RESUMEN
Autism spectrum disorders (ASD) are highly heritable and are characterized by deficits in social communication and restricted and repetitive behaviors. Twin studies on phenotypic subdomains suggest a differing underlying genetic etiology. Studying genetic variation explaining phenotypic variance will help to identify specific underlying pathomechanisms. We investigated the effect of common variation on ASD subdomains in two cohorts including >2500 individuals. Based on the Autism Diagnostic Interview-Revised (ADI-R), we identified and confirmed six subdomains with a SNP-based genetic heritability h2SNP = 0.2-0.4. The subdomains nonverbal communication (NVC), social interaction (SI), and peer interaction (PI) shared genetic risk factors, while the subdomains of repetitive sensory-motor behavior (RB) and restricted interests (RI) were genetically independent of each other. The polygenic risk score (PRS) for ASD as categorical diagnosis explained 2.3-3.3% of the variance of SI, joint attention (JA), and PI, 4.5% for RI, 1.2% of RB, but only 0.7% of NVC. We report eight genome-wide significant hits-partially replicating previous findings-and 292 known and novel candidate genes. The underlying biological mechanisms were related to neuronal transmission and development. At the SNP and gene level, all subdomains showed overlap, with the exception of RB. However, no overlap was observed at the functional level. In summary, the ADI-R algorithm-derived subdomains related to social communication show a shared genetic etiology in contrast to restricted and repetitive behaviors. The ASD-specific PRS overlapped only partially, suggesting an additional role of specific common variation in shaping the phenotypic expression of ASD subdomains.
Asunto(s)
Trastorno del Espectro Autista , Estudio de Asociación del Genoma Completo , Trastorno del Espectro Autista/genética , HumanosRESUMEN
The genetic architecture underlying Autism spectrum disorder (ASD) has been suggested to differ between individuals with lower (IQ ≤ 70; LIQ) and higher intellectual abilities (IQ > 70; HIQ). Among the identified pathomechanisms, the glutamatergic signalling pathway is of specific interest in ASD. We investigated 187 common functional variants of this neurotransmitter system for association with ASD and with symptom severity in two independent samples, a German (German-ALL: N = 583 families) and the Autism Genome Project cohort (AGP-ALL: N = 2001 families), split into HIQ, and LIQ subgroups. We did not identify any association withstanding correction for multiple testing. However, we report a replicated nominal significant under-transmission (OR < 0.79, p < 0.04) of the AKAP13 rs745191-T allele in both LIQ cohorts, but not in the much larger HIQ cohorts. At the phenotypic level, we nominally replicated associations of CAMK2A-rs2241694 with non-verbal communication in both combined LIQ and HIQ ASD cohorts. Variants PLD1-rs2124147 and ADCY1-rs2461127 were nominally associated with impaired non-verbal abilities and AKAP2-rs3739456 with repetitive behaviour in both LIQ cohorts. All four LIQ-associated genes are involved in G-protein coupled signal transduction, a downstream pathway of metabotropic glutamate receptor activation. We conclude that functional common variants of glutamatergic genes do not have a strong impact on ASD, but seem to moderately affect ASD risk and phenotypic expression. Since most of our nominally replicated hits were identified in the LIQ cohort, further investigation of the glutamatergic system in this subpopulation might be warranted.
