Genetic influences on the stability of attention-deficit/hyperactivity disorder symptoms from early to middle childhood

doi:10.1016/j.biopsych.2004.12.032

Biological Psychiatry

Volume 57, Issue 6, 15 March 2005, Pages 647-654

https://doi.org/10.1016/j.biopsych.2004.12.032 Get rights and content

Background

The high heritability of the core symptoms of attention-deficit/hyperactivity disorder (ADHD) has been repeatedly demonstrated, but few studies to date have investigated the extent to which the same genetic influences operate across development or new genes emerge at different developmental periods.

Methods

We report data from a large, population-based study of approximately 4,000 twin pairs, who have been followed up from early to middle childhood.

Results

Parents’ ratings of ADHD symptoms showed moderate stability across the ages, which was mainly due to shared genetic influences. There was also evidence of additional genetic influences, which were not shared with those acting earlier on, emerging at later age periods. The contribution of environmental influences to the stability of the ADHD symptoms over time was small. Parents’ ratings on the Conners’ DSM-IV ADHD subscale at the last assessment point, at an average age of 8 years, did not show the rater contrast effects that were observed in the parents’ ratings at earlier ages with briefer measures. Similar estimates of genetic and environmental influences were obtained for girls and boys.

Conclusions

We discuss the implications of the findings for molecular genetic studies on ADHD symptomatology.

Section snippets

Sample and procedure

Participants are members of the Twins’ Early Development Study (TEDS; Trouton et al 2002), a birth cohort study of twins born in England and Wales, which invited parents of all twins born in 1994–1996 to enroll. All participants have given informed consent and the study has been approved by the Institute of Psychiatry Ethical Committee (approval number 183/94).

Background information regarding pregnancy, birth, and family demographics was obtained when the twins were 18 months old. The parents

Univariate genetic analyses on Conners’ ADHD symptom scores

A square-root transformation was applied to normalize the distribution. The MZ and DZ within-pair correlations (Table 1) provide rough estimates of the extent to which genetic, shared environmental and child-specific environmental factors contribute to ADHD symptom scores. The greater MZ than DZ correlations indicate substantial genetic effects. The moderately high DZ correlations of .47–.51, which are more than half of the MZ correlations, indicate that contrast effects have not affected the

Discussion

The high heritability of ADHD symptoms has been repeatedly demonstrated, but few studies have investigated the extent to which it is the same genetic influences that operate across development, or new genes emerging at different developmental periods. With a large, population-based twin sample followed up to middle childhood, we demonstrated that stability in ADHD symptom scores is mainly due to shared genetic influences. However, the overlap in the aetiological influences across the ages is

