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2.
J Am Acad Child Adolesc Psychiatry ; 58(6): 618-627, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30825496

RESUMO

OBJECTIVE: Parental age at birth has been shown to affect the rates of a range of neurodevelopmental disorders, but the understanding of the mechanisms through which it mediates different outcomes is still lacking. A population-based cohort was used to assess differential effects of parental age on estimates of risk across pediatric-onset neuropsychiatric disorders: autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and Tourette's disorder/chronic tic disorder (TD/CT). METHOD: The study cohort included all singleton births in Denmark from 1980 through 2007 with full information on parental ages (N = 1,490,745) and was followed through December 31, 2013. Cases of ASD, ADHD, OCD, and TD/CT were identified in the Danish Psychiatric Central Register and the National Patient Register. Associations with parental age were modeled using a stratified Cox regression, allowing for changes in baseline diagnostic rates across time. RESULTS: Younger parental age was significantly associated with increased estimates of risk for ADHD and TD/CT, whereas older parental age was associated with ASD and OCD. Except for OCD, no evidence for differential effects of parental ages on male versus female offspring was observed. CONCLUSION: This study provides novel evidence for the association between age at parenthood and TD/CT and OCD and for the first time shows in a population-based sample that parental age confers differential risk rates for pediatric-onset psychiatric disorders. These results are consistent with a model of shared and unshared risk architecture for pediatric-onset neuropsychiatric conditions, highlighting unique contributions of maternal and paternal ages.

3.
J Clin Psychiatry ; 80(1)2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30549495

RESUMO

The International Society of Psychiatric Genetics (ISPG) created a Residency Education Committee with the purpose of identifying key genetic knowledge that should be taught in psychiatric training programs. Thirteen committee members were appointed by the ISPG Board of Directors, based on varied training, expertise, gender, and national origin. The Committee has met quarterly for the past 2 years, with periodic reports to the Board and to the members of the Society. The information summarized includes the existing literature in the field of psychiatric genetics and the output of ongoing large genomics consortia. An outline of clinically relevant areas of genetic knowledge was developed, circulated, and approved. This document was expanded and annotated with appropriate references, and the manuscript was developed. Specific information regarding the contribution of common and rare genetic variants to major psychiatric disorders and treatment response is now available. Current challenges include the following: (1) Genetic testing is recommended in the evaluation of autism and intellectual disability, but its use is limited in current clinical practice. (2) Commercial pharmacogenomic testing is widely available, but its utility has not yet been clearly established. (3) Other methods, such as whole exome and whole genome sequencing, will soon be clinically applicable. The need for informed genetic counseling in psychiatry is greater than ever before, knowledge in the field is rapidly growing, and genetic education should become an integral part of psychiatric training.


Assuntos
Internato e Residência/métodos , Transtornos Mentais/genética , Psiquiatria/educação , Genética/educação , Genética/ética , Humanos , Transtornos Mentais/tratamento farmacológico , Psicotrópicos/uso terapêutico , Sociedades Médicas
5.
Cell Rep ; 24(13): 3441-3454.e12, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30257206

RESUMO

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.

6.
Nat Commun ; 9(1): 2064, 2018 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-29802345

RESUMO

Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND-CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND-CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND-CAs, and as such likely have diagnostic relevance.

7.
Eur Arch Psychiatry Clin Neurosci ; 268(3): 301-316, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28555406

RESUMO

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.


Assuntos
Saúde da Família , Polimorfismo de Nucleotídeo Único/genética , Transtornos de Tique/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Triptofano Hidroxilase/genética , Adulto Jovem
8.
Biol Psychiatry ; 83(7): 589-597, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29100626

