An imaging (behaviour-)genetics perspective on schizotypy and antisaccades

Study One: Substantial genetic overlap between Schizotypy and Neuroticism: A Twin Study Schizotypy can be seen as a cluster of personality traits, phenomologically similar to, yet expressed in an attenuated form compared to the full-blown features of schizophrenia spectrum disorders. By placing schizotypy on the spectrum of schizophrenia spectrum disorders, the former might be used to reveal the aetiology of schizophrenia spectrum disorders. Similar to schizophrenia spectrum disorders, schizotypy correlates phenotypically with personality traits, most notably neuroticism. The aim of the first study was to decompose this phenotypic correlation between schizotypy and neuroticism and quantify its genetic and environmental components. Using a sample of 3,349 (1,449 monozygotic (MZ), 1,105 dizygotic (DZ) same-sex (DZss) and 795 DZ opposite-sex (DZos)) twins, we showed that positive schizotypy, specifically, the perceptual and ideational components of schizotypy, correlated on a phenotypical level with neuroticism (Pearson’s r=.37). Despite the differentiation of positive schizotypy and neuroticism on phenotypical levels, both traits showed a substantial amount of overlap on genetic levels (51% of genetic influences were shared, 95% confidence interval (CI) from 38 to 64%). Even more interesting was that in genetic terms neuroticism was able to explain positive features of schizotypy completely. A Cholesky decomposition including anhedonia, hypomania and impulsivity features of schizotypy fully accounted for the heritable variance in perceptual and ideational components of schizotypy, meaning that the genetic underpinnings of positive features of schizotypy could be explained away by genetic influences on neuroticism and other features of schizotypy (e.g. anhedonia, hypomania and impulsivity). Therefore, positive schizotypy could be considered as an artefact in genetic terms. The findings of the first study help in facilitating and guiding the search for molecular genetic variants of schizotypy and could be extrapolated to the schizophrenia spectrum. Study Two: The Schizotypal Brain - An fMRI Antisaccade Task Study Study two aimed at enriching the detailed investigation of psychometric schizotypy (see Study one) by revealing the neural correlates of psychometric schizotypy. Here, we tried to probe the neural correlates of schizotypy by using a measure that shows associations with schizotypy levels, i.e. performance on the antisaccade task. As shown in Study one, positive features of schizotypy are only present at psychometric levels and can be reduced to genetic variation that impacts on neuroticism and other schizotypy features. In Study two, we therefore focussed specifically on negative and disorganisation-related features of schizotypy and investigated their underlying neural correlates. One hundred forty-two healthy participants underwent functional magnetic resonance imaging (fMRI) during the antisaccade task and assessment of psychometric schizotypy. We did not replicate the association between positive schizotypy and antisaccade error rate at the phenotypic level. We did however replicate the brain network underlying antisaccade task performance. Deactivations in occipital areas were linked to schizotypy features, specifically negative schizotypy. Brain activation patterns in schizotypy were broadly consistent with those demonstrated previously across the schizophrenia spectrum. Findings might be interpreted as supporting the neural overlap between schizotypy and the schizophrenia spectrum and help in gaining a better understanding of the neuropathology underlying schizophrenia spectrum disorders. Study Three: Preliminary Findings of Heritability of the Neural Correlates of Antisaccade Performance Performance on the antisaccade task is impaired across the schizophrenia spectrum and in schizotypy, has been explicitly stated as one of the most useful endophenotypes across the schizophrenia spectrum (Greenwood, Light, Swerdlow, Radant, & Braff, 2012) and is therefore supposed to be a useful tool for revealing the neural correlates underlying these phenotypes. In a third study, we put this assumption to the test by investigating the amount of genetic influences on the neural correlates of antisaccade task performance. Using a twin fMRI design, we successfully replicated the commonly observed brain activations for the antisaccade task including activations in a fronto-parieto-occipital subcortical network. In a sample of one hundred thirty-two healthy same-sex reared-together twins (90 MZ; 32 male and 42 DZ; 24 male), who first performed the antisaccade task in the laboratory, we found evidence for significant genetic influences as estimated by heritability estimates of 47% (95% CI 22 to 65%) to antisaccade task performance. Of these participants, 96 twins (60 MZ, 28 male; 36 DZ, 22 male) underwent fMRI whilst performing the antisaccade task. We found tentative evidence for significant heritability of the blood oxygen level-dependent (BOLD) response in the left thalamus (50%, 95% CI: 18 to 72%) as shown in the contrast comparing the BOLD response during antisaccades with the BOLD response during prosaccades, an oculomotor control task. Due to the small sample of twins further replication in larger samples is warranted to firmly establish the amount of genetic influences on the neural correlates underlying antisaccade task performance

Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder

Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy

Association of a schizophrenia-risk nonsynonymous variant with putamen volume in adolescents

