RESUMO
Tourette Syndrome (TS) is a heritable, early-onset neuropsychiatric disorder that typically begins in early childhood. Identifying rare genetic variants that make a significant contribution to risk in affected families may provide important insights into the molecular aetiology of this complex and heterogeneous syndrome. Here we present a whole-genome sequencing (WGS) analysis from the 11-generation pedigree (>500 individuals) of a densely affected Costa Rican family which shares ancestry from six founder pairs. By conducting an identity-by-descent (IBD) analysis using WGS data from 19 individuals from the extended pedigree we have identified putative risk haplotypes that were not seen in controls, and can be linked with four of the six founder pairs. Rare coding and non-coding variants present on the haplotypes and only seen in haplotype carriers show an enrichment in pathways such as regulation of locomotion and signal transduction, suggesting common mechanisms by which the haplotype-specific variants may be contributing to TS-risk in this pedigree. In particular we have identified a rare deleterious missense variation in RAPGEF1 on a chromosome 9 haplotype and two ultra-rare deleterious intronic variants in ERBB4 and IKZF2 on the same chromosome 2 haplotype. All three genes play a role in neurodevelopment. This study, using WGS data in a pedigree-based approach, shows the importance of investigating both coding and non-coding variants to identify genes that may contribute to disease risk. Together, the genes and variants identified on the IBD haplotypes represent biologically relevant targets for investigation in other pedigree and population-based TS data.
Assuntos
Neurogênese , Síndrome de Tourette , Pré-Escolar , Humanos , Costa Rica , Haplótipos , Linhagem , Transdução de Sinais , Síndrome de Tourette/genética , Neurogênese/genética , Polimorfismo Genético , Sequenciamento Completo do Genoma , Fator 2 de Liberação do Nucleotídeo Guanina/genéticaRESUMO
Attention deficit hyperactivity disorder (ADHD) is associated with substantial functional impairment in children and in adults. Many individuals with ADHD have clear neurocognitive deficits, including problems with visual attention, processing speed, and set shifting. ADHD is etiologically complex, and although genetic factors play a role in its development, much of the genetic contribution to ADHD remains unidentified. We conducted clinical and neuropsychological assessments of 294 individuals (269 with ADHD) from 163 families (48 multigenerational families created using genealogical reconstruction, 78 affected sib pair families, and 37 trios) from the Central Valley of Costa Rica (CVCR). We used principal components analysis (PCA) to group neurocognitive and behavioral variables using the subscales of the Child Behavior Checklist (CBCL) and 15 neuropsychological measures, and created quantitative traits for heritability analyses. We identified seven cognitive and two behavioral domains. Individuals with ADHD were significantly more impaired than their unaffected siblings on most behavioral and cognitive domains. The verbal IQ domain had the highest heritability (92%), followed by auditory attention (87%), visual processing speed and problem solving (85%), and externalizing symptoms (81%). The quantitative traits identified here have high heritabilities, similar to the reported heritability of ADHD (70-90%), and may represent appropriate alternative phenotypes for genetic studies. The use of multigenerational families from a genetically isolated population may facilitate the identification of ADHD risk genes in the face of phenotypic and genetic heterogeneity.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Comportamento , Irmãos , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Criança , Cognição , Costa Rica , Análise Fatorial , Feminino , Predisposição Genética para Doença , Humanos , Padrões de Herança/genética , Masculino , Modelos Genéticos , Testes Neuropsicológicos , Linhagem , Fenótipo , Análise de Componente Principal , Adulto JovemRESUMO
The aim of this study was to examine the prevalence and clinical correlates of explosive outbursts in two large samples of individuals with Tourette syndrome (TS), including one collected primarily from non-clinical sources. Participants included 218 TS-affected individuals who were part of a genetic study (N=104 from Costa Rica (CR) and N=114 from the US). The relationships between explosive outbursts and comorbid attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), tic severity, and prenatal and perinatal complications were examined using regression analyses. Twenty percent of participants had explosive outbursts, with no significant differences in prevalence between the CR (non-clinical) and the US (primarily clinical) samples. In the overall sample, ADHD, greater tic severity, and lower age of tic onset were strongly associated with explosive outbursts. ADHD, prenatal exposure to tobacco, and male gender were significantly associated with explosive outbursts in the US sample. Lower age of onset and greater severity of tics were significantly associated with explosive outbursts in the CR sample. This study confirms previous studies that suggest that clinically significant explosive outbursts are common in TS and associated with ADHD and tic severity. An additional potential risk factor, prenatal exposure to tobacco, was also identified.
