Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

Figure 1 |. Results from GWAS meta-analysis of iPSYCH, deCODE and PGC cohorts including 38,899 cases and 186,843 controls in total.

The y-axis represents −log₁₀(two-sided P-values) from meta-analysis using an inverse-variance weighted fixed effects model. Index variants in each of the genome-wide significant loci are marked as a green diamond (note that two loci on chromosome 3, index variants rs7613360 and rs2311059, are located in close proximity and therefore appear as one diamond in the plot). The red horizontal line represents the threshold for genome-wide significant association (P = 5 × 10⁻⁸).

Figure 2 |. Venn diagrams showing MiXeR results of the estimated number of variants shared between ADHD and psychiatric disorders (with significant genetic correlations with ADHD) and phenotypes representing other domains with high genetic correlation with ADHD.

Circles represent shared variants (gray), unique to ADHD (light blue) and unique to the other phenotype of interest (orange). The number of shared variants (and standard deviations) is shown in thousands. The size of the circles reflects the polygenicity of each phenotype, with larger circles corresponding to greater polygenicity. The estimated genetic correlation (r_g) between ADHD and each phenotype from LDSC is shown below the corresponding Venn diagram, with an accompanying scale (−1 to +1) with blue and red representing negative and positive genetic correlations, respectively. Bivariate results for ADHD, autism spectrum disorder (ASD), major depressive disorder (MDD), schizophrenia (SCZ), body mass index (BMI), smoking initiation (SmoIni), insomnia, educational attainment (EA) and age at first birth (AFB) are shown (see also Supplementary Table 17).

Figure 3 |. Association of ADHD-PGS with measures of cognitive abilities in the PNC cohort (n = 4,973).

Beta values (represented as a dot and standard errors indicated as horizontal bars) from linear regression testing for the association of ADHD-PGS with the 15 neurocognitive measures listed on the y-axis (Wide Range Achievement Test-4 (WRAT). The color bar at the right indicates the −log₁₀(Bonferroni adjusted two-sided P-value) and P-value thresholds are indicated by stars (*P = 0.05; **P = 0.01, ***P = 0.001).