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) has both genetic and environmental origins, including potentially maternal effects. Maternal effects describe the association of one or more maternal phenotypes with liability to ASD in progeny that are independent of maternally transmitted risk alleles. While maternal effects could play an important role, consistent with association to maternal traits such as immune status, no study has estimated maternal, additive genetic, and environmental effects in ASD. METHODS: Using a population-based sample consisting of all children born in Sweden from 1998 to 2007 and their relatives, we fitted statistical models to family data to estimate the variance in ASD liability originating from maternal, additive genetic, and shared environmental effects. We calculated sibling and cousin family recurrence risk ratio as a direct measure of familial, genetic, and environmental risk factors and repeated the calculations on diagnostic subgroups, specifically autistic disorder (AD) and spectrum disorder (SD), which included Asperger's syndrome and/or pervasive developmental disorder not otherwise specified. RESULTS: The sample consisted of 776,212 children of whom 11,231 had a diagnosis of ASD: 4554 with AD, 6677 with SD. We found support for large additive genetic contribution to liability; heritability (95% confidence interval [CI]) was estimated to 84.8% (95% CI: 73.1-87.3) for ASD, 79.6% (95% CI: 61.2-85.1) for AD, and 76.4% (95% CI: 63.0-82.5) for SD. CONCLUSIONS: There was modest, if any, contribution of maternal effects to liability for ASD, including subtypes AD and SD, and there was no support for shared environmental effects. These results show liability to ASD arises largely from additive genetic variation.

9.
BMJ Open ; 7(9): e017172, 2017 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-28928194

RESUMO

OBJECTIVES: Employing national registers for research purposes depends on a high diagnostic validity. The aim of the present study was to examine the diagnostic validity of recorded diagnoses of early-onset obsessive-compulsive disorder (OCD) in the Danish Psychiatric Central Register (DPCR). DESIGN: Review of patient journals selected randomly through the DPCR. METHOD: One hundred cases of OCD were randomly selected from DPCR. Using a predefined coding scheme based on the Children's Yale Brown Obsessive Compulsive Scale (CYBOCS), experienced research nurse or child and adolescent psychiatrists assessed each journal to determine the presence/absence of OCD diagnostic criteria. The detailed assessments were reviewed by two senior child and adolescent psychiatrists to determine if diagnostic criteria were met. PRIMARY OUTCOME MEASUREMENTS: Positive predictive value (PPV) was used as the primary outcome measurement. RESULTS: A total of 3462 children/adolescents received an OCD diagnosis as the main diagnosis between 1 January 1995 and 31 December 2015. The average age at diagnosis was 13.21±2.89 years. The most frequent registered OCD subcode was the combined diagnosis DF42.2. Of the 100 cases we examined, 35 had at least one registered comorbidity. For OCD, the PPV was good (PPV 0.85). Excluding journals with insufficient information, the PPV was 0.96. For the subcode F42.2 the PPV was 0.77. The inter-rater reliability was 0.94. The presence of the CYBOCS in the journal significantly increased the PPV for the OCD diagnosis altogether and for the subcode DF42.2. CONCLUSION: The validity and reliability of International Classification of Disease 10th revision codes for OCD in the DPCR is generally high. The subcodes for predominant obsessions/predominant compulsions are less certain and should be used with caution. The results apply for both children and adolescents and for both older and more recent cases. Altogether, the study suggests that there is a high validity of the OCD diagnosis in the Danish National Registers.


Assuntos
Transtorno Obsessivo-Compulsivo/diagnóstico , Sistema de Registros , Adolescente , Idade de Início , Criança , Transtorno da Personalidade Compulsiva/diagnóstico , Dinamarca , Feminino , Humanos , Classificação Internacional de Doenças , Masculino , Auditoria Médica , Registros Médicos , Variações Dependentes do Observador , Comportamento Obsessivo/diagnóstico , Valor Preditivo dos Testes , Escalas de Graduação Psiquiátrica
10.
J Am Acad Child Adolesc Psychiatry ; 55(9): 784-91, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27566119

