Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5.

Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders. Genetic factors contribute to the underlying liability to develop ADHD. Reports implicate variants of genes important for the synthesis, uptake, transport and receptor binding of dopamine in the etiology of ADHD, including DRD4, DAT1, DRD2, and DRD5. In the present study, we genotyped a large multiplex sample of ADHD affected children and their parents for polymorphisms in genes previously reported to be associated with ADHD. Associations were tested by the transmission disequilibrium test (TDT). The sample is sufficient to detect genotype relative risks (GRRs) for putative risk alleles. The DRD4 gene 120-bp insertion/deletion promoter polymorphism displayed a significant bias in transmission of the insertion (chi(2)=7.58, P=0.006) as suggested by an analysis of a subset of these families. The seven repeat allele of the DRD4 48-bp repeat polymorphism (DRD4.7) was not significantly associated with ADHD in the large sample in contrast to our earlier findings in a smaller subset. We replicate an association of a dinucleotide repeat polymorphism near the DRD5 gene with ADHD by showing biased nontransmission of the 146-bp allele (P=0.02) and a trend toward excess transmission of the 148-bp allele (P=0.053). No evidence for an association was found for polymorphisms in DRD2 or DAT1 in this sample. The DRD5 146-bp (DRD5.146) allele and the DRD4 240-bp (DRD4.240) allele of the promoter polymorphism emerge as the two DNA variants showing a significant association in this large sample of predominantly multiplex families with ADHD, with estimated GRRs of 1.7 and 1.37, respectively.

Genome-wide scan of reading ability in affected sibling pairs with attention-deficit/hyperactivity disorder: unique and shared genetic effects.

Attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) are common highly heritable disorders of childhood, which frequently co-occur. Data from twin and family studies suggest that this overlap is, in part, due to shared genetic underpinnings. Here, we report the first genome-wide linkage analysis of measures of reading ability in children with ADHD, using a sample of 233 affected sibling pairs who previously participated in a genome-wide scan for susceptibility loci in ADHD. Quantitative trait locus (QTL) analysis of a composite reading factor defined from three highly correlated reading measures identified suggestive linkage (multipoint maximum lod score, MLS>2.2) in four chromosomal regions. Two regions (16p, 17q) overlap those implicated by our previous genome-wide scan for ADHD in the same sample: one region (2p) provides replication for an RD susceptibility locus, and one region (10q) falls approximately 35 cM from a modestly highlighted region in an independent genome-wide scan of siblings with ADHD. Investigation of an individual reading measure of Reading Recognition supported linkage to putative RD susceptibility regions on chromosome 8p (MLS=2.4) and 15q (MLS=1.38). Thus, the data support the existence of genetic factors that have pleiotropic effects on ADHD and reading ability--as suggested by shared linkages on 16p, 17q and possibly 10q--but also those that appear to be unique to reading--as indicated by linkages on 2p, 8p and 15q that coincide with those previously found in studies of RD. Our study also suggests that reading measures may represent useful phenotypes in ADHD research. The eventual identification of genes underlying these unique and shared linkages may increase our understanding of ADHD, RD and the relationship between the two.

Biased paternal transmission of SNAP-25 risk alleles in attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is the most common childhood psychiatric disorder, affecting 5-10% of school-age children. Although the biological basis of this disorder is unknown, twin and family studies provide strong evidence that ADHD has a genetic basis involving multiple genes. A previous study found an association between ADHD and two polymorphisms in the 3' untranslated region (UTR) of SNAP-25, a gene encoding a synaptic vesicle docking protein known to play a role in the hyperactivity observed in the Coloboma mouse strain. In this paper, we test biased transmission of the 3' UTR SNAP-25 haplotype using a larger ADHD sample of 113 families with 207 affected children. Using the transmission disequilibrium test (TDT), we found a trend consistent with biased transmission of the TC haplotype of SNAP-25 in all transmissions and detected a significant distortion (P=0.027) when paternal transmissions were evaluated.

Refining the ADHD phenotype using affected sibling pair families.

Attention deficit hyperactivity (ADHD) is a highly heritable behavioral disorder characterized by symptoms of inattention, hyperactivity, and/or impulsivity. Detection of susceptibility genes underlying ADHD may benefit from refinement of the ADHD phenotype into components that reflect more specific gene to behavior pathways and through the reduction of etiological heterogeneity. Using affected sibling pair (ASP) families, we are examining familial clustering of ADHD symptoms, neurocognitive task performance, and the occurrence of comorbid conditions to attempt to refine the phenotype and/or identify clinical features that may be used to stratify ADHD subjects to reduce etiological heterogeneity.