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This suggests that ADHD is the extreme expression of a continuous distribution of symptoms in the population and that the genetic factors that cause ADHD also account for the full range of symptoms in the population. Through development, genetic risk influences both stable and dynamic processes.42,43 The stable component comprises genomic loci common to persistent ADHD and its pediatric form.
Childhood development of psychiatric disorders and related traits
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Genetic research in the area of child and adolescent psychiatry has increased greatly in the past two decades. Through the establishment of large-scale twin studies, which combine longitudinal data collection from early childhood through to adolescence with detailed phenotypic assessments, evidence from twin research has substantially changed our understanding of the etiology and development of childhood psychiatric disorders and related traits. Based on more than 1000 published research articles, it is now clear that genetic factors play an important role in all psychiatric disorders. Yet, the development of child psychiatric problems is the result of a complex interplay between genetic sensitivity and environmental risk-factors. Twin studies have not only established the relative influence of genetic and environmental factors in the etiology of child psychiatric disorders and traits but also clarified developmental stability and change, causes of comorbidity, and begun to unravel complex gene–environment interplay. In this chapter, we provide an overview of what can be concluded about the etiology and development of childhood psychiatric disorders and traits from over two decades of twin research and discuss future direction for the field.
Live fast, die young? A review on the developmental trajectories of ADHD across the lifespan
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Overall, while it is well-established that ADHD is a highly heritable condition with a complex genetic architecture, more research is needed to identify the specific genetic underpinnings of the disorder and its persistence into adulthood. In addition to risk factors stably involved in ADHD throughout the lifespan, the susceptibility to ADHD persistence may be a dynamic process, with specific genetic influences acting at different developmental stages (Chang et al., 2013; Kuntsi et al., 2005). Thus, different sets of genes, and even different alleles at a given risk locus, could be involved in the differentiation between persisting and remitting forms (Franke et al., 2012; Kuntsi et al., 2005) and influence the disorder and associated cognitive deficits differently according to age (gene by age interactions) (Thissen et al., 2015).
Attention-deficit/hyperactivity disorder (ADHD) is highly heritable and the most common neurodevelopmental disorder in childhood. In recent decades, it has been appreciated that in a substantial number of cases the disorder does not remit in puberty, but persists into adulthood. Both in childhood and adulthood, ADHD is characterised by substantial comorbidity including substance use, depression, anxiety, and accidents. However, course and symptoms of the disorder and the comorbidities may fluctuate and change over time, and even age of onset in childhood has recently been questioned. Available evidence to date is poor and largely inconsistent with regard to the predictors of persistence versus remittance. Likewise, the development of comorbid disorders cannot be foreseen early on, hampering preventive measures. These facts call for a lifespan perspective on ADHD from childhood to old age. In this selective review, we summarise current knowledge of the long-term course of ADHD, with an emphasis on clinical symptom and cognitive trajectories, treatment effects over the lifespan, and the development of comorbidities. Also, we summarise current knowledge and important unresolved issues on biological factors underlying different ADHD trajectories. We conclude that a severe lack of knowledge on lifespan aspects in ADHD still exists for nearly every aspect reviewed. We encourage large-scale research efforts to overcome those knowledge gaps through appropriately granular longitudinal studies.
Age-dependent role of pre- and perinatal factors in interaction with genes on ADHD symptoms across adolescence
2017, Journal of Psychiatric Research
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.
A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts
2016, Journal of the American Academy of Child and Adolescent Psychiatry
The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis.
Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated.
SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10⁻⁶ and 2.66 × 10⁻⁶). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96.
The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants.
Assessing aetiological overlap between child and adult attention-deficit hyperactivity disorder symptoms in an extended family design
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Original articlesGenetic influences on the stability of attention-deficit/hyperactivity disorder symptoms from early to middle childhood

Background

Methods

Results

Conclusions

Section snippets

Sample and procedure

Univariate genetic analyses on Conners’ ADHD symptom scores

Discussion

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

Attention deficit hyperactivity disorder in the post-genomic era

European Journal of Child and Adolescent Psychiatry

Current concepts on the neurobiology of Attention-Deficit/Hyperactivity Disorder

J Atten Disord

The revised Conners’ Parent Rating Scale (CPRS-R)factor structure, reliability, and criterion validity

J Abnorm Child Psychol

A model of stability and change in minor psychiatric symptomsresults from three longitudinal studies

Psychol Med Monogr Suppl

Further evidence for the diagnostic continuity between child and adolescent ADHD

J Atten Disord

DNA from buccal swabs recruited by mailevaluation of storage effects on long-term stability and suitability for multiplex polymerase chain reaction genotyping

Behav Genet

Genetic influence on parent-reported attention-related problems in a Norwegian general population twin sample

J Am Acad Child Adolesc Psychiatry

The Strengths and Difficulties Questionnairea research note

J Child Psychol Psychiatry

Developmental change in attention-deficit hyperactivity disorder in boysa four-year longitudinal study

J Abnorm Child Psychol

Emotional and behavioral problems in children

Co-occurrence of ADHD and low IQ has genetic origins

Am J Med Genet

Psychological mechanisms in hyperactivityII The role of genetic factors

J Child Psychol Psychiatry

Original articles
Genetic influences on the stability of attention-deficit/hyperactivity disorder symptoms from early to middle childhood