Testing allele homogeneity: the problem of nested hypotheses

Background: The evaluation of associations between genotypes and diseases in a case-control framework plays an important role in genetic epidemiology. This paper focuses on the evaluation of the homogeneity of both genotypic and allelic frequencies. The traditional test that is used to check allelic homogeneity is known to be valid only under Hardy-Weinberg equilibrium, a property that may not hold in practice. Results: We first describe the flaws of the traditional (chi-squared) tests for both allelic and genotypic homogeneity. Besides the known problem of the allelic procedure, we show that whenever these tests are used, an incoherence may arise: sometimes the genotypic homogeneity hypothesis is not rejected, but the allelic hypothesis is. As we argue, this is logically impossible. Some methods that were recently proposed implicitly rely on the idea that this does not happen. In an attempt to correct this incoherence, we describe an alternative frequentist approach that is appropriate even when Hardy-Weinberg equilibrium does not hold. It is then shown that the problem remains and is intrinsic of frequentist procedures. Finally, we introduce the Full Bayesian Significance Test to test both hypotheses and prove that the incoherence cannot happen with these new tests. To illustrate this, all five tests are applied to real and simulated datasets. Using the celebrated power analysis, we show that the Bayesian method is comparable to the frequentist one and has the advantage of being coherent. Conclusions: Contrary to more traditional approaches, the Full Bayesian Significance Test for association studies provides a simple, coherent and powerful tool for detecting associations

Atualização sobre a Síndrome de Tourette

A síndrome de Tourette tem sido cada vez mais diagnosticada e tratada na rede de atenção primária e em consultórios privados. Na prática clínica vemos que a maioria recebe antipsicóticos. Este artigo objetiva fazer uma atualização do seu tratamento e mostrar que existem alternativas terapeutas mais seguras, como a clonidina. Os antipsicóticos típicos e atípicos podem ser deixados para uma segunda escolha

Genetic association studies in obsessive-compulsive disorder

BACKGROUND: Obsessive-compulsive disorder (OCD) segregates in families. It follows a complex model of genetic transmission, which involves the influence of several small effect genes interacting with the environment. METHODS: A systematic review of genetic association studies in OCD was performed. Articles published until 2012 were searched in the databases PubMed, Embase and SciELO using the terms of MeSH and its associates or synonyms for obsessive-compulsive disorder, gene and genetic association studies. RESULTS: We selected 105 papers and described their main results grouped as genes related to: serotonin, dopamine, glutamate, GABA, white matter, immune system, hormones and other genes. CONCLUSION: There is high variability between findings of association studies among the several candidate genes studied in OCD. Glutamate-related genes are promising candidates for OCD, but there is no conclusive association between any of the candidate genes studied and OCD. Association studies with large sample size, evaluation of more homogeneous subgroups of phenotype and meta-analyses are still needed.INTRODUÇÃO: O caráter familial do transtorno obsessivo-compulsivo (TOC) já é bem estabelecido. Ele segue o modelo complexo de transmissão genética que envolve a influência de diversos genes de pequeno efeito em interação com o ambiente. MÉTODOS: Foi realizada uma revisão sistemática de estudos de associação genética com o TOC por meio de busca de artigos publicados até 2012 nas bases de dados: PubMed, Embase e SciELO, usando os termos MeSH, seus associados ou sinônimos para obsessive-compulsive disorder, gene e genetic association studies. RESULTADOS: Foram selecionados 105 artigos cujos principais resultados foram agrupados em grupos de genes relacionados a serotonina, dopamina, glutamato, GABA, substância branca, hormônios, sistema imune e outros genes (MAO-A, BNDF, COMT). CONCLUSÃO: Há grande variabilidade nos achados de estudos de associação entre os diversos genes candidatos estudados e o TOC. Genes relacionados às vias glutamatérgicas são candidatos promissores, porém não há associação conclusiva entre nenhum dos genes candidatos estudados e o TOC. Estudos de associação com grande tamanho amostral, avaliação de subgrupos mais homogêneos do fenótipo e metanálises ainda são necessários.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade de São Paulo Faculdade de Medicina Departamento e Instituto de PsiquiatriaUniversidade Federal da Bahia Serviço Médico Universitário Dr. Rubens BrasilUFBA Faculdade de Medicina Departamento de Neurociências e Saúde MentalUniversidade Federal de São Paulo (UNIFESP) Departamento de PsiquiatriaUNIFESP, Depto. de PsiquiatriaSciEL

An Inherited Small Microdeletion at 15q13.3 in a Patient with Early- Onset Obsessive-Compulsive Disorder

Copy number variations (CNVs) have been previously associated with several different neurodevelopmen al psychiatric disorders, such as autism, schizophrenia, and attention deficit hyperactivity disorder (ADHD). the present study consisted of pilot genorne-wide screen for CNVs in a cohort of 16 patients with early-onset obsessive-compulsive disorder (OCD) and 2 mentally healthy individuals, using array-based comparative enomic hybridization (aCGH) on 44K arrays. A small rare nal inherited microdeletion (-64 kb) was identified in chromosome 15q13.3 of one male patient with very early onset have OCD. the deletion encompassed part of the FA/IN1 gene, which is involved with the glutamatergic system This finding supports the hypothesis of a complex network of several genes expressed in the brain cant ibuting for h genetic risk of OCD, and also supports the glutamatergic involvement in OCD, which has been previsously reported in the literature.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ São Paulo, Sch Med, Inst & Dept Psychiat, São Paulo, BrazilUniv São Paulo, Inst Math & Stat, Inter Inst Grad Program Bioinformat, São Paulo, BrazilAC Camargo Canc Ctr, Int Res Ctr, São Paulo, BrazilSão Paulo State Univ, Sch Med, São Paulo, BrazilUniversidade Federal de São Paulo, UPIA, São Paulo, BrazilUniversidade Federal de São Paulo, UPIA, São Paulo, BrazilFAPESP: 2008/11537-7CNPq: MCT/CNPq 14/2008Web of Scienc

An Inherited Small Microdeletion at 15q13.3 in a Patient\ud with Early- Onset Obsessive-Compulsive Disorder

Copy number variations (CNVs) have been previously associated with several different neurodevelopmental psychiatric\ud disorders, such as autism, schizophrenia, and attention deficit hyperactivity disorder (ADHD). The present study consisted of\ud a pilot genome-wide screen for CNVs in a cohort of 16 patients with early-onset obsessive-compulsive disorder (OCD) and\ud 12 mentally healthy individuals, using array-based comparative genomic hybridization (aCGH) on 44K arrays. A small rare\ud paternal inherited microdeletion (,64 kb) was identified in chromosome 15q13.3 of one male patient with very early onset\ud OCD. The father did not have OCD. The deletion encompassed part of the FMN1 gene, which is involved with the\ud glutamatergic system. This finding supports the hypothesis of a complex network of several genes expressed in the brain\ud contributing for the genetic risk of OCD, and also supports the glutamatergic involvement in OCD, which has been\ud previously reported in the literature.We wish to thank the patients and heathy controls who volunteered to participate in this study.This study was supported by grants to Dras Cappi and Brentani from the Foundation for Research Support of the State of São Paulo (FAPESP); grant number: 2008/11537-7, and from the Brazilian National Council for Scientific and Technological Development (CNPq; protocol number MCT/CNPq 14/2008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

COMT and MAO-A Polymorphisms and Obsessive-Compulsive Disorder: A Family-Based Association Study

ObjectiveObsessive-compulsive disorder (OCD) is a common and debilitating psychiatric illness. Although a genetic component contributes to its etiology, no single gene or mechanism has been identified to the OCD susceptibility. the catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAO-A) genes have been investigated in previous OCD studies, but the results are still unclear. More recently, Taylor (2013) in a comprehensive meta-analysis of genetic association studies has identified COMT and MAO-A polymorphisms involved with OCD. in an effort to clarify the role of these two genes in OCD vulnerability, a family-based association investigation was performed as an alternative strategy to the classical case-control design.MethodsTransmission disequilibrium analyses were performed after genotyping 13 single-nucleotide polymorphisms (eight in COMT and five in MAO-A) in 783 OCD trios (probands and their parents). Four different OCD phenotypes (from narrow to broad OCD definitions) and a SNP x SNP epistasis were also analyzed.ResultsOCD, broad and narrow phenotypes, were not associated with any of the investigated COMT and MAO-A polymorphisms. in addition, the analyses of gene-gene interaction did not show significant epistatic influences on phenotype between COMT and MAO-A.ConclusionsThe findings do not support an association between DSM-IV OCD and the variants of COMT or MAO-A. However, results from this study cannot exclude the contribution of these genes in the manifestation of OCD. the evaluation of broader spectrum phenotypes could help to understand the role of these and other genes in the pathophysiology of OCD and its spectrum disorders.Brazilian governmental agenciesConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundo de Aprimoramento Academico (FUAA-Grant for Academic Improvement)Department of Psychiatry University of São Paulo School of MedicineUniv São Paulo, Fac Med, Dept & Inst Psychiat, São Paulo, SP, BrazilUniv Fed Bahia, Serv Med Univ, Salvador, BA, BrazilUniv Pernambuco, Fac Ciencias Med, Recife, PE, BrazilUniversidade Federal de São Paulo, São Paulo, SP, BrazilBritish Columbia Mental Hlth & Addict Res Inst, Vancouver, BC, CanadaMassachusetts Gen Hosp, PNGU, Boston, MA 02114 USAMassachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USAUniv Calif San Francisco, Dept Psychiat, San Francisco, CA USAHosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, CanadaUniv Michigan, Dept Psychiat, Ann Arbor, MI 48109 USASunnybrook Hlth Sci Ctr, Frederick W Thompson Anxiety Disorders Ctr, Toronto, ON M4N 3M5, CanadaUniv Toronto, Ctr Addict & Mental Hlth, Toronto, ON, CanadaUniv Fed Rio de Janeiro, Inst Psiquiatria, IPUB, Programa Ansiedade & Depressao, Rio de Janeiro, BrazilUniv São Paulo, Inst Math & Stat, Dept Stat, São Paulo, SP, BrazilUniversidade Federal de São Paulo, São Paulo, SP, BrazilCNPq: 573974/2008-0FAPESP: 2005/55628-08FAPESP: 2008/57896-8Web of Scienc

