Dopamine transporter (DAT1) and dopamine receptor D4 (DRD4) genotypes differentially impact on electrophysiological correlates of error processing

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ADHD and Criminality: A Primer on the Genetic, Neurobiological, Evolutionary, and Treatment Literature for Criminologists

This paper is a primer on ADHD and its major comorbidities for criminologists unfamiliar with the genetic, neurobiological, and evolutionary literature on the subject. With Unnerver, Cullen & Pratt (2003) we are surprised that criminologists do not pay sufficient attention to a disorder that is found at rates in prisons around the world greatly exceeding in prevalence in the general population. Unnerver, Cullen & Pratt (2003) believe that it is because ADHD research has been carried out primarily by biomedical researchers and that criminologists tend to shy away from anything smacking of biology. We believe that the special expertise of criminologists in uncovering environmental correlates of antisocial behavior can benefit biomedical research and that biomedical research can assist criminologists in uncovering the individual-level correlates of antisocial behavior

Role of Dopaminergic and Noradrenergic Systems as Potential Biomarkers in ADHD Diagnosis and Treatment

This chapter aims to identify, among the dopaminergic and noradrenergic molecules strongly associated to aetiopathogenesis of the disorder, potential genetic and biochemical markers linked to ADHD diagnosis and to assess whether treatments can change peripheral levels of a biomarker, to be then useful, if tested, as a response predictor

Genetic polymorphisms in the serotonin, dopamine and opioid pathways influence social attention in rhesus macaques (Macaca mulatta)

Behaviour has a significant heritable component; however, unpicking the variants of interest in the neural circuits and molecular pathways that underpin these has proven difficult. Here, we present a comprehensive analysis of the relationship between known and new candidate genes from identified pathways and key behaviours for survival in 109 adult rhesus macaques (Macaca mulatta). Eight genes involved in emotion were analysed for variation at a total of nine loci. Genetic data were then correlated with cognitive and observational measures of behaviour associated with wellbeing and survival using MCMC-based Bayesian GLMM in R, to account for relatedness within the macaque population. For four loci the variants genotyped were length polymorphisms (SLC6A4 5-hydroxytryptamine transporter length-polymorphic repeat (5-HTTLPR), SLC6A4 STin polymorphism, Tryptophan 5-hydroxylase 2 (TPH2) and Monoamine oxidase A (MAOA)) whilst for the other five (5-hydroxytryptamine receptor 2A (HTR2A), Dopamine Receptor D4 (DRD4), Oxytocin receptor (OXTR), Arginine vasopressin receptor 1A (AVPR1a), Opioid receptor mu(μ) 1 (OPRM1)) SNPs were analysed. STin genotype, DRD4 haplotype and OXTR haplotype were significantly associated with the cognitive and observational measures of behaviour associated with wellbeing and survival. Genotype for 5-HTTLPR, STin and AVPR1a, and haplotype for HTR2A, DRD4 and OXTR were significantly associated with the duration of behaviours including fear and anxiety. Understanding the biological underpinnings of individual variation in negative emotion (e.g., fear and anxiety), together with their impact on social behaviour (e.g., social attention including vigilance for threat) has application for managing primate populations in the wild and captivity, as well as potential translational application for understanding of the genetic basis of emotions in humans.Acknowledgements: We thank the staff at MRC-CFM, particularly Faye Peters and Sebastian Merritt who assisted with data collection.National Centre for the Replacement, Refinement and Reduction of Animals in Research; funder-id: http://dx.doi.org/10.13039/501100000849; Grant(s): grantNC/L000539/1Liverpool John Moores University; funder-id: http://dx.doi.org/10.13039/501100004144; Grant(s): PhD studentshi

Associations between hypothalamic-pituitary-adrenal axis system gene variants and cortisol reactivity in preschoolers: Main effects and gene-environment interactions

Exposure to stressful events during early development has consistently been shown to produce long lasting effects on the hypothalamic-pituitary-adrenal (HPA) axis, which may increase vulnerability to mood and anxiety disorders. Recently reported genetic association studies indicate that these disorders may be influenced, in part, by gene-environment interactions (GxE) involving polymorphisms within the corticotrophin-releasing hormone and monoaminergic system genes. However, little is known about how genetic variants and life stress work to shape children’s neuroendocrine reactivity and emerging symptoms. Therefore, the aim of this thesis is to examine main effects of candidate genes and GxE on the neuroendocrine stress response and internalizing symptoms in a community sample of 409 preschoolers. In Chapter 2 analyses show associations between variants of the CRHR1 and CRHBP genes and children’s cortisol responses to a standardized laboratory stress task. I also found evidence for GxE, where variants of the CRH system genes moderated the impact of childhood stress on early-emerging symptoms of depression and anxiety. A functional polymorphism of the catechol-O-methyltransferase (COMT) gene, the val158met, has been implicated in the etiology of stress-related mood disorders. Therefore, in Chapter 3, I examined links between the val158met polymorphism, cortisol reactivity to stress, and internalizing symptoms. I found evidence for association between the val158met genotype and cortisol reactivity to stress. Additionally, the val158met genotype moderated the link between childhood stress and emerging symptoms of anxiety. Due to the proposed role of dopamine and serotonin gene polymorphisms in research on GxE in internalizing disorders, in Chapters 4 and 5, I examined whether associations between dopaminergic and serotonin candidate gene polymorphisms and childhood cortisol reactivity and internalizing symptoms were moderated by childhood life stress. Analyses showed evidence for GxE predicting children’s symptoms. Specifically, polymorphisms of DRD2 and DAT1 genes moderated the effect of childhood stress on emerging symptoms of anxiety. With regard to serotonin pathway polymorphisms, I found associations between the serotonin transporter promoter polymorphism (5-HTTLPR) and children’s anxious symptoms. Additionally, consistent with previously reported findings, the interaction between MAOA 30bp VNTR and childhood stress predicted child anxiety symptoms. Limitations of this work include a relatively small sample size for genetic analyses, as well as the examination of a limited number of markers at each gene. Additionally, I did not correct for multiple statistical tests in some analyses due to the hypothesis-driven nature of the work. Taken together, the analyses show the complex underpinnings of individual differences in stress regulation, and highlight specific genetic vulnerabilities that influence early psychophysiological reactivity, that may in turn contribute to the development of stress-related disorders later in development

Environmental and genetic influences on early attachment

Attachment theory predicts and subsequent empirical research has amply demonstrated that individual variations in patterns of early attachment behaviour are primarily influenced by differences in sensitive responsiveness of caregivers. However, meta-analyses have shown that parenting behaviour accounts for about one third of the variance in attachment security or disorganisation. The exclusively environmental explanation has been challenged by results demonstrating some, albeit inconclusive, evidence of the effect of infant temperament. In this paper, after reviewing briefly the well-demonstrated familial and wider environmental influences, the evidence is reviewed for genetic and gene-environment interaction effects on developing early attachment relationships. Studies investigating the interaction of genes of monoamine neurotransmission with parenting environment in the course of early relationship development suggest that children's differential susceptibility to the rearing environment depends partly on genetic differences. In addition to the overview of environmental and genetic contributions to infant attachment, and especially to disorganised attachment relevant to mental health issues, the few existing studies of gene-attachment interaction effects on development of childhood behavioural problems are also reviewed. A short account of the most important methodological problems to be overcome in molecular genetic studies of psychological and psychiatric phenotypes is also given. Finally, animal research focusing on brain-structural aspects related to early care and the new, conceptually important direction of studying environmental programming of early development through epigenetic modification of gene functioning is examined in brief

Genetic Influences on the Neural and Physiological Bases of Acute Threat: A Research Domain Criteria (RDoC) Perspective

The NIMH Research Domain Criteria (RDoC) initiative aims to describe key dimensional constructs underlying mental function across multiple units of analysis—from genes to observable behaviors—in order to better understand psychopathology. The acute threat (“fear”) construct of the RDoC Negative Valence System has been studied extensively from a translational perspective, and is highly pertinent to numerous psychiatric conditions, including anxiety and trauma-related disorders. We examined genetic contributions to the construct of acute threat at two units of analysis within the RDoC framework: (1) neural circuits and (2) physiology. Specifically, we focused on genetic influences on activation patterns of frontolimbic neural circuitry and on startle, skin conductance, and heart rate responses. Research on the heritability of activation in threat-related frontolimbic neural circuitry is lacking, but physiological indicators of acute threat have been found to be moderately heritable (35–50%). Genetic studies of the neural circuitry and physiology of acute threat have almost exclusively relied on the candidate gene method and, as in the broader psychiatric genetics literature, most findings have failed to replicate. The most robust support has been demonstrated for associations between variation in the serotonin transporter (SLC6A4) and catechol-O-methyltransferase (COMT) genes with threat-related neural activation and physiological responses. However, unbiased genome-wide approaches using very large samples are needed for gene discovery, and these can be accomplished with collaborative consortium-based research efforts, such as those of the Psychiatric Genomics Consortium (PGC) and Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium. © 2015 Wiley Periodicals, Inc

Genetic polymorphisms in the serotonin, dopamine and opioid pathways influence social attention in rhesus macaques (Macaca mulatta)

Behaviour has a significant heritable component; however, unpicking the variants of interest in the neural circuits and molecular pathways that underpin these has proven difficult. Here, we present a comprehensive analysis of the relationship between known and new candidate genes from identified pathways and key behaviours for survival in 109 adult rhesus macaques (Macaca mulatta). Eight genes involved in emotion were analysed for variation at a total of nine loci. Genetic data were then correlated with cognitive and observational measures of behaviour associated with wellbeing and survival using MCMC-based Bayesian GLMM in R, to account for relatedness within the macaque population. For four loci the variants genotyped were length polymorphisms (SLC6A4 5-hydroxytryptamine transporter length-polymorphic repeat (5-HTTLPR), SLC6A4 STin polymorphism, Tryptophan 5- hydroxylase 2 (TPH2) and Monoamine oxidase A (MAOA)) whilst for the other five (5- hydroxytryptamine receptor 2A (HTR2A), Dopamine Receptor D4 (DRD4), Oxytocin receptor (OXTR), Arginine vasopressin receptor 1A (AVPR1a), Opioid receptor mu(μ) 1 (OPRM1)) SNPs were analysed. STin genotype, DRD4 haplotype and OXTR haplotype were significantly associated with the cognitive and observational measures of behaviour associated with wellbeing and survival. Genotype for 5-HTTLPR, STin and AVPR1a, and haplotype for HTR2A, DRD4 and OXTR were significantly associated with the duration of behaviours including fear and anxiety. Understanding the biological underpinnings of individual variation in negative emotion (e.g., fear and anxiety), together with their impact on social behaviour (e.g., social attention including vigilance for threat) has application for managing primate populations in the wild and captivity, as well as potential translational application for understanding of the genetic basis of emotions in humans