Assuntos
Fúria , Síndrome de Tourette/psicologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Costa Rica/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: While genetic epidemiological studies demonstrate a substantial degree of genetic predisposition for attention-deficit/hyperactivity disorder (ADHD), they also suggest that the genetics are complex and may differ between populations or ethnic groups. OBJECTIVE: This study describes the phenomenology of siblings with ADHD from the genetically isolated population of the Central Valley of Costa Rica. METHODS: Rates of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-defined ADHD subtypes and comorbid conditions were calculated in a sample of 157 ADHD-affected children (probands and siblings) recruited for genetic studies using standardized approaches. Sib-sib comparisons and logistic regressions were conducted to identify significant patterns of concordance. RESULTS: Combined-type ADHD (69.5%) was the most common subtype among probands, followed by the inattentive (27.4%), and hyperactive-impulsive (3.2%) subtypes. Anxiety disorders were prevalent (55.9%), as were disruptive behavior disorders (30.9%) and Tourette disorder (17.0%). Probands and siblings showed high sib-sib concordance for anxiety disorders. CONCLUSIONS: ADHD in Costa Rica is similar in clinical and demographic characteristics to ADHD seen in other parts of the world, although the rates of co-occurring psychiatric disorders differ somewhat from those previously reported in Latin American samples. Comorbid anxiety is prevalent, with high rates of sib-sib concordance, and may represent a distinct, homogeneous subgroup suitable for genetic studies.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtornos Mentais/epidemiologia , Adolescente , Adulto , Idade de Início , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Comorbidade , Costa Rica , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Masculino , Transtornos Mentais/diagnóstico , Prevalência , Índice de Gravidade de Doença , IrmãosRESUMO
Obsessive compulsive disorder (OCD) has a complex etiology that encompasses both genetic and environmental factors. However, to date, despite the identification of several promising candidate genes and linkage regions, the genetic causes of OCD are largely unknown. The objective of this study was to conduct linkage studies of childhood-onset OCD, which is thought to have the strongest genetic etiology, in several OCD-affected families from the genetically isolated population of the Central Valley of Costa Rica (CVCR). The authors used parametric and non-parametric approaches to conduct genome-wide linkage analyses using 5,786 single nucleotide repeat polymorphisms (SNPs) in three CVCR families with multiple childhood-onset OCD-affected individuals. We identified areas of suggestive linkage (LOD score ≥ 2) on chromosomes 1p21, 15q14, 16q24, and 17p12. The strongest evidence for linkage was on chromosome 15q14 (LOD = 3.13), identified using parametric linkage analysis with a recessive model, and overlapping a region identified in a prior linkage study using a Caucasian population. Each CVCR family had a haplotype that co-segregated with OCD across a ~7 Mbp interval within this region, which contains 18 identified brain expressed genes, several of which are potentially relevant to OCD. Exonic sequencing of the strongest candidate gene in this region, the ryanodine receptor 3 (RYR3), identified several genetic variants of potential interest, although none co-segregated with OCD in all three families. These findings provide evidence that chromosome 15q14 is linked to OCD in families from the CVCR, and supports previous findings to suggest that this region may contain one or more OCD susceptibility loci.
