Risk factors and genetic bases: the case of attention deficit hyperactivity disorder. / Factores de riesgo y bases genéticas: el caso del trastorno por déficit de atención e hiperactividad.

Attention deficit hyperactivity disorder (ADHD) is considered to be the most frequent mental disorder in childhood. Although its diagnosis in the most utilized handbook of psychiatry in the world today - the Diagnostic and statistical handbook of mental disorders (DSM-5) - is based on behaviors of inattention, hyperactivity and impulsivity, numerous attempts to describe the biological bases of the disorder can be found, to be used for and also as risk markers. In this paper, we will critically analyze the validity of studies associated with the search for genetic markers of ADHD. First, a characterization of ADHD by the DSM-5 handbook is presented. Subsequently, the link between ADHD, risk factors and genetic markers is developed. Finally, some conclusions are presented which highlight simplifications and omissions that could have significant consequences.

El trastorno por déficit de atención e hiperactividad (TDAH) es el trastorno mental considerado más frecuente en la infancia. Si bien su diagnóstico en el manual de psiquiatría hoy más utilizado en el mundo, el Diagnostic and statistical manual of mental disorders (DSM-5), se basa en los comportamientos de desatención, hiperactividad e impulsividad, se encuentran numerosos intentos de describir las bases biológicas del trastorno para usarlos con fines de diagnóstico y como marcadores de riesgo. En este trabajo analizamos críticamente la validez de los estudios asociados a la búsqueda de marcadores genéticos para el TDAH. En primer lugar, se presenta la caracterización del TDAH en el manual DSM-5; luego, se desarrolla el vínculo entre el TDAH y los factores de riesgo y los marcadores genéticos; y, finalmente, se presentan algunas conclusiones en las que se señalan simplificaciones y omisiones que pueden tener consecuencias significativas.

Factores de riesgo y bases genéticas: el caso del trastorno por déficit de atención e hiperactividad / Risk factors and genetic bases: the case of attention deficit hyperactivity disorder

RESUMEN El trastorno por déficit de atención e hiperactividad (TDAH) es el trastorno mental considerado más frecuente en la infancia. Si bien su diagnóstico en el manual de psiquiatría hoy más utilizado en el mundo, el Diagnostic and statistical manual of mental disorders (DSM-5), se basa en los comportamientos de desatención, hiperactividad e impulsividad, se encuentran numerosos intentos de describir las bases biológicas del trastorno para usarlos con fines de diagnóstico y como marcadores de riesgo. En este trabajo analizamos críticamente la validez de los estudios asociados a la búsqueda de marcadores genéticos para el TDAH. En primer lugar, se presenta la caracterización del TDAH en el manual DSM-5; luego, se desarrolla el vínculo entre el TDAH y los factores de riesgo y los marcadores genéticos; y, finalmente, se presentan algunas conclusiones en las que se señalan simplificaciones y omisiones que pueden tener consecuencias significativas.

ABSTRACT: Attention deficit hyperactivity disorder (ADHD) is considered to be the most frequent mental disorder in childhood. Although its diagnosis in the most utilized handbook of psychiatry in the world today - the Diagnostic and statistical handbook of mental disorders (DSM-5) - is based on behaviors of inattention, hyperactivity and impulsivity, numerous attempts to describe the biological bases of the disorder can be found, to be used for and also as risk markers. In this paper, we will critically analyze the validity of studies associated with the search for genetic markers of ADHD. First, a characterization of ADHD by the DSM-5 handbook is presented. Subsequently, the link between ADHD, risk factors and genetic markers is developed. Finally, some conclusions are presented which highlight simplifications and omissions that could have significant consequences.

Caracterización, alcances y dificultades de las "bases biológicas" del Trastorno por Déficit de Atención e Hiperactividad (TDAH). Un enfoque desde la Filosofía de la Biología / Caracterização, alcances e dificuldades das "bases biológicas" do Transtorno do Déficit de Atenção e Hiperatividade (TDAH). Uma abordagem a partir da Filosofia da Biologia / Characterization, scope and difficulties of the "biological bases" of attention deficit hyperactivity disorder (ADHD). An approach from the Philosophy of Biology

Resumen El trastorno por déficit de atención e hiperactividad (TDAH) se encuentra entre los trastornos psiquiátricos infantiles más prevalentes en la actualidad y, desde áreas biomédicas y neurobiológicas, se considera que presenta una base biológica. En el presente trabajo se analizarán, desde una aproximación filosófica, los discursos que se despliegan desde dichas investigaciones con el objetivo de detectar y clarificar diversos aspectos fenoménicos, teóricos y ontológicos que le subyacen. En términos generales, hemos encontrado que la conceptualización del TDAH está atravesada por al menos cuatro niveles de organización diferentes: genético-molecular (genes y proteínas), tisular (partes del cerebro), órgano (cerebro como un todo) y el organísmico (individuo). Dichos niveles ocupan roles sumamente diferentes; ocupando los niveles inferiores de organización roles predominantes en lo explicativo así como presentando las entidades fundamentales en términos ontológicos. A su vez, el discurso neurocientífico presenta sesgos relacionados con la pérdida de consideración de la heterogeneidad, la omisión de los niveles superiores al organísmico y simplificaciones del ámbito genético-molecular y de la relación genotipo-fenotipo. Así, el tipo de indagación simplificante y que prepondera los niveles inferiores de la jerarquía biológica parece mostrar más dificultades que éxitos, y epistémicamente muestra grietas que no son saldadas.

Resumo O transtorno do déficit de atenção e hiperatividade (TDAH) encontra-se entre os transtornos psiquiátricos infantis mais prevalecentes na atualidade e considera-se, nas áreas biomédicas e neurobiológicas, que ele apresenta uma base biológica. No presente trabalho serão analisados, a partir de uma perspectiva filosófica, os discursos que se desdobram das pesquisas das áreas referidas, com o objetivo de detectar e esclarecer diversos aspectos fenomênicos, teóricos e ontológicos que lhes são subjacentes. Em termos gerais, encontramos que a conceitualização do TDAH está atravessada por pelo menos quatro níveis de organização diferentes: genético-molecular (genes e proteínas), tissular (partes do cérebro), órgão (cérebro como um todo) e o organismo (indivíduo). Esses níveis ocupam papéis sumamente diferentes, estando nos níveis inferiores de organização papéis predominantes no explicativo, assim como apresentam as entidades fundamentais em termos ontológicos. Por sua vez, o discurso neurocientífico contém um viés relacionado com a perda de consideração da heterogeneidade, a omissão dos níveis superiores ao organismo e simplificadores do âmbito genético-molecular e da relação genótipo-fenótipo. Assim, o tipo de indagação simplificadora e preponderante dos níveis inferiores da hierarquia biológica parece mostrar mais dificuldades que êxitos e epistemicamente mostra fissuras que não saldadas.

Abstract Attention deficit hyperactivity disorder (ADHD) is among the most prevalent psychiatric disorders in children at present and, from biomedical and neurobiological areas, it is considered to have a biological basis. In the present work we analyzed from a philosophical approach, the discourses deployed from these investigations in order to detect and clarify various phenomenal, theoretical and ontological aspects that underlie it. In general terms, we have found that the conceptualization of ADHD is traversed by at least four different organizational levels: genetic-molecular (genes and proteins), tissue (parts of the brain), organ (brain as a whole) and the organismic (individual). These levels occupy very different roles; lower levels of organization occupying predominant explanatory roles as well as presenting the fundamental entities in ontological terms. In turn, the neuroscientific discourse presents biases related to the loss of consideration of heterogeneity, the omission of levels superior to organismic and simplifications of the genetic-molecular domain and the genotype-phenotype relation. Thus, the type of simplifying inquiry in the lower levels of the biological hierarchy seems to show more difficulties than successes, and epistemically shows cracks that are not settled.

Positive selection in nucleoporins challenges constraints on early expressed genes in Drosophila development.

Developmental conservation among related species is a common generalization known as von Baer's third law and implies that early stages of development are the most refractory to change. The "hourglass model" is an alternative view that proposes that middle stages are the most constrained during development. To investigate this issue, we undertook a genomic approach and provide insights into how natural selection operates on genes expressed during the first 24 h of Drosophila ontogeny in the six species of the melanogaster group for which whole genome sequences are available. Having studied the rate of evolution of more than 2,000 developmental genes, our results showed differential selective pressures at different moments of embryogenesis. In many Drosophila species, early zygotic genes evolved slower than maternal genes indicating that mid-embryogenesis is the stage most refractory to evolutionary change. Interestingly, positively selected genes were found in all embryonic stages even during the period with the highest developmental constraint, emphasizing that positive selection and negative selection are not mutually exclusive as it is often mistakenly considered. Among the fastest evolving genes, we identified a network of nucleoporins (Nups) as part of the maternal transcriptome. Specifically, the acceleration of Nups was driven by positive selection only in the more recently diverged species. Because many Nups are involved in hybrid incompatibilities between species of the Drosophila melanogaster subgroup, our results link rapid evolution of early developmental genes with reproductive isolation. In summary, our study revealed that even within functional groups of genes evolving under strong negative selection many positively selected genes could be recognized. Understanding these exceptions to the broad evolutionary conservation of early expressed developmental genes can shed light into relevant processes driving the evolution of species divergence.