalence across samples and genders; (2) for construct validity and its equivalence, across samples and genders, using measures of tobacco and cannabis use and family history of alcoholism; and (3) to determine the heritability of the alcohol-consumption factor score using a genetic psychometric model., Results: A single-factor model fit well with factor loadings ranging from .60 to .90. With rare exception, we found support for measurement invariance across the two samples and across genders. Measures of nicotine and cannabis use as well as family history of alcoholism were associated, to a similar extent across samples and genders, with the underlying alcohol-consumption factor. Psychometric twin modeling revealed that each of the alcohol-consumption measures (h2=34%-47%) and the underlying factor score (h2=50%) were heritable, with the remainder of the variance attributable to individual-specific environmental factors. This moderately heritable alcohol-consumption factor also accounted for a majority of the genetic variance in LQNTFRQ, LMAXALC, FIVE, and INTOX., Conclusions: Quantitative measures of alcohol consumption with the favorable attributes of measurement invariance, construct validity, and moderate heritability can greatly enhance future gene-mapping efforts, supplementing information afforded by conventional diagnostic measures of alcohol abuse/dependence.

Cannabis is the most commonly used illicit drug in developed and in developing nations. Twin studies have highlighted the role of genetic influences on early stages of cannabis use, such as a lifetime history of use, early-onset use and frequent use, however, we are not aware of any genomic studies that have examined these phenotypes. Using data on 2314 families consisting of 5600 adult Australian offspring and their parents, all of whom were scanned using 1399 unique autosomal markers, we conducted autosomal linkage analyses for lifetime history of cannabis initiation, early-onset cannabis use and frequency of use, using a variance components approach in the linkage package MERLIN. Suggestive evidence for linkage was found on chromosome 18 (LOD 2.14 for frequency of use, LOD 1.97 for initiation, at 90-97 cM) and also on chromosome 19 (LOD 1.92 for early-onset at 17 cM). These LOD scores did not meet genome-wide significance. Further replication of these linkage regions in other samples will be required, although these initial results suggest further targeted efforts on chromosome 18 may yield interesting candidate genes for early stages of cannabis-related behaviors.

Recent clinic-based and population-based studies have shown evidence of association between ADHD and autistic symptoms in children and adolescents as well as evidence for genetic overlap between these disorders. The objective of the current study was to confirm the association between autistic and ADHD symptoms in a young adult twin sample assessed by self-report, and investigate whether shared genetic and/or environmental factors can explain the association. We performed twin-based structural equation modeling using self-report data from 11 Social Responsiveness Scale (SRS) items and 12 DSM-IV ADHD inattentive and impulsive symptom items obtained from 674 young adult Australian twins. Phenotypic correlation between autistic and ADHD symptoms was moderate. The most parsimonious univariate models for SRS and ADHD included additive genetic effects and unique environmental effects, without sex differences. ADHD and autistic traits were both moderately heritable. In a bivariate model, genetic correlation (r(g)) between SRS and ADHD was 0.72. Our results suggest that in young adults, a substantial proportion of the genetic influences on self-reported autistic and ADHD symptoms may be shared between the two disorders.

Purpose: This study explores the relationship among preschool attention deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), injury-risk-taking behavior, and unintentional injury., Method: An emergency department (ED) casecontrol study of parent-reported child behavior was conducted., Findings: Children with ODD and ADHD had significantly more injury-risk-taking behaviors (odds ratio [OR] = 7.68, 95% confidence interval [CI] 2.25-26.25; OR = 4.87, 95% CI 1.17--20.28, respectively), and injured children had a 17-fold increase in high-risk-taking behaviors (OR 17.2, 95% CI 2.14--138.0). No significant association existed between ODD or ADHD and ED-treated unintentional injury., Implications: Disruptive behavior disorders are not major contributors to ED-treated unintentional injury in preschool children.

Background: To test whether the retrospective reporting of the age of onset impairment criterion for attention deficit/hyperactivity disorder (ADHD) required in the Diagnostic and Statistical Manual of Mental Disorders - IV (DSM-IV) complicates identification of new and known child and adolescent cases later in life., Methods: A birth-records-based cohort of twins assessed at ages 7 to 19 years were blindly reassessed five years later using the MAGIC interview. Study outcome measures were differences in reported ages of onset for attention deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), conduct disorder (CD) and major depressive disorder (MDD)., Results: For all age groups and respondents (parent on youth or youth self-report), later ages of ADHD onset were reported five years later. The same phenomenon was also present for the other diagnostic groups. Of the initial ADHD individuals who continued to meet all other ADHD criteria at follow-up, 46% failed the age of onset criterion five years later. When ignoring the age of onset criterion, late onsets of ages 7-16 years accounted for about 10% of all ADHD., Conclusions: Use of the DSM-IV age of onset criterion for attention deficit/hyperactivity disorder in the assessment of adolescents and young adults results in under-identification of affected individuals. Consideration should be given to revising the current nomenclatures to reflect the reality of retrospective reporting errors in age of onset as well as the presence of late onset cases.