Assuntos
Cromossomos Humanos Par 15 , Ligação Genética , Transtorno Obsessivo-Compulsivo/genética , Idade de Início , Mapeamento Cromossômico/métodos , Costa Rica/epidemiologia , Saúde da Família , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Haplótipos , Humanos , Escore Lod , Masculino , Transtorno Obsessivo-Compulsivo/epidemiologia , Linhagem , Polimorfismo de Nucleotídeo Único , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Análise de Sequência de DNA/métodosRESUMO
This research project sought to estimate the prevalence of Attention-Deficit/Hyperactivity Disorder (ADHD) and to determine if the Swanson Nolan and Pelham Rating Scale IV (SNAP-IV) Spanish version is a useful screening tool in a population of Costa Rican school children. The SNAP-IV Spanish version was given to the parents and teachers of 425 children aged 5 to 13 (mean 8.8). All subjects were also assessed with the Swanson, Kotkin, Agler, M-Flynn and Pelham Scale (SKAMP), along with diagnostic confirmation by clinical interview. The sensitivity and specificity of the SNAP-IV was assessed as a predictor of DSM-IV ADHD diagnosis. The point prevalence of Attention Deficit Hyperactivity Disorder (ADHD) in this sample was 5%. The prevalence of ADHD among girls was 7%, while that among boys was 4%. The optimal screen was the teacher-rated SNAP-IV at a 20% cutoff, which had a sensitivity of 96% and specificity of 82%. Parent sensitivities were lower than teacher sensitivities. SNAP-IV teacher ratings with a cutoff isolating the top 20% of scores correctly categorized 87% of children.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Manual Diagnóstico e Estatístico de Transtornos Mentais , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Costa Rica , Humanos , Pais , PrevalênciaRESUMO
BACKGROUND: It has been suggested that attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), both neurodevelopmental disorders with onset in childhood, are highly comorbid, but previous studies examining ADHD and OCD comorbidity have been quite variable, partly because of inconsistency in excluding individuals with tic disorders. Similarly, ADHD has been postulated to be associated with hoarding although this potential relationship is largely methodologically unexplored. This study aimed to examine the prevalence of ADHD among individuals with childhood-onset OCD but without comorbid tic disorders, as well as to examine the relationship between clinically significant hoarding behaviors (hoarding) and ADHD. METHOD: ADHD prevalence rates and the relationship between ADHD and hoarding were examined in 155 OCD-affected individuals (114 probands and 41 relatives, age range 4-82 years) recruited for genetic studies and compared to pooled prevalence rates derived from previously published studies. RESULTS: In total, 11.8% met criteria for definite ADHD, whereas an additional 8.6% had probable or definite ADHD (total=20.4%). In total, 41.9% of participants with ADHD also had hoarding compared to 29.2% of participants without ADHD. Hoarding was the only demographic or clinical variable independently associated with ADHD (odds ratio=9.54, P<0.0001). CONCLUSION: ADHD rates were elevated in this sample of individuals with childhood-onset OCD compared to the general population rate of ADHD, and there was a strong association between ADHD and clinically significant hoarding behavior. This association is consistent with recent studies suggesting that individuals with hoarding may exhibit substantial executive functioning impairments and/or abnormalities, including attentional problems.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno Obsessivo-Compulsivo/psicologia , Adolescente , Adulto , Idade de Início , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Criança , Costa Rica/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/complicações , Transtorno Obsessivo-Compulsivo/epidemiologia , Estados Unidos/epidemiologiaRESUMO
This study compares the presentation and expression of obsessive-compulsive symptoms between a Latin-American and North American sample. In Costa Rica (CR) and the United States (US), respectively, 26 and 52 affected individuals with early-onset obsessive-compulsive disorder (OCD) were recruited. The Yale Brown Obsessive Compulsive Scale (YBOCS), a semi-structured psychiatric interview, and self-report questionnaires were administered. Age of onset and the distribution of OCD across men and women were similar across groups. Both CR and US participants reported obsessions and compulsions, with similar frequencies of symptoms, and contamination, symmetry, and hoarding as the most common symptom subtypes. The US sample had higher YBOCS total severity scores than the Costa Rican group. Similarly, there were significant ethnicity effects for YBOCS compulsion [F(1, 70)=17.88, P<.001] and obsession severity [F(1, 70)=8.78, P<.001], with Caucasians having higher scores than Costa Ricans on both subscales. Comorbidity rates were higher for US Caucasians than Costa Ricans for all disorders; differences were significant for mood disorders [64.7% versus 34.6%], alcohol use [21.3% versus 3.8%], cannabis use disorders [19.1% versus 0%], and other substance use disorders [39.4% versus 0%]. Regression analyses revealed that ethnicity, trait anxiety, and proband status were the only significant predictors of total YBOCS severity. Findings suggest that the core phenotype of OCD is the same in both CR and the US, and perhaps biologically driven. However some features of OCD, such as impairment, may be culturally influenced, leading to differences in prevalence rates and treatment utilization.
