Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

Bipolar disorder risk alleles in children with ADHD.

Bipolar disorder (BD) and attention deficit/hyperactivity disorder (ADHD) may share common genetic risk factors as indicated by the high co-morbidity of BD and ADHD, their phenotypic overlap especially in pediatric populations, the high heritability of both disorders, and the co-occurrence in families. We therefore examined whether known polygenic BD risk alleles are associated with ADHD. We chose the eight best SNPs of the recent genome-wide association study (GWAS) of BD patients of German ancestry and the nine SNPs from international GWAS meeting a 'genome-wide significance' level of α = 5 × 10(-8). A GWAS was performed in 495 ADHD children and 1,300 population-based controls using HumanHap550v3 and Human660 W-Quadv1 BeadArrays. We found no significant association of childhood ADHD with single BD risk alleles surviving adjustment for multiple testing. Yet, risk alleles for BD and ADHD were directionally consistent at eight of nine loci with the strongest support for three SNPs in or near NCAN, BRE, and LMAN2L. The polygene analysis for the BP risk alleles at all 14 loci indicated a higher probability of being a BD risk allele carrier in the ADHD cases as compared to the controls. At a moderate power to detect association with ADHD, if true effects were close to estimates from GWAS for BD, our results suggest that the possible contribution of BD risk variants to childhood ADHD risk is considerably lower than for BD. Yet, our findings should encourage researchers to search for common genetic risk factors in BD and childhood ADHD in future studies.

Exploring the genetic link between RLS and ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder of childhood onset. Clinical and biological evidence points to shared common central nervous system (CNS) pathology of ADHD and restless legs syndrome (RLS). It was hypothesized that variants previously found to be associated with RLS in two large genome-wide association studies (GWA), will also be associated with ADHD. SNPs located in MEIS1 (rs2300478), BTBD9 (rs9296249, rs3923809, rs6923737), and MAP2K5 (rs12593813, rs4489954) as well as three SNPs tagging the identified haplotype in MEIS1 (rs6710341, rs12469063, rs4544423) were genotyped in a well characterized German sample of 224 families comprising one or more affected sibs (386 children) and both parents. We found no evidence for preferential transmission of the hypothesized variants to ADHD. Subsequent analyses elicited nominal significant association with haplotypes consisting of the three SNPs in BTBD9 (chi2 = 14.8, df = 7, nominal p = 0.039). According to exploratory post hoc analyses, the major contribution to this finding came from the A-A-A-haplotype with a haplotype-wise nominal p-value of 0.009. However, this result did not withstand correction for multiple testing. In view of our results, RLS risk alleles may have a lower effect on ADHD than on RLS or may not be involved in ADHD. The negative findings may additionally result from genetic heterogeneity of ADHD, i.e. risk alleles for RLS may only be relevant for certain subtypes of ADHD. Genes relevant to RLS remain interesting candidates for ADHD; particularly BTBD9 needs further study, as it has been related to iron storage, a potential pathophysiological link between RLS and certain subtypes of ADHD.

Prospects for the classification of mental disorders of children and adolescents.

Suggestions for classification of mental disorders of children and adolescents in DSM-V and ICD-11 have been made, which differ strongly from the current descriptive approach of dimensional classification. These suggestions even comprise a dichotomized system for health care as well as for scientific purposes. Nevertheless it is obvious that we are far behind an "etiological" classification, so that trade-offs have necessarily to be made in DSM-V and ICD-11. Appropriate proposals concern the strict separation of disorders that are typical for children and adolescents as well as for adults. Furthermore a differentiation of diagnosis for infants, toddlers and preschool children is required in both classification systems. As far as it is relevant for treatment, combined diagnosis in DSM-V and subthreshold diagnosis as well as coding-possibilities for findings in molecular biology should be permitted. As personality disorders should only be diagnosed after the age of 16, it is recommended to dimensionally classify personality traits that are pathognomonic for specific symptom patterns and of prognostic relevance. DSM-V and ICD-11 should allow age-specific information on axis-IV. The article discusses the general question of how relational disorders respectively disturbances should be classified and include furthermore special recommendations concerning ICD and DSM categories.

What do we know about the serotonergic genetic heterogeneity in attention-deficit/hyperactivity and autistic disorders?