Asunto(s)
Trastorno del Espectro Autista/genética , Estudios de Asociación Genética , Ácido Glutámico/genética , Niño , Femenino , Humanos , Discapacidad Intelectual/genética , Pruebas de Inteligencia , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
Common variants contribute significantly to the genetics of autism spectrum disorder (ASD), although the identification of individual risk polymorphisms remains still elusive due to their small effect sizes and limited sample sizes available for association studies. During the last decade several genome-wide association studies (GWAS) have enabled the detection of a few plausible risk variants. The three main studies are family-based and pointed at SEMA5A (rs10513025), MACROD2 (rs4141463) and MSNP1 (rs4307059). In our study we attempted to replicate these GWAS hits using a case-control association study in five European populations of ASD patients and gender-matched controls, all Caucasians. Results showed no association of individual variants with ASD in any of the population groups considered or in the combined European sample. We performed a meta-analysis study across five European populations for rs10513025 (1,904 ASD cases and 2,674 controls), seven European populations for rs4141463 (2,855 ASD cases and 36,177 controls) and five European populations for rs4307059 (2,347 ASD cases and 2,764 controls). The results showed an odds ratio (OR) of 1.05 (95% CI = 0.84-1.32) for rs10513025, 1.0002 (95% CI = 0.93-1.08) for rs4141463 and 1.01 (95% CI = 0.92-1.1) for rs4307059, with no significant P-values (rs10513025, P = 0.73; rs4141463, P = 0.95; rs4307059, P = 0.9). No association was found when we considered either only high functioning autism (HFA), genders separately or only multiplex families. Ongoing GWAS projects with larger ASD cohorts will contribute to clarify the role of common variation in the disorder and will likely identify risk variants of modest effect not detected previously. Autism Res 2017, 10: 202-211. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
Asunto(s)
Trastorno del Espectro Autista/genética , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Estudios de Casos y Controles , Europa (Continente) , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Reproducibilidad de los ResultadosRESUMEN
Neuropeptides such as oxytocin (OXT) are known facilitators of social behavior across species. Variants of the OXT receptor gene (OXTR) have been tested for association with autism spectrum disorder (ASD) across manifold ethnicities, yielding both positive and negative findings. A recent meta-analysis, comprising 16 single nucleotide polymorphisms (SNPs), has corroborated the implication of OXTR in the etiology of ASD. Here, we genotyped and tested two additional variants (rs237889 and rs237897) for association with ASD in two German predominantly high-functioning ASD samples. We found nominal over-transmission (OR = 1.48, CI95 = 1.06-2.08, P = 0.022) for the minor A allele of variant rs237889G>A in sample 1 (N = 135 complete parent-offspring trios, 29 parent child duos), but not in sample 2 (362 trios, 69 duos). Still, in a meta-analysis comprising four different studies including the two unreported German data sets (N = 542 families), this finding was confirmed (OR = 1.12; CI95 = 1.01-1.24, random effects P = 0.012). In addition, carriers of the minor risk allele rs237889-A showed significantly increased severity scores, as assessed through the autism diagnostic interview - revised (ADI-R), with highly significant increases in social interaction deficits. Our results corroborate the implication of common OXTR variants in the etiology of ASD. There is a need for functional studies to delineate the neurobiological implications of this and other association findings. (172/250). Autism Res 2016, 9: 1036-1045. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
Asunto(s)
Trastorno del Espectro Autista/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de Oxitocina/genética , Alelos , Niño , Genotipo , HumanosRESUMEN
The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Cromatina/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Sinapsis/metabolismo , Transcripción Genética/genética , Secuencia de Aminoácidos , Trastornos Generalizados del Desarrollo Infantil/patología , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina , Exoma/genética , Femenino , Mutación de Línea Germinal/genética , Humanos , Masculino , Datos de Secuencia Molecular , Mutación Missense/genética , Red Nerviosa/metabolismo , Oportunidad RelativaRESUMEN
Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), â¼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Variaciones en el Número de Copia de ADN , Redes y Vías Metabólicas/genética , Niño , Femenino , Redes Reguladoras de Genes , Humanos , Masculino , Familia de Multigenes , Linaje , Eliminación de SecuenciaRESUMEN
Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (N = 192 and N = 254 families, respectively) and report association for rs7170637 (CYFIP1; set 1 and combined sets), rs6923492 (GRM1; combined sets), and rs25925 (CAMK4; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11-1.53; P = 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the "Strict/European" ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75-0.96; P = 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04-1.64; P = 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/genética , Trastornos Generalizados del Desarrollo Infantil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adolescente , Alelos , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/metabolismo , Niño , Trastornos Generalizados del Desarrollo Infantil/etnología , Trastornos Generalizados del Desarrollo Infantil/metabolismo , Trastornos Generalizados del Desarrollo Infantil/patología , Preescolar , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Regulación de la Expresión Génica , Técnicas de Genotipaje , Humanos , Masculino , Plasticidad Neuronal/genética , Unión Proteica , Factores de Riesgo , Transducción de Señal , Población BlancaRESUMEN
