A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD.

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.

A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication.

Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.

Children and adolescents with obsessive-compulsive disorder and comorbid attention-deficit/hyperactivity disorder: preliminary results of a prospective follow-up study.

In the present study, we have investigated the influence of comorbid attention deficit hyperactivity disorder (ADHD) on early onset obsessive compulsive disorder (OCD). For that purpose, we compared 20 patients with "OCD with ADHD" and 20 randomly selected patients with "OCD without ADHD". "OCD with ADHD" patients tended to show an earlier age of OCD onset, a higher severity of symptoms and a higher persistence rate than OCD patients without ADHD. Both groups appear to develop different patterns of comorbid disorders.

A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs.

Three groups have previously performed genome scans in attention-deficit/hyperactivity disorder (ADHD); linkage to chromosome 5p13 was detected in all of the respective studies. In the current study, we performed a whole-genome scan with 102 German families with two or more offspring who currently fulfilled the diagnostic criteria for ADHD. Including subsequent fine mapping on chromosome 5p, a total of 523 markers were genotyped. The highest nonparametric multipoint LOD score of 2.59 (empirical genome-wide significance 0.1) was obtained for chromosome 5p at 17 cM (according to the Marshfield map). Subsequent analyses revealed (a) a higher LOD score of 3.37 at 39 cM for a quantitative severity score based on symptoms of inattention than for hyperactivity/impulsivity (LOD score of 1.11 at 59 cM), and (b) an HLOD of 4.75 (empirical genome-wide significance 0.001) based on a parametric model assuming dominant inheritance. The locus of the solute carrier 6A3 (SLC6A3; dopamine transporter 1; DAT1) localizes to 5p15.33; the gene has repeatedly been implicated in the etiology of ADHD. However, in our sample the DAT1 VNTR did not show association with ADHD. We additionally identified nominal evidence for linkage to chromosomes 6q, 7p, 9q, 11 q, 12q and 17p, which had also been identified in previous scans. Despite differences in ethnicity, ascertainment and phenotyping schemes, linkage results in ADHD appear remarkably consistent.

Mutation screen of the brain derived neurotrophic factor gene (BDNF): identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention-deficit/hyperactivity disorder.

Several lines of evidence indicate an involvement of brain derived neurotrophic factor (BDNF) in body weight regulation and activity: heterozygous Bdnf knockout mice (Bdnf(+/-)) are hyperphagic, obese, and hyperactive; furthermore, central infusion of BDNF leads to severe, dose-dependent appetite suppression and weight loss in rats. We searched for the role of BDNF variants in obesity, eating disorders, and attention-deficit/hyperactivity disorder (ADHD). A mutation screen (SSCP and DHPLC) of the translated region of BDNF in 183 extremely obese children and adolescents and 187 underweight students was performed. Additionally, we genotyped two common polymorphisms (rs6265: p.V66M; c.-46C > T) in 118 patients with anorexia nervosa, 80 patients with bulimia nervosa, 88 patients with ADHD, and 96 normal weight controls. Three rare variants (c.5C > T: p.T2I; c.273G > A; c.*137A > G) and the known polymorphism (p.V66M) were identified. A role of the I2 allele in the etiology of obesity cannot be excluded. We found no association between p.V66M or the additionally genotyped variant c.-46C > T and obesity, ADHD or eating disorders. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html.

[Obsessive-compulsive disorders in children and adolescents--a review]. / Der Verlauf von Zwangsstörungen mit Beginn im Kindes- und Jugendalter--eine Literaturübersicht.

OBJECTIVE: Presented is a review of the literature on the medium- and long-term course of obsessive-compulsive disorder (OCD) with onset in childhood or adolescence. METHODS: Using the data bank MEDLINE, relevant studies published since 1983 were investigated. Older studies were included if their results complemented those of recent studies. RESULTS: Follow-up studies point to a rather unfavorable course of childhood OCD. At the time of follow-up investigations, 30% to 70% of the patients still suffered from obsessive-compulsive symptoms or had a diagnosis of OCD. Other clinical disorders were diagnosed in 20% to 95% of them. One to two thirds of former patients had received at least one diagnosis of a personality disorder. Multicomorbidity was common. Impairment of the patients' psychosocial adjustment especially affected relationships and sexuality. Most of the variables examined in childhood or adolescence had no significant predictive power as to the course of obsessive-compulsive disorders. CONCLUSIONS: Differences between the results of the follow-up studies can partly be explained by the different study designs employed. Results on the course of childhood OCD point to the high stability of the disorder and the accompanying rate of comorbidity. This has to be taken into account in the diagnosis (supplementary diagnosis of comorbid disorders and family diagnostics) and therapy of childhood OCD (offering long-term therapeutic advice and booster sessions, treatment of comorbid disorder, inclusion of the family).

[Formal genetic findings in attention-deficit/hyperactivity-disorder]. / Formalgenetische Befunde zur Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung.

Twin, family and adoption studies have led to a solid understanding of the contribution of both genetic and environmental factors to the development of attention deficit/hyperactivity disorder (ADHD). We review recent studies under consideration of both methodological aspects and relevant findings. Heritability estimates in the range of 0.6 - 0.8 surpass those for most other child and adolescent psychiatric disorders. First degree relatives have elevated rates for ADHD, affective disorders, conduct disorders and substance abuse and dependency. The ADHD subtype of the index patient does not predict the subtype of other family members affected with ADHD; hence non-genetic factors seemingly account for this intrafamilial variability. Because the familial rates for ADHD are not higher in families of female in comparison to male index patients, there is no indication that the genetic loading is higher in affected females. Recently, rater effects have been discussed broadly: Whereas the heritability estimates are uniformly high independent of the informant (mother, father, teacher), the correlations between quantitatively rated symptoms are low between different informants. Knowledge of the formal genetic aspects of ADHD is a prerequisite for understanding the results of recent molecular genetic studies.

[Diagnostic testing methods for skill assessment in reading, writing, and arithmetic. A critical review]. / Testdiagnostische Verfahren zur Uberprüfung der Fertigkeiten im Lesen, Rechtschreiben und Rechnen. Eine kritische Ubersicht.

OBJECTIVES: The diagnosis of a specific developmental disorder of reading, writing and arithmetic can be made based upon individually applied standardized methods for testing scholastic achievement and IQ. To make the choice of suitable methods easier for the administrator of the test, a critical survey of German-language methods for assessing skills in reading, writing and arithmetic is presented. METHODS: Test intention and psychometric properties for scholastic achievement are summarized. The methods are assessed with regard to their utility in the diagnosis of congenital alexia and dyscalculia. Supplementary suggestions for clinical assessment are given. RESULTS: In summary, beyond the primary school area there is a lack of current standardized methods that meet the current standards of quality. Particularly the assessment of arithmetic skills above those of the 4th grade level require resorting to methods of dubious curricular validity. Coverage is once again better for the upper elementary and middle school levels. CONCLUSIONS: There is a need for new constructions, respectively a need to update published scholastic achievement tests.

[Current developments in the treatment of obsessive-compulsive disorders in children and adolescents]. / Aktuelle Entwicklungen in der Therapie von Zwangsstörungen im Kindes- und Jugendalter.

For the treatment of obsessive-compulsive disorders during childhood and adolescence, multidimensional therapeutical approaches have proven useful in clinical practice. First controlled studies have demonstrated the efficacy of both psychotherapeutical and pharmacological strategies. Exposure and response prevention are considered the most efficient psychotherapeutical methods. On the basis of the available data, the question of the pharmacological dose can not be answered definitely. For Clomipramin, the dose most probably is between 75 mg and 150 mg, where as for Fluoxetine and Fluvoxamine 20 mg-60 mg and 100 mg-250 mg respectively. However, it has to be kept in mind that sometimes improvement of symptoms is not seen after 8-10 weeks of treatment. Basically it can be stated that to date there is an urgent need for therapeutical studies of obsessive-compulsive disorders in the childhood and adolescence. Most relevant would be studies evaluating pharmacological treatment versus a placebo control groups and carefully designed controlled psychotherapeutical treatment studies as well studies comparing pharmacological and psychotherapeutical approaches.