Importance Deviation from normal adolescent brain development precedes manifestations of many major psychiatric symptoms. Such altered developmental trajectories in adolescents may be linked to genetic risk for psychopathology. Objective To identify genetic variants associated with adolescent brain structure and explore psychopathologic relevance of such associations. Design, Setting, and Participants Voxelwise genome-wide association study in a cohort of healthy adolescents aged 14 years and validation of the findings using 4 independent samples across the life span with allele-specific expression analysis of top hits. Group comparison of the identified gene-brain association among patients with schizophrenia, unaffected siblings, and healthy control individuals. This was a population-based, multicenter study combined with a clinical sample that included participants from the IMAGEN cohort, Saguenay Youth Study, Three-City Study, and Lieber Institute for Brain Development sample cohorts and UK biobank who were assessed for both brain imaging and genetic sequencing. Clinical samples included patients with schizophrenia and unaffected siblings of patients from the Lieber Institute for Brain Development study. Data were analyzed between October 2015 and April 2018. Main Outcomes and Measures Gray matter volume was assessed by neuroimaging and genetic variants were genotyped by Illumina BeadChip. Results The discovery sample included 1721 adolescents (873 girls [50.7%]), with a mean (SD) age of 14.44 (0.41) years. The replication samples consisted of 8690 healthy adults (4497 women [51.8%]) from 4 independent studies across the life span. A nonsynonymous genetic variant (minor T allele of rs13107325 in SLC39A8, a gene implicated in schizophrenia) was associated with greater gray matter volume of the putamen (variance explained of 4.21% in the left hemisphere; 8.66; 95% CI, 6.59-10.81; P = 5.35 × 10−18; and 4.44% in the right hemisphere; t = 8.90; 95% CI, 6.75-11.19; P = 6.80 × 10−19) and also with a lower gene expression of SLC39A8 specifically in the putamen (t127 = −3.87; P = 1.70 × 10−4). The identified association was validated in samples across the life span but was significantly weakened in both patients with schizophrenia (z = −3.05; P = .002; n = 157) and unaffected siblings (z = −2.08; P = .04; n = 149). Conclusions and Relevance Our results show that a missense mutation in gene SLC39A8 is associated with larger gray matter volume in the putamen and that this association is significantly weakened in schizophrenia. These results may suggest a role for aberrant ion transport in the etiology of psychosis and provide a target for preemptive developmental interventions aimed at restoring the functional effect of this mutation

Impact of a common genetic variation associated with putamen volume on neural mechanisms of ADHD

Objective: In a recent genome-wide association study of subcortical brain volumes, we have identified common genetic variation at rs945270 as having the strongest effect on putamen volume, a brain measure linked to familial risk for attentiondeficit/hyperactivity disorder (ADHD). To determine whether rs945270 is a genetic determinant of ADHD, we now explored it impacts on ADHD related symptoms and on neural mechanisms of ADHD, such as response inhibition and reward sensitivity.Method: We used a large population sample of 1,834 14 years old adolescents to test the effects of rs945270 on (i) ADHD symptoms accessed through the Strengths and Difficulties Questionnaire (SDQ) and (ii) Region-of interest (ROI) analyses of putamen activation by functional magnetic resonance imaging (fMRI) using the Stop Signal (SST) and monetary incentive delay (MID) tasks, assessing response inhibition and rewards sensitivity, respectively.Results: We found a significant link between rs945270 and ADHD symptoms scores, the C-allele being associated with lower symptoms scores, most notably hyperactivity. We also observed sex-specific effects of this variant on the brain. In boys, the C-allele associated with lower putamen activity during successful response inhibition, a brain response that was not associated with ADHD symptoms. In girls, putamen activation during reward anticipation increased with the number of C-alleles, most significantly in the right putamen. Remarkably, right putamen activation during reward anticipation tended to negatively correlate with ADHD symptoms.Conclusions: Our results indicate that rs945270 may contribute to the genetic risk of ADHD partly through its effects on hyperactivity and reward processing in girls

Impact of a common genetic variation associated with putamen volume on neural mechanisms of ADHD

Objective: In a recent genome-wide association study of subcortical brain volumes, we have identified common genetic variation at rs945270 as having the strongest effect on putamen volume, a brain measure linked to familial risk for attentiondeficit/hyperactivity disorder (ADHD). To determine whether rs945270 is a genetic determinant of ADHD, we now explored it impacts on ADHD related symptoms and on neural mechanisms of ADHD, such as response inhibition and reward sensitivity. Method: We used a large population sample of 1,834 14 years old adolescents to test the effects of rs945270 on (i) ADHD symptoms accessed through the Strengths and Difficulties Questionnaire (SDQ) and (ii) Region-of interest (ROI) analyses of putamen activation by functional magnetic resonance imaging (fMRI) using the Stop Signal (SST) and monetary incentive delay (MID) tasks, assessing response inhibition and rewards sensitivity, respectively. Results: We found a significant link between rs945270 and ADHD symptoms scores, the C-allele being associated with lower symptoms scores, most notably hyperactivity. We also observed sex-specific effects of this variant on the brain. In boys, the C-allele associated with lower putamen activity during successful response inhibition, a brain response that was not associated with ADHD symptoms. In girls, putamen activation during reward anticipation increased with the number of C-alleles, most significantly in the right putamen. Remarkably, right putamen activation during reward anticipation tended to negatively correlate with ADHD symptoms. Conclusions: Our results indicate that rs945270 may contribute to the genetic risk of ADHD partly through its effects on hyperactivity and reward processing in girls

Neural basis of reward anticipation and its genetic determinants

Dysfunctional reward processing is implicated in various mental disorders, including attention deficit hyperactivity disorder (ADHD) and addictions. Such impairments might involve different components of the reward process, including brain activity during reward anticipation. We examined brain nodes engaged by reward anticipation in 1,544 adolescents and identified a network containing a core striatal node and cortical nodes facilitating outcome prediction and response preparation. Distinct nodes and functional connections were preferentially associated with either adolescent hyperactivity or alcohol consumption, thus conveying specificity of reward processing to clinically relevant behavior. We observed associations between the striatal node, hyperactivity, and the vacuolar protein sorting-associated protein 4A (VPS4A) gene in humans, and the causal role of Vps4 for hyperactivity was validated in Drosophila. Our data provide a neurobehavioral model explaining the heterogeneity of reward-related behaviors and generate a hypothesis accounting for their enduring nature

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness