Mill J, Petronis A. Pre- and peri-natal environmental risks for attention-deficit hyperactivity disorder (ADHD): the potential role of epigenetic processes in mediating susceptibility. J Child Psychol Psychiatry 49: 1020-1030

Institute of Psychiatry, SGDP Research Centre, London, UK.
Journal of Child Psychology and Psychiatry (Impact Factor: 6.46). 06/2008; 49(10):1020-30. DOI: 10.1111/j.1469-7610.2008.01909.x
Source: PubMed


Attention-deficit hyperactivity disorder (ADHD) is a common childhood neurobehavioural disorder defined by symptoms of developmentally inappropriate inattention, impulsivity and hyperactivity. As is the norm for most psychiatric phenotypes, traditional aetiological studies have focused primarily on the interplay between genetic and environmental factors. It is likely that epigenetic factors, i.e., heritable, but reversible changes to genomic function that are independent of DNA sequence, are also important. It is known that epigenetic processes can be induced following exposure to a range of external factors, and thus provide a mechanism by which the environment can lead to long-term alterations in phenotype. In this article we hypothesise that epigenetic dysregulation may mediate the association observed between early-development environmental insults and ADHD. We propose that understanding the epigenetic processes involved in linking specific environmental pathogens to an increased risk for ADHD may offer new possibilities for preventative and therapeutic intervention.

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    • "We also found effects of neonatal complications on toddler withdrawal, emotional reactivity, and somatic complaints (as well as internalizing problems more broadly), above and beyond genetic risk. In the literature, neonatal complications are more often examined in relation to externalizing problems, ADHD in particular (Ben Amor et al., 2005; Mill & Petronis, 2008). Our findings suggest that neonatal complications may also be important for the development of internalizing problems. "
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    ABSTRACT: This study demonstrates the unique contributions of perinatal risk and genetic and environmental influences on child behavior using data from 561 domestic US adoption triads (birth mothers, adopted child, and adoptive parents). Findings show distinct patterns of associations among genetic (birth mother psychopathology), prenatal (six maternal reported aggregate scores characterizing total obstetric complications, perinatal internalizing symptoms, pregnancy complications, exposure to toxins, substance use, and neonatal complications), and postnatal influences (adoptive parent 18-month internalizing symptoms and over-reactive parenting) and toddler behavior problems (CBCL subscales at 27 months). Findings highlight multiple pathways for toddler’s behavioral development, including genetic, pregnancy, and postnatal main effects. Findings suggest distinct types of pregnancy risk may transmit genetic influences for specific behavior problems rather than broadband problems.
    International Journal of Behavioral Development 07/2013; 37(4):366-375. DOI:10.1177/0165025413489378 · 1.58 Impact Factor
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    • "The cerebellum may be particularly vulnerable to effects of prenatal adversity, as its development begins early in intrauterine life and is markedly protracted (Limperopoulos et al., 2005; Ten Donkelaar et al., 2003; Tiemeier et al., 2010). One measure often used as a proxy for intrauterine conditions is birth weight (Mill and Petronis, 2008). The association of low and very low birth weight (defined as a birth weight b 2500 and b 1500 g respectively) with atypical cognitive and behavioral development is well established (Aarnoudse-Moens et al., 2009; Mick et al., 2002; Nigg and Breslau, 2007; Rice et al., 2007), with a number of neuroimaging studies showing changes in cerebellum in children born with (very) low birth weight (Limperopoulos et al., 2005; Lowe et al., 2011; Parker et al., 2008; Peterson et al., 2000; Shah et al., 2006; Srinivasan et al., 2006; Taylor et al., 2011). "
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    ABSTRACT: This study investigates the effects of XKR4, a recently identified candidate gene for Attention-Deficit/Hyperactivity Disorder (ADHD), birth weight, and their interaction on brain volume in ADHD. XKR4 is expressed in cerebellum and low birth weight has been associated both with changes in cerebellum and with ADHD, probably due to its relation with prenatal adversity. Anatomical MRI scans were acquired in 58 children with ADHD and 64 typically developing controls and processed to obtain volumes of cerebrum, cerebellum and gray and white matter in each structure. DNA was collected from saliva. Analyses including data on birth weight were conducted in a subset of 37 children with ADHD and 51 controls where these data were retrospectively collected using questionnaires. There was an interaction between genotype and birth weight for cerebellum gray matter volume (p = .020). The combination of homozygosity for the G-allele (the allele previously found to be overtransmitted in ADHD) and higher birth weight was associated with smaller volume. Furthermore, birth weight was positively associated with cerebellar white matter volume in controls, but not ADHD (interaction: p = .021). The interaction of genotype with birth weight affecting cerebellum gray matter is consistent with models that emphasize increased influence of genetic risk-factors in an otherwise favorable prenatal environment. The absence of an association between birth weight and cerebellum white matter volume in ADHD suggests that other genetic or environmental effects may be at play, unrelated to XKR4. These results underscore the importance of considering environmental effects in imaging genetics studies.
    Clinical neuroimaging 12/2012; 2(1):103-10. DOI:10.1016/j.nicl.2012.11.010 · 2.53 Impact Factor
    • "Epigenetic differences in methylation have been proposed to contribute to the development of psychiatric disorders including ADHD in comparison with normal controls (for a review see, e.g., Mill and Petronis 2008). McGowan et al. (2009) conducted a study to investigate epigenetic mechanisms in suicide victims (with and without early pathogenic care) and controls. "
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    ABSTRACT: Early pathogenic care that is characterised by disregard for the child's basic emotional needs can lead to severe global psychosocial and cognitive dysfunction and deviant developmental trajectories of brain maturation. Reactive attachment disorder (RAD) is a developmental disorder associated with early pathogenic care that is characterised by markedly disturbed ways of relating socially in most contexts. In addition to other severe emotional dysfunctions, children suffering from RAD often display a high number of comorbid attention deficit/hyperactivity disorder (ADHD) symptoms such as inattention, impulsivity and hyperactivity. It is not yet clear whether ADHD-like symptoms in children exposed to pathogenic care represent a true comorbidity of ADHD or similarities in behavioural dysfunction with a different neurodevelopmental pathway in terms of a phenocopy. In this review, we summarise the findings on the neurobiological consequences of early pathogenic care. Pathogenic care is considered a form of care by a primary caretaker involving a lack or a loss of expectable care, e.g., by early separation, frequent change in caregivers, institutionalisation or neglect. The reviewed studies suggest that a primary dysfunction of limbic brain circuits after early pathogenic care might lead to an interference by motivational or emotional cues impinging on prefrontal executive functions resulting in behavioural similarities with ADHD. Thus, the complex phenotype observed after early pathogenic care might be best described by a dimensional approach with behavioural and neurobiological similarities to ADHD coinciding to a certain degree as a function of early experience. Based on this evidence, suggestions for the treatment of ADHD-like symptoms in children after adverse early life experiences are provided.
    Journal of Neural Transmission 06/2012; 119(9):1023-36. DOI:10.1007/s00702-012-0809-8 · 2.40 Impact Factor
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