RESUMO

OBJECTIVE: We assessed the role of prenatal maternal smoking in risk for Tourette syndrome and chronic tic disorder (TS/CT) and pediatric-onset obsessive-compulsive disorder (OCD). METHOD: In an analysis of 73,073 singleton pregnancies from the Danish National Birth Cohort, we calculated incidence rates (IR) per 1,000 person-year for TS/CT and OCD. We then determined crude and adjusted hazard ratios and 95% CIs associated with prenatal maternal smoking, considering smoking as a dichotomous (yes/no) variable or a stratified variable (no smoking, light smoking, and heavy smoking [≥10 cigarettes/day]). Additional analyses examined the effect of maternal smoking on risk for TS/CT with other comorbid psychiatric conditions. RESULTS: In final adjusted analyses, heavy smoking was associated with a 66% increased risk for TS/CT (adjusted hazard ratio = 1.66, 95% CI = 1.17-2.35). In addition, heavy smoking was associated with a 2-fold increased risk for TS/CT with comorbid attention-deficit/hyperactivity disorder (ADHD), and both light and heavy smoking were associated with a more than 2-fold increased risk for TS/CT with any non-ADHD psychiatric comorbidity. Our parallel analyses of pediatric-onset OCD were likely underpowered but showed similar relationships. CONCLUSION: Prenatal maternal smoking was associated with increased risk for TS/CT as well as TS/CT with comorbid psychiatric conditions, even after adjustment for several important variables, including maternal psychiatric history, socioeconomic status, and partner smoking. Our findings point to a pathway linking prenatal tobacco exposure and altered brain development to TS/CT.


Assuntos
Transtorno Obsessivo-Compulsivo/etiologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Fumar/efeitos adversos , Transtornos de Tique/etiologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Lactente , Masculino , Transtorno Obsessivo-Compulsivo/epidemiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fumar/epidemiologia , Transtornos de Tique/epidemiologia , Síndrome de Tourette/epidemiologia , Síndrome de Tourette/etiologia
11.
J Psychiatr Res ; 82: 126-35, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27494079

RESUMO

Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR = 1.72) and morning sickness requiring medical attention (OR = 2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR = 1.07). Furthermore, neonatal complications were related to the presence (OR = 1.46) and severity (b = 2.27) of co-occurring OCD and also to ADHD severity (b = 1.09). Delivery complications were only related to co-occurring OCD (OR = 1.49). We conclude that early exposure to adverse situations during pregnancy is related to the presence of chronic tic disorders. Exposure at a later stage, at birth or during the first weeks of life, appears to be associated with co-occurring OCD and ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno Obsessivo-Compulsivo/epidemiologia , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/fisiopatologia , Síndrome de Tourette/etiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Estudos de Casos e Controles , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/diagnóstico , Relações Pais-Filho , Gravidez , Escalas de Graduação Psiquiátrica , República da Coreia , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores Sexuais , Transtornos de Tique , Estados Unidos , Adulto Jovem
12.
Neuron ; 87(6): 1215-1233, 2015 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-26402605

RESUMO

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).


Assuntos
Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genética , Loci Gênicos/genética , Variação Genética/genética , Mapas de Interação de Proteínas/genética , Feminino , Humanos , Masculino
13.
JAMA Psychiatry ; 72(4): 359-66, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25692669

RESUMO

IMPORTANCE: Tourette syndrome/chronic tic disorder (TS/CT) and obsessive-compulsive disorder (OCD) overlap in their phenomenological features and often co-occur in affected individuals and families. Understanding how these disorders cluster in families provides important clinical information and is an important step in understanding the causes of these disorders. OBJECTIVE: To determine familial recurrence for TS/CT and OCD using a national epidemiologic sample. DESIGN, SETTING, AND PARTICIPANTS: We performed a population-based study of national health registries in Denmark, including all individuals (n = 1 741 271) born in Denmark from January 1, 1980, through December 31, 2007, and followed up through December 31, 2013. We identified those with TS/CT and/or OCD. MAIN OUTCOMES AND MEASURES: The prevalence of TS/CT and OCD and relative recurrence risk (RRR) for TS/CT or OCD among individuals with an oldest sibling or a parent diagnosed as having TS/CT or OCD compared with individuals without an affected oldest sibling or an affected parent. RESULTS: In this sample, 5596 individuals were diagnosed as having TS/CT; 6191, OCD; and 412, both disorders. The overall cohort prevalence of TS/CT was 0.42% (95% CI, 0.41%-0.43%) and of OCD, 0.84% (95% CI, 0.81%-0.87%). The mean sibling recurrence risk for TS/CT across all birth years was 9.88% (95% CI, 8.02%-12.16%) and for OCD, 4.01% (95% CI, 2.78%-5.76%). The sibling RRR for TS/CT was 18.63 (95% CI, 15.34-22.63). In contrast, the sibling RRR for OCD was 4.89 (95% CI, 3.45-6.93). The parent-offspring RRR for TS/CT was 61.02 (95% CI, 44.43-83.82), whereas the parent-offspring RRR for OCD was 6.25 (95% CI, 4.82-8.11). The sibling and parent-offspring cross-disorder risks were also significant, ranging from 3.20 (95% CI, 2.22-4.62) to 10.27 (95% CI, 5.17-20.39). CONCLUSIONS AND RELEVANCE: Tourette syndrome/CT and OCD cluster in families. The familial aggregation of TS/CT is profound and substantially higher than the familial aggregation for OCD. The recurrence risk estimates provide an important clinical framework for identifying individuals at risk and provide insights into the causes of these disorders.