Neurobiology of Tourette\u27s syndrome: the autoimmune post-streptococcal hypothesis

CONTEXTO: A síndrome de Tourette (ST) caracteriza-se pela presença de tiques motores e pelo menos um tique fônico. Algumas semelhanças clínicas com a coréia reumática ou de Sydenham (CS) incentivaram a formulação da hipótese da existência de um grupo de transtornos neuropsiquiátricos associados a processo auto-imune decorrente de infecção estreptocócica (PANDAS). OBJETIVO: Revisar a literatura quanto às evidências em relação à hipótese de que mecanismos auto-imunes pós-estreptocócicos estão envolvidos na etiopatogênese da ST. MÉTODOS: Revisão sistemática na base de dados MedLine com os termos "Tourette", "tic", "PANDAS", "antibodies", "streptococcal" e "rheumatic". RESULTADOS: Retornaram 238 artigos da busca. Selecionaram-se 53 trabalhos, os quais tiveram suas referências bibliográficas também revisadas. São apresentados os resultados de estudos que avaliaram aspectos imunes na ST, incluindo anticorpos antiestreptocócicos e antinúcleos da base, e sua terapêutica imunebaseada, discutindo a validade do conceito de PANDAS. CONCLUSÕES: As evidências ainda não são satisfatórias no que tange a uma base auto-imune pós-estreptocócica para a ST. Um aprimoramento dos métodos investigativos e na seleção das amostras pode trazer maiores contribuições à questão.BACKGROUND: Tourette\u27s syndrome (TS) is characterized by the presence of motor tics and at least one phonic tic. Some clinical similarities with Sydenham\u27s chorea (SC) lead to the hypothesis of a new group of disorders associated with an autoimmune process due to a streptococcal infection (PANDAS). Objective: To review the literature in search of evidence on the existence of post-streptococcal autoimmune mechanisms involved with the etiopathogenesis of TS. METHODS: A systematic review with the terms "Tourette", "tic", "PANDAS", "antibodies", "streptococcal" and "rheumatic" was carried on using the MedLine. RESULTS: The search found 238 articles. Fifty and three articles were selected which also had their references reviewed. The results of studies that investigated autoimmune aspects of TS, including anti-streptococcal and anti-basal ganglia anti-bodies, and immune-based therapy, were presented and discussed. DISCUSSION: The evidences to date are not satisfactory regarding a post-streptococcal auto-immune process in ST. The improvement on investigative methods and sample selection might contribute to this question

Mechanical behaviour of corrugated laminates

The present research work intends to perform a wide set of structural analyses upon corrugated composite laminated panels and based on these analyses, to assess their mechanical response in correspondence to the constructive solutions, which may range from the composite materials selection to the geometrical features and other modelling parameters. To improve the mechanical performance of those panels one may consider enhancing their geometrical characteristics, their corrugation shape configuration and the materials used to build them. In this latter case, when considering materials selection, laminated composites may also constitute an important alternative. In any case it is considered necessary to assess the impact that each of these parameters may have in the static and in the free vibration behaviour of the structures, in a comprehensive and detailed way. To achieve the main objective of this research work, a comprehensive and diversified set of case studies is considered in order to characterize the influence that each of the modelling, material and geometrical parameters and characteristics may have in the mechanical response of a corrugated panel. This study allowed concluding that for the wide set of design parameters considered, the fibre orientation and corrugation parameters are the ones responsible for the majority of the significantly improved performances.info:eu-repo/semantics/publishedVersio