Predictors of accidental fatal drug overdose among a cohort of injection drug users.

OBJECTIVES: This study evaluated factors associated with accidental fatal drug overdose among a cohort of injection drug users (IDUs). METHODS: In a prospective cohort study of 2849 IDUs in King County, Washington, deaths were identified by electronically merging subject identifiers with death certificate records. Univariate and multivariate Cox regression analyses were performed to identify predictors of overdose mortality. RESULTS: Thirty-two overdoses were observed. Independent predictors of overdose mortality were bisexual sexual orientation (relative risk [RR] = 4.86; 95% confidence interval [CI] = 2.30, 13.2), homelessness (RR = 2.30; 95% CI = 1.06, 5.01), infrequent injection of speedballs (RR = 5.36; 95% CI = 1.58, 18.1), daily use of powdered cocaine (RR = 4.84; 95% CI = 1.13, 20.8), and daily use of poppers (RR = 22.0; 95% CI = 1.74, 278). CONCLUSIONS: Sexual orientation, homelessness, and drug use identify IDUs who may benefit from targeted interventions.

Methodological issues in designing a multisite trial of risperidone in children and adolescents with autism.

OBJECTIVE: To describe the methodological challenges and decisions made in developing a multisite, controlled study of risperidone in children and adolescents with autism. METHODS: Review the design considerations for clinical trials in children with autistic disorder accompanied by severe tantrums, aggressive and/or self-injurious behaviors. These design considerations include the definition of inclusion criteria that are relevant to clinical practice and matching study design to the goal of evaluating short- and long-term effects. Additional ethical and scientific issues concern the length of trial and sample size. RESULTS: We undertook a short-term, placebo-controlled study to evaluate the efficacy and safety of risperidone in children and adolescents with autistic disorder. This trial design was followed by an extended open-label maintenance on risperidone to confirm durability of treatment effects and to monitor safety. Finally, a placebo-controlled discontinuation study tested the need for continuous treatment. CONCLUSIONS: In the absence of standard pharmacological treatment for children with autistic disorder, a placebo-controlled study remains the most appropriate method of testing efficacy and safety. The clinical relevance of this study is enhanced by the addition of an extended maintenance phase followed by a placebo discontinuation.

Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD).

Attention deficit hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder. Evidence from twin, adoption, and family studies provide support for a genetic contribution to the etiology of ADHD. Several candidate gene studies have identified an association between a 7-repeat variant in exon 3 of the dopamine 4 receptor gene (DRD4) and ADHD. However, in spite of the positive reports finding association of the exon 3 VNTR with ADHD, several other polymorphisms within DRD4 have been identified that conceivably could contribute to risk for ADHD. Recently, another common polymorphism of the DRD4 gene has been described involving a 120-bp repeat element upstream of the 5' transcription initiation site. In this report, we describe results of analysis of the DRD4 120-bp repeat promoter polymorphism in a sample of 371 children with ADHD and their parents, using the transmission disequilibrium test (TDT). Results showed a significant preferential transmission of the 240-bp (long) allele with ADHD. Exploratory analyses of the Inattentive phenotypic subtype of ADHD strengthened the evidence for linkage. These data add further support for the role of DRD4 variants conferring increased risk for ADHD, and imply that additional studies of DRD4 and other related genes are needed.

Reduced injection frequency and increased entry and retention in drug treatment associated with needle-exchange participation in Seattle drug injectors.

The association between needle exchange, change in drug use frequency and enrollment and retention in methadone drug treatment was studied in a cohort of Seattle injection drug users (IDUs). Participants included IDUs classified according to whether they had used a needle exchange by study enrollment and during the 12-month follow-up period. The relative risk (RR) and the adjusted RR (ARR) were estimated as measures of the association. It was found that IDUs who had formerly been exchange users were more likely than never-exchangers to report a substantial (> or= 75%) reduction in injection (ARR = 2.85, 95% confidence limit [CL] 1.47-5.51), to stop injecting altogether (ARR = 3.5, 95% CL 2.1-5.9), and to remain in drug treatment. New users of the exchange were five times more likely to enter drug treatment than never-exchangers. We conclude that reduced drug use and increased drug treatment enrollment associated with needle exchange participation may have many public health benefits, including prevention of blood-borne viral transmission.

