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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. (Contains 3 figures and 5 tables.)

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. (Contains 2 figures and 6 tables.)

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.

A study is conducted to examine the concurrence between parent-reported motor problems and clinical autistic symptoms in children with and without attention-deficit/hyperactivity disorder (ADHD). Results suggest that children with ADHD and parent-reported motor problems are likely to have more severe autistic symptoms than those with ADHD alone.

A 5-year prospective study attempts to determine the predictors of stability of attention-deficit/hyperactivity disorder (ADHD) subtypes from childhood to young adulthood. The results conclude that population-defined ADHD subtype criteria indicate improved diagnostic stability over 5 years.

Background: Most diagnostic nomenclatures do not allow for the concurrent diagnosis of autism and attention-deficit/hyperactivity disorder (ADHD). Clinic-based studies suggest autistic symptoms are common in children with ADHD, but such studies are prone to referral bias. This study assesses whether children with ADHD selected from the general twin population have elevated levels of autistic traits. Methods: Nine hundred forty-six twins identified by Missouri birth records were assigned to DSM-IV ADHD diagnoses and seven population-derived ADHD subtypes defined through latent class analysis of DSM-IV ADHD symptoms. The Social Responsiveness Scale (SRS) was used as a quantitative measure of autistic traits. Linear regression was used to evaluate whether mean SRS scores differed between ADHD diagnostic groups. Results: Mean SRS scores for DSM-IV predominantly inattentive subtype and combined subtype ADHD groups were significantly higher than for subjects without DSM-IV ADHD (p less than 0.001, both comparisons). Five of the population-derived ADHD subtypes (talkative-impulsive, mild and severe inattentive, mild and severe combined) had significantly higher mean SRS scores compared to the latent class subtype with few ADHD symptoms (p less than 0.001, all comparisons). DSM-IV combined subtype and the population-derived severe combined subtype had the highest mean total SRS scores and the highest mean scores for each of the three autism symptom domains, with a substantial proportion of individuals scoring in the clinically significant range. Conclusions: This study provides population-based evidence for clinically significant elevations of autistic traits in children meeting diagnostic criteria for ADHD. These results have implications for the design and interpretation of studies of both disorders.

Objective: To determine treatment patterns for youth attention-deficit/hyperactivity disorder (ADHD) symptoms in a general population sample of 1,610 twins. Method: Twin pairs ages 7 to 17 years and parents ascertained from birth records in the state of Missouri were interviewed using the Missouri Assessment of Genetics Interview for Children between 1996 and 2001. Multivariate logistic regression analyses were used to determine which factors were significant in answering three questions about treatment for ADHD. Results: Of 302 boys, 177 (58.6%) and 26 of 57 girls (45.6%) who met full "DSM-IV" criteria for ADHD received stimulant medication in this sample. Of 314 youths, 111 (35.4%) who received stimulant medication did not meet "DSM-IV" criteria for ADHD. When controlling for comorbidity and other factors, the number of impairing ADHD symptoms and having a cotwin who was also brought to treatment for ADHD correlated with referral or treatment in youths without ADHD. Youths without ADHD who were treated had a large number of ADHD symptoms. Conclusion: As is shown in earlier studies, children with ADHD are being undertreated. Complex factors, including comorbid disorders and family history of ADHD treatment, affect treatment patterns in the general population. (Contains 3 tables.)

Background: The purpose of this study was to determine a score on the Obsessive Compulsive Scale (OCS) from the Child Behavior Checklist (CBCL) to screen for obsessive compulsive disorder (OCD) in children and to rigorously test the specificity and sensitivity of a single cutpoint. Methods: A receiver operating characteristic (ROC) curve analysis was applied to data from 61 patients with clinically determined OCD, 64 clinical controls and 73 general population controls to determine the best sum score on the CBCL-OCS to predict confirmed OCD in children. Using the ROC-determined cutoff, this score was applied to a national sample of CBCL data from 2460 singleton children ages 4-18 and to 20,016 children ages 7-18 from three large general population twin samples to determine the estimated prevalence in the general population. Results: Using a CBCL-OCS score of 5 demonstrated an area under the curve (AUC) of 0.88 with high sensitivity (92%) and moderate specificity (67%) compared to clinical controls. Compared to the general population controls, the AUC was 0.96 with high sensitivity (92%) and specificity (89%). In the twin samples, the number of participants with CBCL-OCS scores above this cutpoint was 2.3-7.1%. Conclusions: These findings suggest that the OCS of the CBCL may provide a highly effective way to screen for childhood OCD, and that the prevalence of childhood OCD may have been underestimated, thus prompting the need for further research into screening children for this condition.