While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Alelos , Niño , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Desarrollo del Lenguaje , Masculino , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (nâ=â396 patients and nâ=â659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (Pâ=â0.004, ORâ=â2.37, 95% CIâ=â1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (Pâ=â0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Proteínas del Tejido Nervioso/genética , Eliminación de Secuencia/genética , Sinapsis/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Empalme Alternativo/genética , Línea Celular , Niño , Preescolar , Femenino , Dosificación de Gen/genética , Regulación de la Expresión Génica , Humanos , Masculino , Neuronas/citología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Sitios de Empalme de ARN/genética , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Sinapsis/patología , Distribución Tisular , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Haplotipos/genética , Adulto , Niño , Análisis por Conglomerados , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Femenino , Genotipo , Homocigoto , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Núcleo Familiar , Polimorfismo de Nucleótido SimpleRESUMEN
The Autism Genome Project (AGP) Consortium recently reported genome-wide significant association between autism and an intronic single nucleotide polymorphism marker, rs4141463, within the MACROD2 gene. In the present study we attempted to replicate this finding using an independent case-control design of 1,170 cases with autism spectrum disorder (ASD) (874 of which fulfilled narrow criteria for Autism (A)) from five centers within Europe (UK, Germany, the Netherlands, Italy, and Iceland), and 35,307 controls. The combined sample size gave us a non-centrality parameter (NCP) of 11.9, with 93% power to detect allelic association of rs4141463 at an alpha of 0.05 with odds ratio of 0.84 (the best odds ratio estimate of the AGP Consortium data), and for the narrow diagnosis of autism, an NCP of 8.9 and power of 85%. Our case-control data were analyzed for association, stratified by each center, and the summary statistics were combined using the meta-analysis program, GWAMA. This resulted in an odds ratio (OR) of 1.03 (95% CI 0.944-1.133), with a P-value of 0.5 for ASD and OR of 0.99 (95% CI 0.88-1.11) with P-value = 0.85 for the Autism (A) sub-group. Therefore, this study does not provide support for the reported association between rs4141463 and autism.
Asunto(s)
Trastorno Autístico/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Europa (Continente) , Predisposición Genética a la Enfermedad , Genotipo , HumanosRESUMEN
Despite the skewed sex ratio, few studies have addressed possible cognitive sex differences in autism spectrum disorders (ASDs). This study compared visual attention to detail (ATTD) and selected executive functions (EF) in 35 males and 21 females with higher-functioning ASD and unaffected sibling controls. Females with ASD outperformed males on EF as assessed by the Trail Making Test B-A. Males with ASD showed superior performance for ATTD as measured by the Block Design Test (BD) when compared with females. EF difficulties in males were correlated with more stereotypic behaviours and interests on the Autism Diagnostic Interview-Revised or the Autism Diagnostic Observation Schedule. The results indicated clinically meaningful cognitive sex differences in ASD, particularly an association between EF and stereotypic behaviours and interests. ATTD as a potential basis for specific cognitive strengths (e.g. scientific/savant skills) might be more pronounced in males with ASD.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/psicología , Cognición , Adolescente , Atención , Estudios de Casos y Controles , Niño , Función Ejecutiva , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Pruebas Psicológicas , Factores Sexuales , Conducta EstereotipadaRESUMEN
Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
Asunto(s)
Trastorno Autístico/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Alelos , Variaciones en el Número de Copia de ADN , Bases de Datos Genéticas , Variación Genética , Genoma Humano , Genotipo , Humanos , Factores de Riesgo , Población Blanca/genéticaRESUMEN
The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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Trastornos Generalizados del Desarrollo Infantil/genética , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Variaciones en el Número de Copia de ADN/genética , Dosificación de Gen/genética , Predisposición Genética a la Enfermedad/genética , Estudios de Casos y Controles , Movimiento Celular , Niño , Trastornos Generalizados del Desarrollo Infantil/patología , Citoprotección , Europa (Continente)/etnología , Estudio de Asociación del Genoma Completo , Humanos , Transducción de Señal , Conducta SocialRESUMEN
OBJECTIVES: Increasing admission and prevalence rates of bipolar disorder (BD) are a matter of controversy in international child and adolescent psychiatry. We seek to contribute to this discussion by presenting data obtained in a population of German children and adolescents. METHODS: Nationwide, whole population changes in inpatient admissions of BD and other psychiatric disorders between 2000 and 2007 were analyzed in individuals aged up to 19 years using registry data from the German Federal Health Monitoring System. RESULTS: Inpatient admissions for BD in individuals aged up to 19 years increased from 1.13 to 1.91 per 100,000 or 68.5% between 2000 and 2007 (odds ratio: 1.69; 95% confidence interval: 1.41-2.02), with a nonsignificant decline in children less than 15 years and the largest relative increase in adolescents aged 15-19 years. Inpatient rates for depressive disorders increased by 219.6% and for hyperkinetic disorder by 111.3%. Conduct disorders increased by 18.1%, considerably less than the 38.1% general rise for all mental disorders in children and adolescents. The only significant decline in a diagnostic category occurred for psychotic disorders (-11.8%). BD inpatient admission represented only 0.22% of all mental disorder admissions in 2000 and 0.27% in 2007. CONCLUSIONS: An elevation of inpatient admissions of BD in Germany in adolescents was detected, exceeding the general trend for increased mental disorder admissions. The results may indicate a higher clinical awareness and appreciation of mood symptoms at earlier ages and, in part, a reconceptualization of previously diagnosed psychotic disorders in youth. However, a diagnosis of BD in youngsters is still extremely rare in Germany. Diagnoses were based on the judgment of the treating physician. A correction for multiple admissions in the data set is not possible.