Familial clustering of symptoms and disruptive behaviors in multiplex families with attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine familial clustering of attention-deficit/hyperactivity disorder (ADHD), ADHD subtypes, symptoms, and oppositional behaviors in affected sibling pairs (ASPs) and their parents. METHOD: One hundred thirty-two ASPs, ranging in age from 5 to 25 years and ascertained through clinic and volunteer referrals, were examined for DSM-IV ADHD subtypes, oppositional defiant disorder (ODD), and conduct disorder (CD) with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL). Two hundred fifty-six parents in these families were assessed by means of the SADS-Lifetime version, Modified for the Study of Anxiety Disorders, Updated for DSM-IV (SADS-LA-IV), and the Behavioral Disorders supplement of the K-SADS-PL to determine ADHD, ODD, and CD. RESULTS: Fifty-five percent of families ascertained through an ASP have at least one parent with a lifetime diagnosis of ADHD. The frequency of ADHD in at least one parent was higher in families with at least one affected girl (63%) than in families with only affected boys (45%) (p = .02). There was no evidence that affected siblings or parents within ASP families showed similar patterns of ADHD symptoms, such as ADHD subtype classification. In contrast, CD significantly clustered in ASP families. CONCLUSIONS: The sex difference in prevalence of ADHD among ASPs is consistent with a model of inheritance in which girls require a greater loading of familial influences to develop ADHD. The lack of familial clustering of ADHD symptoms within ASP families suggests that hyperactive and inattentive symptoms reflect common familial underpinnings and not unique familial effects. In contrast, CD seems to reflect unique familial underpinnings distinct from those underlying ADHD.

Assessment of attention deficit hyperactivity disorder: a review of recent literature.

Attention deficit hyperactivity disorder is one of the most common behavioral disorders of childhood and is frequently assessed and treated by pediatricians and other primary care physicians. The diagnosis of attention deficit hyperactivity disorder is based on the careful synthesis of clinical data derived from multiple sources, notably, the patient, parents, and teachers. Standard behavioral rating scales simplify and standardize collection of clinical data but by themselves are not sufficient for a diagnosis. Recognition and treatment of disorders comorbid with attention deficit hyperactivity disorder are necessary for optimal outcomes. Psychoeducational testing is useful in the assessment of suspected associated learning disabilities, but there is no evidence at present to support use of psychologic testing, laboratory measures of attention, electroencephalography, or neuroimaging studies in the clinical assessment of attention deficit hyperactivity disorder.

Assessment in multisite randomized clinical trials of patients with autistic disorder: the Autism RUPP Network. Research Units on Pediatric Psychopharmacology.

Assessment of autistic disorder (autism) symptoms, primary and secondary, poses more challenging problems than ordinarily found in multisite randomized clinical trial (RCT) assessments. For example, subjects may be uncommunicative and extremely heterogeneous in problem presentation, and current pharmacological treatments are not likely to alter most core features of autism. The Autism Research Units on Pediatric Psychopharmacology (RUPP Autism Network) resolved some of these problems during the design of a risperidone RCT in children/adolescents. The inappropriateness of the usual anchors for a Clinical Global Impression of Severity (CGI-S) was resolved by defining uncomplicated autism without secondary symptoms as a CGI-S of 3, mildly ill. The communication problems, compromising use of the patient as an informant, were addressed by several strategies, including careful questioning of care providers, rating scales, laboratory tests, and physical exams. The broad subject heterogeneity requires outcome measures sensitive to individual change over a wide spectrum of treatment response and side effects. The problems of neuropsychologically testing nonverbal, lower functioning, sometimes noncompliant subjects requires careful instrument selection/adaptation and flexible administration techniques. The problems of assessing low-end IQs, neglected by most standardized test developers, was resolved by an algorithm of test hierarchy. Scarcity of other autism-adapted cognitive and neuropsychological tests and lack of standardization required development of a new, specially adapted battery. Reliability on the Autism Diagnostic Interview (currently the most valid diagnostic instrument) and other clinician instruments required extensive cross-site training (in-person, videotape, and teleconference sessions). Definition of a treatment responder required focus on individually relevant target symptoms, synthesis of possible modest improvements in many domains, and acceptance of attainable though imperfect goals. The assessment strategy developed is implemented in a RCT of risperidone (McDougle et al., 2000) for which the design and other methodological challenges are described elsewhere (Scahill et al., 2000). Some of these problems and solutions are partially shared with RCTs of other treatments and other disorders.

