Age-dependent role of pre- and perinatal factors in interaction with genes on ADHD symptoms across adolescence

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Abstract

Little is known about the effects of risk factors on attention-deficit/hyperactivity disorder (ADHD) symptom over time. Here, we longitudinally studied the role of candidate genes, pre- and perinatal factors, and their interactions on ADHD symptoms between ages 10 and 18 years. Subjects were part of the general population or clinic-referred cohort of the TRacking Adolescents' Individual Lives Survey (n = 1667). At mean ages of 11.1 (T1), 13.4 (T2), and 16.2 years (T3), ADHD symptoms were assessed with the Child Behavior Checklist. Linear Mixed Models were used to examine the association of candidate genes (i.e., DRD4, DRD2, 5-HTTLPR, COMT, and MAOA), pre- and perinatal factors (i.e., index measure of various pregnancy and delivery complications, maternal smoking, maternal drinking, and low birth weight), and their interactions with ADHD symptoms across adolescence. Pregnancy and delivery complications were associated with a higher level of ADHD symptoms across all time points, but with a significantly declining influence over time (p = 0.006). We found no main effects of the candidate genes on ADHD symptoms throughout adolescence. The simultaneous presence of the low activity MAOA genotype and low birth weight (p < 0.001) and of the 5-HTTLPR LL-allele and respectively pregnancy and delivery complications (p = 0.04) and maternal smoking (p = 0.04) were associated with more ADHD symptoms particularly during early adolescence, and these influences significantly decreased over time. Findings suggest an age-dependent role of gene-environment interactions on ADHD symptoms across adolescence.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset disorder with age-inappropriate symptoms of inattention and hyperactivity/impulsivity (American Psychiatric Association, 2013), which tend to decrease over time (Faraone et al., 2006), but with a highly variable long-term course (van Lier et al., 2007). Although genetic (Faraone and Mick, 2010, Gizer et al., 2009), pre- and perinatal factors (most notably maternal smoking during pregnancy and low birth weight; Banerjee et al., 2007), and gene-environment (G×E) interactions (Neuman et al., 2007) have been implicated in the etiology of ADHD, their possibly changing effect over time on ADHD symptoms remains largely unknown. Recent research in twins indicated that inter-individual differences in the overall decline in ADHD symptoms could be explained by genetic and environmental influences that are largely distinct from those influencing the onset of symptoms (Pingault et al., 2015). This is consistent with the idea that the role of risk factors for ADHD may change over time (Thapar et al., 2007).

In contrast to the wealth of cross-sectional studies that investigated genes in association with ADHD (Faraone and Mick, 2010, Gizer et al., 2009, Brookes et al., 2006), few studies have examined the role of genetic factors during the course of ADHD symptoms. The dopamine D4 receptor gene (DRD4) 7-repeat was found to be associated with a more persistent course of ADHD symptom severity over time (Biederman et al., 2009, Langley et al., 2009), whereas the presence of the long version of the serotonin transporter gene (5-HTTLPR) was not associated with the course of ADHD (Biederman et al., 2009).

It is reasonable to assume that pre- and perinatal factors have a long lasting role on ADHD symptoms, given that unfavorable prenatal conditions were linked to persistently high trajectories of ADHD symptoms from infancy to middle childhood (Galéra et al., 2011), and were associated with a diagnosis of ADHD, even up to 40 years after birth (Halmøy et al., 2012). However, no studies are available that examined the role of pre- and perinatal variables on ADHD symptom levels during the course of adolescence.

The aim of the current study was to investigate the association of a number of ADHD candidate genes (DRD4, 5-HTTLPR, dopamine D2 receptor [DRD2], catechol-O-methyl transferase [COMT], and monoamine oxidase A [MAOA]), a set of pre- and perinatal factors (an index of various pregnancy and delivery complications, maternal smoking during pregnancy, maternal drinking during pregnancy, and low birth weight), and their interactions with changing levels of ADHD symptom from early to late adolescence.

Section snippets

Study sample

The present study contained 1667 adolescents (92.0% Dutch descent) of whom genetic information was available and who participated in the first (T1; Mage = 11.09), second (T2; Mage = 13.37), and/or third (T3; Mage = 16.16) wave of the Tracking Adolescents' Individual Lives Survey (TRAILS). TRAILS consists of a general population cohort (n = 2230 at T1) and a parallel clinic-referred cohort (n = 543 at T1; see Oldehinkel et al., 2015, de Winter et al., 2005 for more sample characteristics).

Sample descriptives

Table 1 presents sample characteristics and the genotypic distributions. ADHD symptom severity decreased in a similar pattern in both sexes, with a stronger decline from T1 to T2 than from T2 to T3. ADHD symptom levels in the clinical range were observed for 176 (10.6%) of the adolescents at T1, 118 (7.1%) at T2, and 71 (4.3%) at T3. Subclinical levels were found for 135 adolescents (8.1%) at T1, 137 (8.7%) at T2, and 126 (8.6%) at T3.

Candidate genes during the course of ADHD symptoms

None of the candidate genes were related to ADHD symptoms

Discussion

This study investigated the role of several ADHD candidate genes, pre- and perinatal adversities, and their interactions on ADHD symptom levels across three time points in a pooled population and clinic-referred sample of adolescents from age 10–18 years. Our results indicate age-dependency of a number of G×E interactions on ADHD symptom levels across adolescence; G×E interactions were primarily apparent in early adolescence and tended to level off over time. In line with the literature (

Conclusions

This study supports the notion that genetic factors in interaction with exposure to pre- and perinatal adversities have a changing role during the course of ADHD symptoms beyond childhood. Importantly, our findings suggest that the here reported G×E interactions on ADHD symptom severity decrease over time and may not carry over into adult age. This highlights the importance of taking developmental age into account when studying risk factors for ADHD, especially in cross-sectional studies with

Acknowledgements

This research is part of the TRacking Adolescents' Individual Lives Survey (TRAILS). Participating centers of TRAILS include the University Medical Center and University of Groningen, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Bavo group, all in the Netherlands. TRAILS has been financially supported by various grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940-38-011; ZonMW Brainpower grant

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