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30 Oct 2021

Rahman S et al. BMC Medicine 2021; 19: 229

Genetic factors, as well as other factors including birth weight, have been implicated in the onset of ADHD traits among children. This study aimed to elucidate to what extent the genetic risk of ADHD moderates the association between low birth weight and ADHD traits among Japanese children.

This study used data from the Hamamatsu Birth Cohort for Mothers and Children (HBC) study* (Takagai et al, 2016), which is a birth-cohort study of children born in Hamamatsu City, Japan, between November 2007 and March 2011. Birth weight was categorised as <2000 g, ≥2000 to ≤2499 g (intermediate) and ≥2500 g (normal). Polygenic risk score for ADHD (ADHD-PRS) was generated using participants’ genomic data from the HBC study, and the ADHD Rating Scale IV (ADHD-RS-IV) was utilised to assess ADHD traits (inattention and hyperactivity/impulsivity) based on parental reports. Multivariable negative binomial regression was applied to evaluate the association between birth weight and ADHD traits, whilst adjusting for potential covariates.

In total, 796 of 826 children (50.8% males) in the HBC study (N=1258) who were successfully followed up until age 8 to 9 years were included in this study, as well as their parents. The mean (standard deviation [SD]) birth weight and gestational age at birth were 2949.3 (440.1) g and 38.9 (1.52) weeks, respectively. The majority (87.3%) of children had a birth weight of ≥2500 g, whilst 10.3% had a birth weight of ≥2000 to ≤2499 g, and 2.4% had a birth weight <2000 g. The median (interquartile range) scores for ADHD combined traits were significantly higher among children who had a lower birth weight (10 [4–15], 4 [1–8] and 5 [1–10] for <2000 g, ≥2000 to ≤2499 and ≥2500 g, respectively; p<0.008), and similar findings were observed for both inattention and hyperactivity traits.

Independent effects of birth weight and ADHD

In the negative binomial models, birth weight was not significantly associated with ADHD score when considered continuous; however, when considered categorical, birth weight <2000 g was significantly associated with higher ADHD trait scores (rate ratio [RR] 1.60; 95% confidence interval [CI] 1.16–2.22). Similar findings were observed for both inattention (RR 1.50; 95% CI 1.10–2.06) and hyperactivity (RR 1.82; 95% CI 1.17–2.83) traits, compared with ≥2500 g. This significance remained after adjusting for potential covariates for both inattention (RR 1.49; 95% CI 1.15–1.94) and hyperactivity traits (RR 1.78; 95% CI 1.19–2.67).

Effects of genetic risk of ADHD and birth weight on ADHD traits

A significant interaction effect of birth weight categories and ADHD-PRS on ADHD scores was observed (Wald Chi-Squared Test, p<0.05 for ADHD total score), therefore interaction of birth weight categories and binary polygenic risk variables were included in the model. Higher genetic risk of ADHD and birth weight <2000 g were associated with more severe ADHD traits (RR 1.82; 95% CI 1.10–3.01) compared with those with lower genetic risk or those in the ≥2500 g birth weight category, and similar findings were observed for both inattention and hyperactivity traits. Birth weight <2000 g and higher genetic risk of ADHD were significantly associated with higher scores of inattention (RR 1.70; 95% CI 1.02–2.83) and hyperactivity (RR 2.10; 95% CI 1.10–3.98). After adjusting for potential confounders, these results remained statistically significant for inattention (RR 1.56; 95% CI 1.07–2.27) and hyperactivity (RR 1.87; 95% CI 1.14‍–‍3.06) traits.

The authors discussed the limitations of this study. Firstly, they noted that the sample size was relatively small, particularly due to the exclusion of participants without genomic DNA collection, and was only comprised of Japanese children. Therefore, the generalisability of the findings is limited to this study population. Furthermore, the study lacked diagnostic assessment of ADHD and ADHD traits were measured based on parental reports on their children using ADHD-RS-IV, which may be biased due to social desirability. In addition, participants with ADHD-PRS values higher than the median were considered as having ‘higher genetic risk than average for ADHD’, since PRS was classified into a binary variable, using the median value as the threshold, to facilitate interpretation. Caution should therefore be taken when generalising the results of this study because ‘higher genetic risk’ in this study indicates a higher risk than the average population.

It was concluded by the authors that birth weight <2000 g was significantly associated with an increase in the severity of inattention, hyperactivity, and combined ADHD traits among Japanese children aged 8 to 9 years in this study. Further to this, they stated that the presence of higher genetic risk for ADHD among children with reduced birth weight further elevates such risk. The authors proposed that implementing effective interventions aimed at reducing the incidence of low birth weight, especially among children whose parents have known ADHD symptoms and diagnoses, may reduce the risk of developing ADHD.

Read more about the association between birth weight and ADHD traits here


*The HBC study was designed to investigate the neurodevelopmental trajectories of Japanese children in the general population (Takagai S et al, 2016)
Polygenic risk score (PRS) represents the approximate genetic liability for a disease or disorder using the number of risk alleles from a set of single genetic variants (Lewis & Vassos, 2017)
Sex of the child, birth order of the child, gestational age at birth, mother’s age at delivery, educational attainment, pre-pregnancy body mass index, pre-pregnancy or during-pregnancy smoking status, alcohol consumption during pregnancy, father’s age at birth of child, father’s educational attainment and annual family income at birth were considered as potential covariates

Disclaimer: The views expressed here are the views of the author(s) and not those of Takeda.

Lewis CM, Vassos E. Prospects for using risk scores in polygenic medicine. Genome Med 2017; 9: 96.

Rahman MS, Takahashi N, Toshiki Iwabuchi, et al. Elevated risk of attention deficit hyperactivity disorder (ADHD) in Japanese children with higher genetic susceptibility to ADHD with a birth weight under 2000 g. BMC Med 2021; 19: 229.

Takagai S, Tsuchiya KJ, Itoh H, et al. Cohort profile: Hamamatsu Birth Cohort for Mothers and Children (HBC study). Int J Epidemiol 2016; 45: 333-342.

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