Epigenetics in Developmental Disorder: ADHD and Endophenotypes

Abstract

Heterogeneity in attention-deficit/hyperactivity disorder (ADHD), with complex interactive operations of genetic and environmental factors, is expressed in a variety of disorder manifestations: severity, co-morbidities of symptoms, and the effects of genes on phenotypes. Neurodevelopmental influences of genomic imprinting have set the stage for the structuralphysiological variations that modulate the cognitive, affective, and pathophysiological domains of ADHD. The relative contributions of genetic and environmental factors provide rapidly proliferating insights into the developmental trajectory of the condition, both structurally and functionally. Parent-of-origin effects seem to support the notion that genetic risks for disease process debut often interact with the social environment, i.e., the parental environment in infants and young children. The notion of endophenotypes, markers of an underlying liability to the disorder, may facilitate detection of genetic risks relative to a complex clinical disorder. Simple genetic association has proven insufficient to explain the spectrum of ADHD. At a primary level of analysis, the consideration of epigenetic regulation of brain signalling mechanisms, dopamine, serotonin, and noradrenaline is examined. Neurotrophic factors that participate in the neurogenesis, survival, and functional maintenance of brain systems, are involved in neuroplasticity alterations underlying brain disorders, and are implicated in the genetic predisposition to ADHD, but not obviously, nor in a simple or straightforward fashion. In the context of intervention, genetic linkage studies of ADHD pharmacological intervention have demonstrated that associations have fitted the "drug response phenotype," rather than the disorder diagnosis. Despite conflicting evidence for the existence, or not, of genetic associations between disorder diagnosis and genes regulating the structure and function of neurotransmitters and brainderived neurotrophic factor (BDNF), associations between symptoms-profiles endophenotypes and single nucleotide polymorphisms appear reassuring.

ADHD etiology

“…As reviewed by Elia and colleagues [33] and Archer and colleagues [34], epigenetic factors, impacting during prenatal as well as postnatal periods, are considered important in the etiology of human ADHD and welldesigned studies are clarifying the effects of some contributing factors. For example, the finding that maternal smoking during pregnancy is an environmental factor conferring risk for ADHD in the child is being disproven by studies taking into account inheritance factors [35], similar to what is reported for prenatal alcohol exposure [36].…”

Heterogeneidade cognitiva nas dificuldades de aprendizagem da matemática: uma revisão bibliográfica

“…Os endofenótipos são fenótipos intermediários, subjacente a transtornos que podem facilitar a detecção de riscos genéticos relativos a condição clínica complexa em questão (Archer, Oscar-Berman & Blum, 2011). Por exemplo, memória de trabalho pode ser um endofenótipo em relação ao TDAH.…”

Low Dopamine Function in Attention Deficit/Hyperactivity Disorder: Should Genotyping Signify Early Diagnosis in Children?

“…Complex polygenic and heterogenic mechanisms contribute to variability in the phenotypic manifestation, comorbidities, and the severity of symptoms in neuropsychiatric and developmental disorders. 3 The persistence of childhood ADHD into adolescence and adulthood has been recognized so that the criterion for what constitutes ADHD has been expanded to include more female adolescents and adults. The larger demographic is being diagnosed earlier and treated for longer periods of time with stimulant medication.…”