The link between attention deficit hyperactivity disorder (ADHD) symptoms and obesity-related traits: genetic and prenatal explanations

Abstract

Attention-deficit/hyperactivity disorder (ADHD) often co-occurs with obesity, however, the potential causality between the traits remains unclear. We examined both genetic and prenatal evidence for causality using Mendelian Randomisation (MR) and polygenic risk scores (PRS). We conducted bi-directional MR on ADHD liability and six obesity-related traits using summary statistics from the largest available meta-analyses of genome-wide association studies. We also examined the shared genetic aetiology between ADHD symptoms (inattention and hyperactivity) and body mass index (BMI) by PRS association analysis using longitudinal data from Northern Finland Birth Cohort 1986 (NFBC1986, n = 2984). Lastly, we examined the impact of the prenatal environment by association analysis of maternal pre-pregnancy BMI and offspring ADHD symptoms, adjusted for PRS of both traits, in NFBC1986 dataset. Through MR analyses, we found evidence for bidirectional causality between ADHD liability and obesity-related traits. PRS association analyses showed evidence for genetic overlap between ADHD symptoms and BMI. We found no evidence for a difference between inattention and hyperactivity symptoms, suggesting that neither symptom subtype is driving the association. We found evidence for association between maternal pre-pregnancy BMI and offspring ADHD symptoms after adjusting for both BMI and ADHD PRS (association p-value = 0.027 for inattention, p = 0.008 for hyperactivity). These results are consistent with the hypothesis that the co-occurrence between ADHD and obesity has both genetic and prenatal environmental origins.

Fig. 1. Directed acyclic graph of potential relations between maternal BMI and offspring ADHD.

The dashed line represents the effect of interest and solid lines represent other hypothesised associations.

Fig. 2. Forest plot of MR estimates and their 95% confidence intervals for the effect of ADHD liability on obesity-related traits (left panel), and for the effect of obesity-related traits on ADHD (right panel).

BMI body mass index, WC waist circumference, WHR waist-hip-ratio, BFP body fat percentage, BMR basal metabolic rate, IVW inverse-variance weighted estimate, WM weighted median estimate.

Fig. 3. Effect size estimates and their 95% confidence intervals per 1-standard deviation increase in BMI PRS on increasing number of ADHD symptom types according to rater and age.

P values are for testing the difference between inattention and hyperactivity effect size estimates.

Fig. 4. Association between maternal pre-pregnancy BMI and the log-odds of increasing number of teacher-rated inattention (top panels) and hyperactivity (bottom panels) symptoms at eight years, adjusted for parity, maternal education, smoking during pregnancy, age at delivery and offspring sex.

Left panels show the associations without an additional adjustment for PRS of ADHD and BMI, and right panels show the associations with the adjustment.