Background: It has been proposed that some of the variability in reporting of associations between attention deficit hyperactivity disorder (ADHD) and candidate genes may result from mixing of genetically heterogeneous forms of ADHD using DSM-IV criteria. The goal of the current study is to test whether population-based ADHD subtypes defined by latent class analysis help resolve issues of variable findings across individual gene association studies. Methods: Three studies which had previously reported no associations between polymorphisms of the DRD4 and DAT genes and DSM-IV defined ADHD were reanalyzed using population-based and DSM-IV defined ADHD subtypes. Results: Across studies no significant associations were found for either DRD4 or DAT polymorphisms using DSM-IV ADHD subtypes. In contrast, a significant association was found between the combined data set for the 440 base pair 3' DAT VNTR polymorphism and population-defined severe combined ADHD (OR = 1.25, p = 0.01). A marginally significant association was also found between the 7 repeat DRD4 allele and population-defined severe combined ADHD. Conclusion: Use of alternative population-based defined ADHD subtypes may help resolve some of the variable results presented for candidate gene association studies in ADHD.

Objective: Clinical and population samples demonstrate that attention-deficit/hyperactivity disorder (ADHD) occurs with other disorders. Comorbid disorder clustering within ADHD subtypes is not well studied. Method: Latent class analysis (LCA) examined the co-occurrence of DSM-IV ADHD, oppositional defiant disorder (ODD), conduct disorder (CD), and depression symptoms in a population twin sample. The authors fit separate models for ADHD and comorbid disorder symptoms. Twin concordance ratios (monozygotic versus dizygotic) were compared examining genetic influence on class membership. Results: LCA of ADHD symptoms resulted in seven classes including inattentive, combined, and hyperactive subtypes in 1,616 subjects. The few ADHD symptoms (53.4%) and severe inattentive (12.3%) classes were most frequent. LCA of ODD, CD, and depression symptoms in 1,587 subjects revealed five classes including ODD (19.4%), depression (14.5%), and two composite classes: ODD/CD (6.9%) and ODD/CD/depression (7.2%). Internalizing and externalizing comorbid disorders were present across all ADHD subtypes. Odds ratios (ORs) for twin concordance indicate genetic influence on severe inattentive (OR = 4.18; 95% confidence interval [CI], 1.52-11.53) and combined (OR = 5.25; 95% CI, 1.32-20.78) ADHD classes and ODD (OR = 1.49; 95% CI, 0.70-3.17), ODD/CD (OR = 3.32; 95% CI, 0.57-19.28), and ODD/CD/depression (OR = 1.20; 95% CI, 0.30-4.77) classes. Conclusions: Internalizing and externalizing disorders did not cluster differentially within ADHD subtypes. LCA may provide a more precise characterization of comorbidity with ADHD.

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 whether "sub-threshold" autistic 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.

Objective: To determine the impact of including sluggish cognitive tempo items on the factor and latent class structure of attention-deficit/hyperactivity disorder (ADHD) subtypes in boys and girls. Method: Parent report of two sluggish cognitive tempo items on a population-based sample of 1,430 female twins and 1,414 male twins were analyzed along with parent report of the 18 DSM-IV ADHD items using principal components analysis and latent class analysis. Results: The inclusion of the two sluggish cognitive tempo items resulted in distinct factor structures for boys and girls. For boys there were separate inattentive, hyperactive/impulsive, and sluggish factors. For girls there were separate inattentive/sluggish, hyperactive, and impulsive factors. In contrast, sluggish cognitive tempo items had minimal impact on the latent class structure of ADHD for both boys and girls. Conclusions: The inclusion of sluggish cognitive tempo items markedly changed ADHD symptom associations for boys and girls in a factor analytic framework. In contrast, latent class subtyping of ADHD shows limited impact of the inclusion of sluggish cognitive tempo items, emphasizing the very different assumptions about underlying continua of behavior rather than discrete classes that distinguish the two approaches. J. Am. Acad. Child Adolesc. Psychiatry, 2004;43(5):588-597. Key Words: attention-deficit/hyperactivity disorder, latent class analysis, factor analysis, sluggish cognitive tempo.