BACKGROUND: Shared candidate gene regions point to a link between autistic disorders and attention-deficit/hyperactivity disorder (ADHD). Although they represent nosologically different diagnoses, the disorders do show some shared symptoms, above all inattention. For both disorders, the association with the serotonergic system is a focus of current research. SAMPLING AND METHODS: The current work provides an overview of serotonergic mechanisms in ADHD and autistic disorders as well as the resulting pharmacogenetic approaches. RESULTS: No uniform picture emerges either for ADHD or for autistic disorders. In pharmacogenetic terms, there are some isolated studies on associations between serotonergic mechanisms and pharmacotherapy. For the area of autism, such studies are still lacking. CONCLUSIONS: The presented serotonergic mechanisms show relationships of this polymorphism to ADHD and autistic disorders, but they do not result in a uniform picture. The overlaps can best be explained by a dimensional classification approach. As yet, only a small number of studies on attentional disorders in autism and ADHD using shared samples have been carried out. With regard to diagnostics and therapy, analyses on the etiology of the attentional disorder of ADHD and autism are required.

[Autism and ADHD - are there common traits?]. / Autismus und ADHS - Gibt es Gemeinsamkeiten?

INTRODUCTION: Genetic, neuropsychological and psychopathological findings refer to a connection of autism and attention deficit/hyperactivity disorder (ADHD). Although the disorders represent different nosological diagnoses they partly include similar symptoms like hyperactivity, impulsivity and attention deficit disorder. METHODS: This paper gives an overview of genetic, morphological, neurophysiological and -psychological studies concerning ADHD and autism. In addition, results concerning pharmacotherapy and the development of both disorders in adulthood are described. RESULTS: With regard to genetics, common candidate regions are discussed. Under a morphological perspective, results on the one hand point out identical brain regions or functional systems but on the other hand underline that these regions are not equally affected. The morphological results could not be replicated on a neuropsychological basis. So far findings of studies which involved combined ADHD- and autistic samples lead to controversal results. CONCLUSION: At present, there exist only few studies which include the issue of attention disorders in autism and ADHD in a same sample. With regard to diagnosis and therapeutical interventions, further research concerning the etiology of both disorders is necessary.

[Absences as differential diagnosis in children with attention-deficit disorder]. / Absenzen als Differenzialdiagnose bei Kindern mit Aufmerksamkeitsdefizit-Syndrom.

OBJECTIVES: Absences are regarded as one of the most important differential diagnosis of attention and resulting school-problems. Attention deficit-symptoms might develop through absences, even though there is no diagnosis of attention-deficit/ hyperactivity disorder or attention-deficit disorder (ADHD or ADD). Routine EEG-wavings are made, in order to exclude epilepsy as a reason for attention-deficits. METHODS: In this paper the EEGs of 8 132 male and female children and adolescents from two hospitals for child and adolescent psychiatry were analyzed retrospectively. The aim of the study was to assess how many patients with absences do occur and whether they do present a specific psychopathology. RESULTS: In summary for the first time diagnosed absences occurred in 0.44 % (N = 12) of the patients in the first centre and in none of the patients in the second centre. The average age was 9.5 years. 50 % of the patients were diagnosed with ADHD. A specific psychopathology of the patients was not found. CONCLUSIONS: There is a minimal occurrence of absences in child and adolescent patients. Therefore it is not a main differential diagnosis, that has to be considered in children with attention-deficit problems. Due to the late age at the time of diagnosis and the possible good treatability with antiepileptics, it is nevertheless important to regard absences as a rare differential diagnosis.

Myelinopathia centralis diffusa (vanishing white matter disease) in a four-year-old boy.

A four-year-old boy presented with moderate ataxia triggered by a minor head trauma several weeks ago. Discrepantly severe signal changes of cerebral white matter with almost CSF-isointense signal on all pulse sequences were detected at cranial MRI. Localized proton MR spectroscopy of cerebral white matter demonstrated an even decrease of all metabolites. Glycine was found elevated in CSF. This pattern of clinical history, MR imaging and spectroscopy features and elevated glycine in CSF is characteristic for a novel entity amongst the leukoencephalopathies of childhood. It was originally termed "myelinopathia centralis diffusa" and renamed "vanishing white matter disease" later.