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

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.

Dissecting the heterogeneous subcortical brain volume of autism spectrum disorder using community detection.

Structural brain alterations in autism spectrum disorder (ASD) are heterogeneous, with limited effect sizes overall. In this study, we aimed to identify subgroups in ASD, based on neuroanatomical profiles; we hypothesized that the effect sizes for case/control differences would be increased in the newly defined subgroups. Analyzing a large data set from the ENIGMA-ASD working group (n = 2661), we applied exploratory factor analysis (EFA) to seven subcortical volumes of individuals with and without ASD to uncover the underlying organization of subcortical structures. Based on earlier findings and data availability, we focused on three age groups: boys (<=14 years), male adolescents (15-22 years), and adult men (> = 22 years). The resulting factor scores were used in a community detection (CD) analysis to cluster participants into subgroups. Three factors were found in each subsample; the factor structure in adult men differed from that in boys and male adolescents. From these factors, CD uncovered four distinct communities in boys and three communities in adolescents and adult men, irrespective of ASD diagnosis. The effect sizes for case/control comparisons were more pronounced than in the combined sample, for some communities. A significant group difference in ADOS scores between communities was observed in boys and male adolescents with ASD. We succeeded in stratifying participants into more homogeneous subgroups based on subcortical brain volumes. This stratification enhanced our ability to observe case/control differences in subcortical brain volumes in ASD, and may help to explain the heterogeneity of previous findings in ASD. LAY SUMMARY: Structural brain alterations in ASD are heterogeneous, with overall limited effect sizes. Here we aimed to identify subgroups in ASD based on neuroimaging measures. We tested whether the effect sizes for case/control differences would be increased in the newly defined subgroups. Based on neuroanatomical profiles, we succeeded in stratifying our participants into more homogeneous subgroups. The effect sizes of case/control differences were more pronounced in some subgroups than those in the whole sample.

Characterizing neuroanatomic heterogeneity in people with and without ADHD based on subcortical brain volumes.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. Neuroanatomic heterogeneity limits our understanding of ADHD's etiology. This study aimed to parse heterogeneity of ADHD and to determine whether patient subgroups could be discerned based on subcortical brain volumes. METHODS: Using the large ENIGMA-ADHD Working Group dataset, four subsamples of 993 boys with and without ADHD and to subsamples of 653 adult men, 400 girls, and 447 women were included in analyses. We applied exploratory factor analysis (EFA) to seven subcortical volumes in order to constrain the complexity of the input variables and ensure more stable clustering results. Factor scores derived from the EFA were used to build networks. A community detection (CD) algorithm clustered participants into subgroups based on the networks. RESULTS: Exploratory factor analysis revealed three factors (basal ganglia, limbic system, and thalamus) in boys and men with and without ADHD. Factor structures for girls and women differed from those in males. Given sample size considerations, we concentrated subsequent analyses on males. Male participants could be separated into four communities, of which one was absent in healthy men. Significant case-control differences of subcortical volumes were observed within communities in boys, often with stronger effect sizes compared to the entire sample. As in the entire sample, none were observed in men. Affected men in two of the communities presented comorbidities more frequently than those in other communities. There were no significant differences in ADHD symptom severity, IQ, and medication use between communities in either boys or men. CONCLUSIONS: Our results indicate that neuroanatomic heterogeneity in subcortical volumes exists, irrespective of ADHD diagnosis. Effect sizes of case-control differences appear more pronounced at least in some of the subgroups.

Genetic Markers of ADHD-Related Variations in Intracranial Volume.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, and putamen are smaller in people with ADHD compared with healthy individuals. The authors investigated the overlap between common genetic variation associated with ADHD risk and these brain volume measures to identify underlying biological processes contributing to the disorder. METHODS: The authors combined genome-wide association results from the largest available studies of ADHD (N=55,374) and brain volumes (N=11,221-24,704), using a set of complementary methods to investigate overlap at the level of global common variant genetic architecture and at the single variant level. RESULTS: Analyses revealed a significant negative genetic correlation between ADHD and ICV (rg=-0.22). Meta-analysis of single variants revealed two significant loci of interest associated with both ADHD risk and ICV; four additional loci were identified for ADHD and volumes of the amygdala, caudate nucleus, and putamen. Exploratory gene-based and gene-set analyses in the ADHD-ICV meta-analytic data showed association with variation in neurite outgrowth-related genes. CONCLUSIONS: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. These findings can help us develop new hypotheses about biological mechanisms by which brain structure alterations may be involved in ADHD disease etiology.