Background: Findings from family and twin-based studies of Attention Deficit/Hyperactivity Disorder (ADHD) have indicated that inattentive and combined subtypes cluster together among sibling pairs who both express ADHD symptoms. The current report examines the familial clustering of ADHD subtypes, defined according to latent class and DSM-IV criteria, in a general population sample of 2,848 Australian twins, 1,013 of their non-twin siblings and 4,036 female twins from Missouri, USA. Significant clustering of DSM-IV inattentive and combined subtypes, and significant clustering of the same latent classes among siblings was predicted. Method: Logistic regression was used to assess 1) the clustering of same and different subtype combinations among twin and twin-sibling pairs and 2) whether genetic influences contribute significantly to the observed patterns of subtype combinations among siblings. Results: With the exception of the DSM-IV hyperactive-impulsive subtype and the severe hyperactive-impulsive latent class, all other sibling DSM-IV and latent class ADHD subtypes consistently exhibited significant same-subtype clustering with MZ probands, DZ probands and their siblings in both samples. Furthermore, a significant genetic influence contributing to subtype concordance was detected for every DSM-IV subtype excluding hyperactive-impulsive, and for all eight latent classes. While some instances of significant different-subtype clustering among siblings was observed across both classification systems and samples, the particular subtype combinations involved were largely inconsistent across samples and no significant genetic influences contributing towards these discordant subtype combinations were detected. Conclusions: For both DSM-IV and latent class subtypes, the overall pattern of findings in both samples indicated significant familial clustering of same-subtype combinations and significant genetic influences contributing to these patterns of subtype concordance, despite important sample differences. These findings further extend previous work and are most consistent with the presence of multiple independent forms of ADHD.

A study compared the Social Responsiveness Scale (SRS) with the Autism Diagnostic Interview-Revised in 61 children (ages 4-16) with autism. Correlations between the test 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. (Contains references.) (Author/CR)

The influences of child maltreatment and inherited liability on the development of antisocial behavior were examined. Child maltreatment and inherited liability had an additive effect on antisocial development.

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 ([h.sup.2] - 34%-47%) and the underlying factor score ([h.sup.2] - 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., MEASURES OF SUBSTANCE-USE PROBLEMS as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; American Psychiatric Association, 1994), are becoming more widely applied in genomic studies [...]

A study compared teachers' ratings of autistic symptomatology with those of parents, experienced clinicians and trained raters. The results concluded that quantitative assessments by teachers and parents were a cost-effective method for tracking the severity of autistic symptomatology.

A genomewide linkage screen of simple heavy-smoking quantitative trait is conducted using two independent samples. The study found significant evidence of linkage to chromosome 20 in the Finnish sample.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.addbeh.2006.03.046 Byline: Alexandre A. Todorov (a), Michael T. Lynskey (a), Julia D. Grant (a), Jeffrey F. Scherrer (a)(b), Richard D. Todd (a), Kathleen Keenan Bucholz (a) Keywords: Alcohol use disorder; Substance use disorder; Psychiatric co-morbidity; Genetic association study Abstract: Psychiatric comorbidity with drug dependence has been widely documented. In the present study, we reanalyze DSM-III-R diagnostic data on middle-aged male twin pairs from the VETR study using latent class methods. We identify four subtypes based on 15 diagnostic categories. We then show that these subtypes are strongly associated with differential rates of transitions in drug use histories, with increased risks in relatives for depression, alcohol, drug and ASPD, as well as with a variety of non-normative and deviant behaviors in youth and in adulthood. We use the result of these analyses to show how the use of a particular drug disorder phenotype for selecting cases could impact final sample composition. Author Affiliation: (a) Department of Psychiatry, Midwest Alcoholism Research Center, Washington University School of Medicine, 660 South Euclid Avenue, Box 8134, St. Louis, MO 63110-1502, United States (b) Research Service, St. Louis VAMC, St. Louis, MO, United States

This article discusses the genetic aspects of attention deficit hyperactivity disorder and other conduct disorders in teenage twins. Topics include depression, separation anxiety, mood disorder, and zygosity.