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Trastorno Bipolar/epidemiología , Pacientes Internos/estadística & datos numéricos , Admisión del Paciente/tendencias , Adolescente , Factores de Edad , Trastorno Bipolar/diagnóstico , Niño , Trastorno de la Conducta/diagnóstico , Trastorno de la Conducta/epidemiología , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/epidemiología , Femenino , Alemania/epidemiología , Humanos , Hipercinesia/diagnóstico , Hipercinesia/epidemiología , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/epidemiología , Admisión del Paciente/estadística & datos numéricos , Prevalencia , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/epidemiología , Factores de Tiempo , Adulto JovenRESUMEN
Twin and family studies in autistic disorders (AD) have elucidated a high heritability of AD. In this literature review, we will present an overview on molecular genetic studies in AD and highlight the most recent findings of an increased rate of copy number variations in AD. An extensive literature search in the PubMed database was performed to obtain English published articles on genetic findings in autism. Results of linkage, (genome wide) association and cytogenetic studies are presented, and putative aetiopathological pathways are discussed. Implications of the different genetic findings for genetic counselling and genetic testing at present will be described. The article ends with a prospectus on future directions.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Análisis Mutacional de ADN , Enfermedades en Gemelos/genética , Marcadores Genéticos/genética , Adolescente , Niño , Trastornos Generalizados del Desarrollo Infantil/diagnóstico , Trastornos Generalizados del Desarrollo Infantil/psicología , Mapeo Cromosómico , Análisis Citogenético , Variaciones en el Número de Copia de ADN/fisiología , Asesoramiento Genético , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
BACKGROUND: The relationship of bipolar disorder (BD) and altered thyroid function is increasingly recognized. Recently, a behavioral phenotype of co-occurring deviance on the Anxious/Depressed (A/D), Attention Problems (AP), and Aggressive Behavior (AB) syndrome scales has been identified as the Child Behavior Checklist Dysregulation Profile (CBCL-DP), which itself has been linked to BD. This study tested for differences in thyroid function within a sample of n=114 psychiatric children and adolescents with and without the CBCL-DP. METHOD: A CBCL-DP score was generated based on the composite of the crucial CBCL syndrome scales (A/D, AP, AB). Participants with a CBCL-DP score >or=2.5 SDs above average constituted the CBCL-DP subgroup (n=53). Those with CBCL-DP scores of 1 SD or less above average percentile were regarded as controls (n=61). Groups were compared regarding serum levels of TSH, fT3 and fT4. RESULTS: In participants showing the CBCL-DP, basal serum TSH was elevated compared to controls. More CBCL-DP subjects than controls showed subclinical hypothyroidism. No differences were observed for serum fT3 and fT4 levels. CONCLUSIONS: This is the first study to demonstrate associations between CBCL-DP and subclinical hypothyroidism. Future research should address the long-term outcome of CBCL-DP with coexisting hypothyroidism, the potential benefits of supplementation with thyroid hormone, and the association between severe dysregulation and the bipolar spectrum.