Aims: To develop a panel of markers able to extract full haplotype information for candidate genes in alcoholism, other addictions and disorders of mood and anxiety., Methods: A total of 130 genes were haplotype tagged and genotyped in 7 case/control populations and 51 reference populations using Illumina GoldenGate SNP genotyping technology, determining haplotype coverage. We also constructed and determined the efficacy of a panel of 186 ancestry informative markers., Results: An average of 1465 loci were genotyped at an average completion rate of 91.3%, with an average call rate of 98.3% and replication rate of 99.7%. Completion and call rates were lowered by the performance of two datasets, highlighting the importance of the DNA quality in high throughput assays. A comparison of haplotypes captured by the Addictions Array tagging SNPs and commercially available whole-genome arrays from Illumina and Affymetrix shows comparable performance of the tag SNPs to the best whole-genome array in all populations for which data are available., Conclusions: Arrays of haplotype-tagged candidate genes, such as this addictions-focused array, represent a cost-effective approach to generate high-quality SNP genotyping data useful for the haplotype-based analysis of panels of genes such as these 130 genes of interest to alcohol and addictions researchers. The inclusion of the 186 ancestry informative markers allows for the detection and correction for admixture and further enhances the utility of the array.

Gene polymorphisms of the 3' untranslated region (3'-UTR) of the dopamine transporter (DAT1), Dopamine receptor exon 3 D4 variable number tandem repeat (DRD4VNTR), nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) and serotonin transporter promoter (SLC6A4-5HTTLPR) are under consideration as potential risk factors for attention-deficit/hyperactivity disorder (ADHD). A post-hoc attempt was made to investigate the association between the allelic variations of these candidate genes and retrospective parental report of response to methylphenidate in an ADHD-enriched, population-based twin sample. Subjects (N = 243) were selected from the twin sample based on parent report that the child had been treated with methylphenidate for ADHD symptoms. The functional polymorphisms screened were the VNTR located in the 3'-UTR of the dopamine transporter, DRD4 VNTR, CHRNA4 (rs1044396 and rs6090384) and the long (L(A) and L(G)) and short (S) forms of the serotonin transporter promoter region. Logistic regression did not demonstrate a significant association between methylphenidate treatment response and the relevant polymorphisms. The sample size had high power to detect effect sizes similar to those reported in some prior methylphenidate pharmacogenetic studies; however, the categorical (yes/no) measure of parent-reported treatment response may not have been sensitive enough to pick up statistically significant differences in treatment response based on genotype. Further studies including quantitative measures of treatment response are warranted., ((c) 2007 Wiley-Liss, Inc.)

Alcohol dependence symptoms and consumption measures were examined for stability and heritability. Data were collected from 12,045 individuals (5376 twin pairs, 1293 single twins) aged 19 to 90 years in telephone interviews conducted in three collection phases. Phases 1 and 2 were independent samples, but Phase 3 targeted families of smokers and drinkers from the Phase 1 and 2 samples. The stability of dependence symptoms and consumption was examined for 1158 individuals interviewed in both Phases 1 and 3 (mean interval = 11.0 years). For 1818 individuals interviewed in Phases 2 and 3 (mean interval = 5.5 years) the stability of consumption was examined. Heritability was examined for each collection phase and retest samples from the selected Phase 3 collection. The measures examined were a dependence score, based on DSM-IIIR and DSM-IV criteria for substance dependence, and a quantity x frequency measure. Measures were moderately stable, with test-retest correlations ranging from .58 to .61 for dependence and from .55 to .64 for consumption. However, the pattern of changes over time for dependence suggested that the measure may more strongly reflect recent than lifetime experience. Similar to previous findings, heritabilities ranged from .42 to .51 for dependence and from .31 to .51 for consumption. Consumption was significantly less heritable in the younger Phase 2 cohort (23-39 years) compared to the older Phase 1 cohort (28-90 years).

