Quantitative genome-wide association study of six phenotypic subdomains identifies novel genome-wide significant variants in autism spectrum disorder

Autism spectrum disorders (ASD) are highly heritable and are characterized by deficits in social communication and restricted and repetitive behaviors. Twin studies on phenotypic subdomains suggest a differing underlying genetic etiology. Studying genetic variation explaining phenotypic variance will help to identify specific underlying pathomechanisms. We investigated the effect of common variation on ASD subdomains in two cohorts including >2500 individuals. Based on the Autism Diagnostic Interview-Revised (ADI-R), we identified and confirmed six subdomains with a SNP-based genetic heritability h2SNP = 0.2–0.4. The subdomains nonverbal communication (NVC), social interaction (SI), and peer interaction (PI) shared genetic risk factors, while the subdomains of repetitive sensory-motor behavior (RB) and restricted interests (RI) were genetically independent of each other. The polygenic risk score (PRS) for ASD as categorical diagnosis explained 2.3–3.3% of the variance of SI, joint attention (JA), and PI, 4.5% for RI, 1.2% of RB, but only 0.7% of NVC. We report eight genome-wide significant hits—partially replicating previous findings—and 292 known and novel candidate genes. The underlying biological mechanisms were related to neuronal transmission and development. At the SNP and gene level, all subdomains showed overlap, with the exception of RB. However, no overlap was observed at the functional level. In summary, the ADI-R algorithm-derived subdomains related to social communication show a shared genetic etiology in contrast to restricted and repetitive behaviors. The ASD-specific PRS overlapped only partially, suggesting an additional role of specific common variation in shaping the phenotypic expression of ASD subdomains

Inter-individual differences in empathy are reflected in human brain structure

Empathy is a multi-faceted concept consisting of our ability not only to share emotions but also to exert cognitive control and perspective taking in our interactions with others. Here we examined whether inter-individual variability in different components of empathy was related to differences in brain structure assessed using voxel-based morphometry. Following a magnetic resonance imaging (MRI) scan, participants completed the Interpersonal Reactivity Index (IRI). Multiple regression was then used to assess the relationship between individual differences in grey matter volume and individual differences in empathy traits. We found that individual differences in affective empathic abilities oriented towards another person were negatively correlated with grey matter volume in the precuneus, inferior frontal gyrus, and anterior cingulate. Differences in self-oriented affective empathy were negatively correlated with grey matter volume of the somatosensory cortex, but positively correlated with volume in the insula; cognitive perspective taking abilities were positively correlated with grey matter volume of the anterior cingulate; and the ability to empathise with fictional characters was positively related to grey matter changes in the right dorsolateral prefrontal cortex. These findings are discussed in relation to neurocognitive models of empathy

A Bayesian Latent Group Analysis for Detecting Poor Effort in the Assessment of Malingering

Ortega A, Wagenmakers E-J, Lee MD, Markowitsch HJ, Piefke M. A Bayesian Latent Group Analysis for Detecting Poor Effort in the Assessment of Malingering. Archives of Clinical Neuropsychology. 2012;27(4):453-465.Despite their theoretical appeal, Bayesian methods for the assessment of poor effort and malingering are still rarely used in neuropsychological research and clinical diagnosis. In this article, we outline a novel and easy-to-use Bayesian latent group analysis of malingering whose goal is to identify participants displaying poor effort when tested. Our Bayesian approach also quantifies the confidence with which each participant is classified and estimates the base rates of malingering from the observed data. We implement our Bayesian approach and compare its utility in effort assessment to that of the classic below-chance criterion of symptom validity testing (SVT). In two experiments, we evaluate the accuracy of both a Bayesian latent group analysis and the below-chance criterion of SVT in recovering the membership of participants assigned to the malingering group. Experiment 1 uses a simulation research design, whereas Experiment 2 involves the differentiation of patients with a history of stroke from coached malingerers. In both experiments, sensitivity levels are high for the Bayesian method, but low for the below-chance criterion of SVT. Additionally, the Bayesian approach proves to be resistant to possible effects of coaching. We conclude that Bayesian latent group methods complement existing methods in making more informed choices about malingering

Synaptic, transcriptional and chromatin genes disrupted in autism

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones

Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis

Background Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. Methods In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0.0156. Findings Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0.15), amygdala (d=-0.19), caudate (d=-0.11), hippocampus (d=-0.11), putamen (d=-0.14), and intracranial volume (d=-0.10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0.95) and thalamus (p=0.39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children ( 21 years): in the accumbens (Cohen's d=-0.19 vs -0.10), amygdala (d=-0.18 vs -0.14), caudate (d=-0.13 vs -0.07), hippocampus (d=-0.12 vs -0.06), putamen (d=-0.18 vs -0.08), and intracranial volume (d=-0.14 vs 0.01). There was no difference between children and adults for the pallidum (p=0.79) or thalamus (p=0.89). Case-control differences in adults were non-significant (all p > 0.03). Psychostimulant medication use (all p > 0.15) or symptom scores (all p > 0.02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p > 0.5). Interpretation With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes