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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    • "Prenatal ischemia-hypoxia is a common element to multiple early risk factors for ADHD including maternal smoking [Bush et al., 2000] and maternal alcohol use during pregnancy [Bosco and Diaz, 2012] as well as ischemia-hypoxia related obstetric complications [Pineda et al., 2007; Rennie et al., 2007; Getahun et al., 2013]. Consistent with the Developmental Origins of Health and Disease (DOHaD) framework [Gluckman et al., 2004; Mill et al., 2008; Swanson and Wadhwa, 2008; Swanson et al., 2009; Wadhwa et al., 2009], the association between lower birth weight and ADHD may arise from prenatal ischemia-hypoxia. Prenatal ischemia-hypoxia may directly disrupt or delay development or lead to structural or functional adaptations to the adverse intrauterine environment. "
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    ABSTRACT: Low birth weight is associated with increased risk for Attention-Deficit/Hyperactivity Disorder (ADHD); however, the etiological underpinnings of this relationship remain unclear. This study investigated if genetic variants in angiogenic, dopaminergic, neurotrophic, kynurenine, and cytokine-related biological pathways moderate the relationship between birth weight and ADHD symptom severity. A total of 398 youth from two multi-site, family-based studies of ADHD were included in the analysis. The sample consisted of 360 ADHD probands, 21 affected siblings, and 17 unaffected siblings. A set of 164 SNPs from 31 candidate genes, representing five biological pathways, were included in our analyses. Birth weight and gestational age data were collected from a state birth registry, medical records, and parent report. Generalized Estimating Equations tested for main effects and interactions between individual SNPs and birth weight centile in predicting ADHD symptom severity. SNPs within neurotrophic (NTRK3) and cytokine genes (CNTFR) were associated with ADHD inattentive symptom severity. There was no main effect of birth weight centile on ADHD symptom severity. SNPs within angiogenic (NRP1 & NRP2), neurotrophic (NTRK1 & NTRK3), cytokine (IL16 & S100B), and kynurenine (CCBL1 & CCBL2) genes moderate the association between birth weight centile and ADHD symptom severity. The SNP main effects and SNP × birth weight centile interactions remained significant after adjusting for multiple testing. Genetic variability in angiogenic, neurotrophic, and inflammatory systems may moderate the association between restricted prenatal growth, a proxy for an adverse prenatal environment, and risk to develop ADHD. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Oct 2014 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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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.
    Full-text · Article · Jul 2013 · International Journal of Behavioral Development
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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.
    Full-text · Article · Dec 2012 · Clinical neuroimaging
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