Volunteer bias in nonrandomized evaluations of the efficacy of needle-exchange programs.

OBJECTIVE: Nonrandomized comparisons of the incidence of HIV and hepatitis B and C between injection drug users (IDUs) who do and do not attend voluntary needle-exchange programs may be subject to bias. To explore possible sources of bias, we examined characteristics associated with voluntarily beginning or ceasing to participate in the Seattle needle exchange. METHODS: In a cohort of 2,879 IDUs, a standardized questionnaire measured characteristics present at enrollment. We examined the relation of these characteristics to the proportion of IDUs who began to use the program during the ensuing 12-month follow-up period and to the proportion of current exchangers who dropped out during that period of time. RESULTS: Of the 494 never-exchangers at baseline, 32% attended the exchange program during follow-up; those who reported sharing syringes or who were homeless at enrollment were more likely to become new exchange users (adjusted risk ratio [ARR] for becoming an exchange user = 1.8 for those who shared syringes, and ARR = 2.2 for those who were homeless). Of 1,274 current exchangers, 16% stopped using the exchange during followup, with daily injectors (ARR = 0.6) and those who reported backloading (ARR = 0.6) being relatively less likely to drop out of the exchange. CONCLUSIONS: The analysis suggests that IDUs participating in needle-exchange programs at a given point in time may include a particularly high proportion of those injectors whose pattern of drug use puts them at elevated risk of blood-borne viral infections.

Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Background and rationale for an initial controlled study of risperidone.

This article has reviewed the background and rationale for the choice of risperidone as the first drug to be studied by the RUPP Autism Network. Risperidone has potent effects on 5-HT and DA neuronal systems, both of which have been implicated in the pathophysiology of autism. Unlike the typical antipsychotics, haloperidol and pimozide, which have been shown to be effective for reducing many of the maladaptive behaviors associated with autism, risperidone's 5-HT2A/DA D2 ratio of receptor blockade appears to produce a lower risk of acute and chronic extrapyramidal side effects, as well as enhanced efficacy for the "negative" symptoms of autism. Indirect clinical and preclinical evidence supports the use of risperidone to treat impaired social behavior, interfering repetitive phenomena, and aggression, targets of pharmacotherapy for many patients with autism. Numerous published open-label trials in children and adolescents with autism and related PDDs and one double-blind, placebo-controlled study in adults suggest that risperidone has promise for the treatment of children and adolescents with autism. Because most of these studies have been short-term, open-label trials in small samples, however, a large-scale controlled study of risperidone in children and adolescents with autism is needed to confirm these results. Finally, because it is likely that children who demonstrate short-term benefit from risperidone will remain on the medication indefinitely, the longer-term effectiveness and safety of risperidone in this population also needs to be determined. The design of this study and the assessments used are described separately.

Syringe exchange and risk of infection with hepatitis B and C viruses.

The authors utilized a cohort study among Seattle injection drug users (IDUs) to assess whether participation in a syringe exchange program was associated with incidence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Susceptible IDU subjects (187 seronegative for antibody to HCV, and 460 seronegative for core antibody to HBV) were identified in drug treatment, corrections, and social service agencies from June 1994 to January 1996, and followed for seroconversion one year later. The subjects included in the analysis were Seattle-King County (Washington State) area IDUs enrolled in a larger multipurpose cohort study, the Risk Activity Variables, Epidemiology, and Network Study (RAVEN Study). There were 39 HCV infections (20.9/100/year) and 46 HBV infections (10.0/100/year). There was no apparent protective effect of syringe exchange against HBV (former exchange users, relative risk (RR) = 0.68, 95% confidence interval (CI) 0.2-2.5; sporadic exchange users, RR = 2.4, 95% CI 0.9-6.5; regular users, RR = 1.81, 95% CI 0.7-4.8; vs. RR = 1.0 for nonusers of the exchange; adjusted for daily drug injection). Neither did the exchange protect against HCV infection (sporadic users, RR = 2.6, 95% CI 0.8-8.5; regular users, RR = 1.3, 95% CI 0.8-2.2; vs. RR = 1.0 for nonusers; adjusted for recent onset of injection and syringe sharing prior to enrollment). While it is possible that uncontrolled confounding or other bias obscured a true beneficial impact of exchange use, these data suggest that no such benefit occurred during the period of the study.

Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral problem afflicting 5-10% of children and adolescents and persisting into adulthood in 30-50% or more of cases. Family, twin, and adoption studies suggest genetic factors contribute to ADHD and symptoms of inattention, impulsivity, and hyperactivity. Because stimulant intervention is effective in reducing ADHD symptoms in about 70-80% of cases, molecular genetic investigations of genes involved in dopamine regulation are currently underway by many groups. In a case control study of the dopamine D4 receptor gene (DRD4) and ADHD, La Hoste and colleagues found an increase of a 7-repeat variant of a 48-bp VNTR in exon 3 among ADHD subjects compared to controls. Swanson and colleagues replicated this finding in a sample of 52 ADHD probands and their biological parents using a haplotype relative risk analysis. Here, we describe linkage investigations of the VNTR and ADHD in affected sibling pair (ASP) families and singleton families using both the transmission disequilibrium test (TDT) and a mean test of identity-by-descent (IBD) sharing. Using the TDT in the total sample, the 7 allele is differentially transmitted to ADHD children (P = 0.03) while the mean test revealed no evidence of increased IBD sharing among ASPs. In the current sample, the 7 allele attributes a 1.5-fold risk for developing ADHD over non-carriers of the allele estimated under a model described by Risch and Merikangas.

Prevalence of HTLV types I and II among drug users in King County, Washington.

We investigated the prevalence of human T-cell lymphotropic virus (HTLV) types I and II among drug users entering treatment in King County, Washington, between 1988 and 1990. Of 762 injection-drug users, 81 (10.6%) were HTLV-positive; of 89 noninjection-drug users, 2 (2%) were HTLV-positive. Most (95.8%) of those typed) were HTLV-II-positive. The relationship between HTLV and demographic and behavioral characteristics was further evaluated among injection-drug users. The prevalence rates for HTLV increased 25-fold from the youngest age group (15 to 24 years) to the oldest (older than 45 years), after adjusting for race. After adjustment for age, American Indians or Alaska Natives were 7.9 times, blacks 6.2 times, Asians or Pacific Islanders 4.7 times, and Hispanics 4.1 times as likely as whites to be HTLV-positive. The prevalence of HTLV among heroin injectors was more than double that observed among injectors of other drugs after adjusting for age, although this association was only marginally significant. The strong association between HTLV prevalence and age suggests that HTLV-II (the predominant virus) has been endemic among King County injection-drug users for some time. Its relatively high prevalence indicates that there is both an opportunity and a need to further investigate the epidemiologic and clinical implications of HTLV-II infection.

Risk factors for HIV infection among injection drug users: results of blinded surveys in drug treatment centers, King County, Washington 1988-1991.

Among injection drug users (IDUs) entering drug treatment in King County, Washington between 1988 and 1991, we investigated HIV seroprevalence in relationship to demographic, sexual, and drug-use characteristics. Eighty-two of 3,039 (2.7%) IDUs tested HIV positive. Gay or bisexual men had the highest HIV prevalence (37.1%), followed by lesbian or bisexual women (8.3%), heterosexual men (2.3%), and heterosexual women (1.5%). American Indians were more likely to be infected with HIV than were whites. Those with no permanent address were more likely to be infected than those with an address. Unexpectedly, the prevalence of HIV infection among amphetamine injectors (13.1% of 168) was higher than among those who did not report using amphetamines. After adjustment for sexual orientation, HIV prevalence was four times higher among primary amphetamine injectors and three times higher among secondary amphetamine injectors than among injectors of other drugs. The basis for the strong association observed between HIV infection and a history of injection of amphetamines is not known and should be clarified through further research that obtains more detailed information on IDUs.

Utility of the SCL-90-R with depressed and conduct-disordered adolescent inpatients.

We assessed the diagnostic utility of the Symptom Checklist-90-Revised (SCL-90-R) in a sample of adolescent inpatients. In Part 1 (n = 79), convergent and discriminant validity were demonstrated for SCL-90-R scales measuring depression and paranoid ideation. Canonical correlation showed that SCL-90-R scales tapped two dimensions of adolescent psychopathology, a primary dimension of dysphoria and a secondary dimension of anger and mistrust. In Part 2 (n = 50), adolescents diagnosed as having major depression showed significant elevations on scales measuring depression, anxiety, and obsessive-compulsive features. Although several scales had high diagnostic specificity for major depression and conduct disorder, sensitivity was low.