Assuntos
Saúde da Família/estatística & dados numéricos , Transtorno Obsessivo-Compulsivo/epidemiologia , Transtornos de Tique/epidemiologia , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/complicações , Prevalência , Sistema de Registros , Fatores de Risco , Transtornos de Tique/complicações
14.
Biol Psychiatry ; 77(9): 775-84, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25534755

RESUMO

BACKGROUND: Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. METHODS: Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. RESULTS: Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. CONCLUSIONS: In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Fenótipo , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Transtorno Autístico/fisiopatologia , Transtorno Autístico/psicologia , Família , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
15.
Eur Child Adolesc Psychiatry ; 24(2): 173-83, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24796725

RESUMO

The objective of this study is to compare the time trend of reported diagnoses of autism spectrum disorder (ASD), hyperkinetic disorder, Tourette's syndrome, and obsessive-compulsive disorder across four countries after standardizing the study period, diagnostic codes used to define the conditions and statistical analyses across countries. We use a population-based cohort, including all live-born children in Denmark, Finland, Sweden and Western Australia, from January 1, 1990, through December 31, 2007 and followed through December 31, 2011. The main outcome measure is age-specific prevalence of diagnoses reported to population-based registry systems in each country. We observe an increase in age-specific prevalence for reported diagnoses of all four disorders across birth-year cohorts in Denmark, Finland, Sweden, and (for ASD) Western Australia. Our results highlight the increase in the last 20 years in the number of children and families in contact with health care systems for diagnosis and services for an array of childhood neuropsychiatric disorders, a phenomenon not limited to ASD. Also, the age of diagnosis of the studied disorders was often much higher than what is known of the typical age of onset of symptoms, and we observe limited leveling off in the incidence rate with increasing age.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Transtorno Obsessivo-Compulsivo/epidemiologia , Síndrome de Tourette/epidemiologia , Distribuição por Idade , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Pré-Escolar , Comparação Transcultural , Assistência à Saúde/estatística & dados numéricos , Dinamarca/epidemiologia , Feminino , Finlândia/epidemiologia , Humanos , Incidência , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico , Vigilância da População , Prevalência , Suécia/epidemiologia , Síndrome de Tourette/diagnóstico , Austrália Ocidental/epidemiologia
16.
Psychiatr Clin North Am ; 37(3): 257-67, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25150561

RESUMO

This article reviews the clinical features and neurochemical hypotheses of obsessive-compulsive disorder (OCD) with a focus on the serotonin system. In DSM-5, OCD was moved from the anxiety disorders to a new category of Obsessive-Compulsive and Related Disorders. OCD is a common, typically persistent disorder marked by intrusive and disturbing thoughts (obsessions) and repetitive behaviors (compulsions) that the person feels driven to perform. The preferential efficacy of serotonin reuptake inhibitors (SRIs) in OCD led to the so-called serotonin hypothesis. However, direct support for a role of serotonin in the pathophysiology (e.g., biomarkers in pharmacological challenge studies) of OCD remains elusive. A role of the glutamatergic system in OCD has been gaining traction based on imaging data, genomic studies and animal models of aberrant grooming behavior. These findings have spurred interest in testing the efficacy of medications that modulate glutamate function. A role of glutamate is compatible with circuit-based theories of OCD.