Asunto(s)
Agresión/fisiología , Trastorno de Personalidad Antisocial/sangre , Trastornos de Ansiedad/sangre , Trastorno por Déficit de Atención con Hiperactividad/sangre , Trastorno Bipolar/sangre , Trastorno Depresivo/sangre , Tirotropina/sangre , Adolescente , Agresión/psicología , Trastorno de Personalidad Antisocial/diagnóstico , Trastorno de Personalidad Antisocial/epidemiología , Trastorno de Personalidad Antisocial/psicología , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/psicología , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/epidemiología , Trastorno Bipolar/psicología , Niño , Preescolar , Comorbilidad , Estudios Transversales , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/epidemiología , Trastorno Depresivo/psicología , Femenino , Alemania , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/diagnóstico , Hipotiroidismo/epidemiología , Hipotiroidismo/psicología , Masculino , Pruebas de Función de la Tiroides , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
BACKGROUND: The chronic abuse of Gamma-Hydroxybutyrate (GHB) as a designer drug as well as it's physiological precursors Gamma-Butyrolactone (GBL) and 1,4-Butandiole (1,4-BD) confronts child and adolescent psychiatrists with new challenges. The acute withdrawal of GHB with its cardiovascular and delirant symptoms is of particular importance for child and adolescent psychiatrists. METHODS: In the present paper theoretical and biological aspects of acute GHB-/GBL-/1,4-BD-withdrawal syndrome are presented, and selected cases are discussed as regards potential treatment. RESULTS: High dose treatment with benzodiazepines was successful in some cases of acute GHB-/GBL-/1,4-BD-withdrawal syndrome. Complications were severe dystonia under neuroleptic treatment, and also side-effects of treatment with benzodiazepines. Further problems were vegetative symptoms, electrocardiographic changes, rhabdomyolysis, acute renal failure, and death. CONCLUSION: Acute GHB-withdrawal syndrome is a life-threatening condition which requires immediate intensive care treatment along with continuous monitoring of vital parameters. As acute GHB-withdrawal syndrome can present with symptoms close to psychotic episodes or acute alcohol withdrawal this condition is relevant for child and adolescent psychiatrists.
Asunto(s)
Anestésicos Intravenosos/efectos adversos , Deluciones/inducido químicamente , Oxibato de Sodio/efectos adversos , Síndrome de Abstinencia a Sustancias/diagnóstico , Trastornos Relacionados con Sustancias/rehabilitación , 4-Butirolactona/efectos adversos , Enfermedad Aguda , Adolescente , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Benzodiazepinas/efectos adversos , Benzodiazepinas/uso terapéutico , Butileno Glicoles/efectos adversos , Niño , Cuidados Críticos , Deluciones/diagnóstico , Deluciones/tratamiento farmacológico , Diagnóstico Diferencial , Interacciones Farmacológicas , Humanos , Psicosis Inducidas por Sustancias/diagnóstico , Psicosis Inducidas por Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológicoRESUMEN
We tested the psychometric properties of the Hypomania Checklist (HCL-32) in a sample of nonclinical adolescents, examined the association with current psychopathology, and tested if "hypomanic" adolescents differ from other participants regarding HCL-scores and psychopathology. A total of 294 students completed the HCL-32 and the SDQ, a screening for psychopathology. In adolescence, the internal structure of hypomania seems to be represented by a triple structure. The first factor "active-elated" is an indicator of symptoms related to energy and activity. The adult factor "irritable-risk taking" is better reflected by two separate factors ("disinhibited/stimulation-seeking" and "irritable-erratic"). These factors were associated with externalizing problems. "Hypomanic" adolescents showed higher HCL total and disinhibited/stimulation-seeking scores and reported more conduct problems than "non-hypomanic" youngsters. The internal structure of the HCL in adolescents mirrors the association of juvenile bipolarity with substance use and symptoms of ADHD and conduct disorder and presents preliminary evidence for its validity.
Asunto(s)
Trastorno Bipolar/fisiopatología , Psicometría , Encuestas y Cuestionarios/normas , Adolescente , Trastorno por Déficit de Atención con Hiperactividad , Trastorno de la Conducta , Análisis Factorial , Femenino , Alemania , Humanos , Masculino , Trastornos Relacionados con SustanciasRESUMEN
The objective of this pilot study was to evaluate the effectiveness of a group-based intervention aiming at improving social and communication skills in individuals with autism spectrum disorder. Over a period of 11 months, N = 17 children and adolescents received treatment according to the manualised Frankfurt Social Skills Training (KONTAKT). Parent, teacher, expert and blind expert ratings were assessed to judge outcome regarding peer interaction, autistic behaviours, adaptive functioning and family burden. The participants exhibited improvements pre to follow-up treatment, particularly in the area of autistic symptomatology. Effect sizes (partial eta squared) ranged from 0.02 to 0.69. Among other things, regression models showed a positive influence of IQ and language skills on gains in social skills. Findings indicate that KONTAKT might be useful for enhancing social skills and reducing autism-related psychopathology over time in different contexts. Nevertheless, controlled trials are needed to reassure its effectiveness.