Assuntos
Comparação Transcultural , Hispânico ou Latino/psicologia , Transtorno Obsessivo-Compulsivo/etnologia , População Branca/psicologia , Adolescente , Adulto , Idoso , Criança , Costa Rica , Estudos Transversais , Feminino , Hispânico ou Latino/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/psicologia , Determinação da Personalidade/estatística & dados numéricos , Fenótipo , Psicometria , Estados Unidos , População Branca/estatística & dados numéricosRESUMO
BACKGROUND: Tourette Syndrome (TS) has a complex etiology and wide variability in phenotypic expression. Identifying underlying symptom patterns may be useful for etiological and outcome studies of TS. METHODS: Lifetime tic and related symptom data were collected between 1996 and 2001 in 121 TS subjects from the Central Valley of Costa Rica and 133 TS subjects from the Ashkenazi Jewish (AS) population in the US. Subjects were grouped by tic symptoms using an agglomerative hierarchical cluster analysis. Cluster membership was tested for association with available ancillary information (age of onset, tic severity, comorbid disorders, medication treatment and family history). RESULTS: Cluster analysis identified two distinct groups in each sample, those with predominantly simple tics (cluster 1), and those with multiple complex tics (cluster 2). Membership in cluster 2 was correlated with increased tic severity, global impairment, medication treatment, and presence of comorbid obsessive-compulsive symptoms in both samples, and with family history of tics, lower verbal IQ, earlier age of onset, and comorbid obsessive-compulsive disorder and attention-deficit/hyperactivity disorder in the AS sample. CONCLUSIONS: This study provides evidence for consistent and reproducible symptom profiles in two independent TS study samples. These findings have implications for etiological studies of TS.
Assuntos
Tiques/psicologia , Síndrome de Tourette/psicologia , Adolescente , Adulto , Idade de Início , Antipsicóticos/uso terapêutico , Criança , Análise por Conglomerados , Costa Rica/epidemiologia , Análise Fatorial , Família , Feminino , Humanos , Testes de Inteligência , Judeus , Masculino , Transtorno Obsessivo-Compulsivo/epidemiologia , Transtorno Obsessivo-Compulsivo/psicologia , Escalas de Graduação Psiquiátrica , Tiques/tratamento farmacológico , Tiques/epidemiologia , Síndrome de Tourette/tratamento farmacológico , Síndrome de Tourette/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Rare sequence variants may be important in understanding the biology of common diseases, but clearly establishing their association with disease is often difficult. Association studies of such variants are becoming increasingly common as large-scale sequence analysis of candidate genes has become feasible. A recent report suggested SLITRK1 (Slit and Trk-like 1) as a candidate gene for Tourette Syndrome (TS). The statistical evidence for this suggestion came from association analyses of a rare 3'-UTR variant, var321, which was observed in two patients but not observed in more than 2000 controls. We genotyped 307 Costa Rican and 515 Ashkenazi individuals (TS probands and their parents) and observed var321 in five independent Ashkenazi parents, two of whom did not transmit this variant to their affected child. Furthermore, we identified var321 in one subject from an Ashkenazi control sample. Our findings do not support the previously reported association and suggest that var321 is overrepresented among Ashkenazi Jews compared with other populations of European origin. The results further suggest that overrepresentation of rare variants in a specific ethnic group may complicate the interpretation of association analyses of such variants, highlighting the particular importance of precisely matching case and control populations for association analyses of rare variants.