Influence of candidate genes on attention problems in children: a longitudinal study

Abstract

Attention problems form one of the core characteristics of Attention-Deficit Hyperactive Disorder (ADHD), a multifactorial neurodevelopmental disorder. From twin research it is clear that genes play a considerable role in the etiology and in the stability of ADHD in childhood. Association studies have focused on genes involved in the dopaminergic and serotoninergic systems, but with inconclusive results. This study investigated the effect of 26 Single Nucleotide Polymorphisms (SNPs) in genes encoding for serotonin receptors 2A (HTR2A), Catechol-O-Methyltransferase (COMT), Tryptophane Hydroxylase type 2 (TPH2), and Brain Derived Neurotrophic Factor (BDNF). Attention problems (AP) were assessed by parental report at ages 3, 7, 10, and 12 years in more than 16,000 twin pairs. There were 1148 genotyped children with AP data. We developed a longitudinal framework to test the genetic association effect. Based on all phenotypic data, a longitudinal model was formulated with one latent factor loading on all AP measures over time. The broad heritability for the AP latent factor was 82%, and the latent factor explained around 55% of the total phenotypic variance. The association of SNPs with AP was then modeled at the level of this factor. None of the SNPs showed a significant association with AP. The lowest p-value was found for the rs6265 SNP in the BDNF gene (p = 0.035). Overall, our results suggest no evidence for a role of these genes in childhood AP.

Fig. 1

Factorial association model. The latent AP factor loads on the longitudinal AP measures (4 maternal (mo) and 4 paternal (fa) at age 3, 7, 10 and 12), reflecting the stability across time and across raters. The effect of the SNP is modeled on the AP means through the AP factor. The arrow between the latent factors reflects the twin correlation. The latent factors e1 to e8 denote unique factors that account for the residual variances of the observed variables (squares). The arrows between the unique factors reflect the twin correlations that allow for age-dependent familial effects. The correlations differ for MZ and DZ twin pairs. Not shown in the Figure (for the sake of clarity), but included in the model: the variance of the AP factor, which is constrained to 1 and the effect of sex on the means