Assuntos
Modelos Neurológicos , Transtorno Obsessivo-Compulsivo , Animais , Humanos , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/epidemiologia , Transtorno Obsessivo-Compulsivo/etiologia
17.
Psychiatr Clin North Am ; 37(3): 319-35, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25150565

RESUMO

Twin and family studies support a significant genetic contribution to obsessive-compulsive disorder (OCD) and related disorders, such as chronic tic disorders, trichotillomania, skin-picking disorder, body dysmorphic disorder, and hoarding disorder. Recently, population-based studies and novel laboratory-based methods have confirmed substantial heritability in OCD. Genome-wide association studies and candidate gene association studies have provided information on specific gene variations that may be involved in the pathobiology of OCD, though a substantial portion of the genetic risk architecture remains unknown.


Assuntos
Transtornos Dismórficos Corporais/genética , Transtorno Obsessivo-Compulsivo/genética , Transtornos de Tique/genética , Síndrome de Tourette/genética , Tricotilomania/genética , Animais , Doença Crônica , Modelos Animais de Doenças , Doenças em Gêmeos/genética , Saúde da Família , Estudos de Associação Genética/métodos , Humanos , Recidiva
18.
Autism Res ; 7(3): 355-62, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24821083

RESUMO

The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença/genética , Adulto , Criança , Feminino , Humanos , Masculino
19.
PLoS One ; 8(8): e70376, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23990902

RESUMO

Obsessive compulsive disorder (OCD) is a syndrome characterized by recurrent and intrusive thoughts and ritualistic behaviors or mental acts that a person feels compelled to perform. Twin studies, family studies, and segregation analyses provide compelling evidence that OCD has a strong genetic component. The SLITRK1 gene encodes a developmentally regulated stimulator of neurite outgrowth and previous studies have implicated rare variants in this gene in disorders in the OC spectrum, specifically Tourette syndrome (TS) and trichotillomania (TTM). The objective of the current study was to evaluate rare genetic variation in SLITRK1 in risk for OCD and to functionally characterize associated coding variants. We sequenced SLITRK1 coding exons in 381 individuals with OCD as well as in 356 control samples and identified three novel variants in seven individuals. We found that the combined mutation load in OCD relative to controls was significant (p = 0.036). We identified a missense N400I change in an individual with OCD, which was not found in more than 1000 control samples (P<0.05). In addition, we showed the the N400I variant failed to enhance neurite outgrowth in primary neuronal cultures, in contrast to wildtype SLITRK1, which enhanced neurite outgrowth in this assay. These important functional differences in the N400I variant, as compared to the wildtype SLITRK1 sequence, may contribute to OCD and OC spectrum symptoms. A synonymous L63L change identified in an individual with OCD and an additional missense change, T418S, was found in four individuals with OCD and in one individual without an OCD spectrum disorder. Examination of additional samples will help assess the role of rare SLITRK1 variation in OCD and in related psychiatric illness.


Assuntos
Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Transtorno Obsessivo-Compulsivo/genética , Adulto , Sequência de Aminoácidos , Animais , Encéfalo/embriologia , Estudos de Casos e Controles , Criança , Feminino , Variação Genética , Humanos , Masculino , Transtornos Mentais/genética , Camundongos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Mutação de Sentido Incorreto , Neuritos/metabolismo , Fenótipo , Homologia de Sequência de Aminoácidos , Síndrome de Tourette/genética
20.
Biol Psychiatry ; 74(8): 576-84, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23746936

RESUMO

BACKGROUND: Brain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort. METHODS: We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters. RESULTS: Gender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC. CONCLUSIONS: Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation.


Assuntos
Transtorno Autístico/patologia , Cabeça/patologia , Característica Quantitativa Herdável , Adulto , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Pesos e Medidas Corporais , Criança , Família , Feminino , Humanos , Inteligência/fisiologia , Masculino
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