Context: Despite accumulating evidence that there is a genetic basis for cannabis use disorders (ie, abuse and dependence), few studies have identified genomic regions that may harbor biological risk and protective factors., Objective: To conduct autosomal linkage analyses that identify genomic regions that may harbor genes conferring a vulnerability to cannabis use disorders., Design: In 289 Australian families who participated in the Nicotine Addiction Genetics Project, 423 autosomal markers were genotyped. Families were ascertained for heavy cigarette smoking. Linkage was conducted for DSM-IV cannabis dependence and for a novel factor score representing problems with cannabis use, including occurrence of 3 of 4 abuse criteria (excluding legal problems) and 6 DSM-IV dependence criteria., Results: A maximum logarithm of odds (LOD) of 3.36 was noted for the cannabis problems factor score on chromosome arm 1p. An LOD of 2.2 was noted on chromosome 4 in the region of the gamma-aminobutyric acid type A gene cluster, including GABRA2, which has been implicated in drug use disorders. For DSM-IV cannabis dependence, a modest LOD score on chromosome 6 (1.42) near cannabinoid receptor 1 (CNR1) was identified. In addition, support for an elevation on chromosome 3, identified in prior independent studies, was noted for the factor score and cannabis dependence (LOD, 1.4)., Conclusions: Genes such as ELTD1 on chromosome 1, in addition to genes on chromosomes 4 (eg, GABRA2) and 6 (eg, CNR1), may be associated with the genetic risk for cannabis use disorders. We introduce a novel quantitative phenotype, a cannabis problems factor score composed of DSM-IV abuse and dependence criteria, that may be useful for future linkage and association studies.

The Diagnostic and Statistical Manual of Mental Disorders (4th Edition) prohibits the co-diagnosis of attention-deficit/hyperactivity disorder (ADHD) and an autism spectrum disorder (ASD). However, recent studies indicate that co-occurrence of clinically significant ADHD and autistic symptoms is common, and that some genes may influence both disorders. Children with the combination of ADHD and motor coordination problems are particularly likely to have an ASD. These co-occurrences of symptoms are important since children with ASD in addition to ADHD symptoms may respond poorly to standard ADHD treatments or have increased side effects. Such children may benefit from additional classes of pharmacologic agents (i.e., alpha-agonists, selective serotonin reuptake inhibitors and neuroleptics). They may also benefit from social skills therapy, individual and family psychotherapy, behavioral therapy and other nonpharmacologic interventions.

Objective: To determine the 5-year prospective stability of population-based and DSM-IV subtypes of attention-deficit/hyperactivity disorder (ADHD) as well as to explore predictors of stability., Method: A total of 708 twins ages 7 to 19 years who were identified from birth records of the state of Missouri and had participated in a study of ADHD were reassessed 5 years later in a blinded fashion. Stabilities of DSM-IV and population-based ADHD subtypes were compared using percentage of agreement with significance tested by the kappa statistic. Predictors of stability of subtype diagnosis were determined using multivariate logistic regression., Results: In general, 5-year ADHD subtype stability was poor to modest and ranged from 11.1% to 24.0% for DSM-IV for subtypes and from 14.3% to 35.3% for clinically significant population-derived subtypes. There were no predictors of diagnostic stability that applied across subtypes. There were subtype-specific predictors including a diagnosis of oppositional defiant disorder for DSM-IV primarily inattentive ADHD; lower verbal IQ for DSM-IV combined type ADHD; and younger age, oppositional defiant disorder, and medication use for population-defined severe combined ADHD., Conclusions: Population-defined ADHD subtype criteria demonstrated modestly improved diagnostic stability over 5 years compared to DSM-IV subtypes. Few correlates or predictors of stability were identified.

To determine the mechanism of interaction of prenatal smoking exposure and child genotype in the development of attention deficit/hyperactivity disorder (ADHD), polymorphisms in the CHRNA4 gene were tested for interactions with prenatal smoking exposure on risk for ADHD subtypes using multiple logistic regression. An exon 5 polymorphism demonstrated a significant interaction with history of maternal smoking during pregnancy for increasing risk for severe combined type ADHD (OR = 3.0, 95% CI 1.1-8.4 for population-defined severe combined type, OR = 3.9 95% CI 1.2-13.1 for DSM-IV defined combined subtype ADHD). This interaction increased the effects of previously reported interactions for the DRD4 and DAT1 genes with prenatal smoking exposure. Given the known functions and the known areas of expression of these three genes at the dopaminergic synapse in the pre-frontal cortex, the results are compatible with a synapse-based model of the development of this form of ADHD. The subtype specificity of these findings supports the concept that ADHD is composed of a group of distinct disorders., (2007 Wiley-Liss, Inc.)