Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

Fig. 1. Manhattan plots of the three GWAS meta-analyses conducted.

(a) GWAS-MA of nine cohorts of persistent ADHD in adults, (b) GWAS-MA of ten cohorts of ADHD in childhood, and (c) GWAS-MA of all datasets of ADHD across the lifespan (ADHD in childhood + persistent ADHD). Horizontal lines indicate suggestive (P value = 5.00E−06) and genome-wide significant (P = 5.00E−08) thresholds in a-b, and c, respectively.

Fig. 2. Polygenic risk scores for ADHD in childhood tested on persistent ADHD as target sample.

a Bar plot and b quintile plot of meta-analysis odds ratios (OR meta) with 95% confidence intervals for P value threshold = 0.4 using the third quintile as baseline.

Fig. 3. Regional association plots for genome-wide significant loci identified in the GWAS meta-analysis of ADHD across the lifespan.

Each plot includes information about the locus, the location and orientation of the genes in the region, the local estimates of recombination rate (in the right corner), and the LD estimates of surrounding SNPs with the index SNP (r² values are estimated based on 1000 Genomes European reference panel), which is indicated by color (in the upper left corner).

Fig. 4. Genetic correlation of ADHD and several traits.

a Dots represent genetic correlations (rg) for all traits considered (with h² > 0.1 and z-score > 4) and those traits that met Bonferroni correction in both children and adult ADHD groups are presented in grey. r indicates Pearson’s correlation coefficient. b The ten strongest genetic correlations (with 95% confidence intervals) surpassing Bonferroni corrections in the children and persistent ADHD analysis are shown for each trait and ADHD.