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Abstract The caudate nucleus is a part of the striatum, and striatal hyperdopaminergia is considered central to the pathophysiology of schizophrenia. How caudate volume is affected in schizophrenia and what role antipsychotics play remains unclear. In early-onset schizophrenia (EOS), where psychosis emerges during a neurodevelopmentally critical phase, the caudate may exhibit a heightened vulnerability to the effects of antipsychotic medications. We hypothesized effects of both antipsychotic medication use and age of onset on caudate in schizophrenia. We included adult patients with EOS (n = 83) and adult-onset schizophrenia (AOS) (n = 246), adult healthy controls (HC, n = 774), adolescent patients with non-affective psychosis (n = 56) and adolescent HC (n = 97). We obtained T1-weighted MRI scans using a 1.5T Siemens scanner and General Electric 3T scanners. In our main analysis, we tested for main and interaction effects of diagnosis and current antipsychotic medication use on caudate volume. Adult patients with EOS (p

Abstract Toxoplasma gondii (TOXO) infection typically results in chronic latency due to its ability to form cysts in the brain and other organs. Latent toxoplasmosis could promote innate immune responses and impact brain function. A large body of evidence has linked TOXO infection to severe mental illness (SMI). We hypothesized that TOXO immunoglobulin G (IgG) seropositivity, reflecting previous infection and current latency, is associated with increased circulating neuron-specific enolase (NSE), a marker of brain damage, and interleukin-18 (IL-18), an innate immune marker, mainly in SMI. We included 735 patients with SMI (schizophrenia or bipolar spectrum) (mean age 32 years, 47% women), and 518 healthy controls (HC) (mean age 33 years, 43% women). TOXO IgG, expressed as seropositivity/seronegativity, NSE and IL-18 were measured with immunoassays. We searched for main and interaction effects of TOXO, patient/control status and sex on NSE and IL-18. In the whole sample as well as among patients and HC separately, IL-18 and NSE concentrations were positively correlated (p

Abstract Autonomic adverse effects of antipsychotic drugs (APs) cause clinical challenges, but few studies have investigated sex differences and their underlying biological pathways. Sex-specific regulation of relevant hormones could be involved. We investigated sex differences in autonomic adverse effects related to olanzapine, quetiapine, risperidone, and aripiprazole, and the role of hormones related to APs. Patients with severe mental disorders (N = 1318) were included and grouped based on AP monotherapy: olanzapine (N = 364), quetiapine (N = 211), risperidone (N = 102), aripiprazole (N = 138), and no AP (N = 503). Autonomic symptoms from the Udvalg for Kliniske Undersøgelser (UKU) side effect scale was analyzed with logistic regression, adjusting for age, diagnosis, and polypharmacy. Further, we analyzed associations between autonomic symptoms and hormones related to APs. We found associations between autonomic adverse effects and APs, with sex-specific risk for palpitations/tachycardia associated with hormonal changes related to APs. Results showed increased salivation associated with aripiprazole, reduced salivation with quetiapine, and nausea/vomiting and palpitations/tachycardia with olanzapine, and higher risk of nausea/vomiting, diarrhea, constipation, polyuria/polydipsia, and palpitations/tachycardia in females. Significant sex x AP interaction was found for palpitations/tachycardia, with higher risk in risperidone-treated males, which was associated with different hormone profiles of prolactin, cortisol, and insulin. Our findings implicate a role of several hormones in the sex-specific autonomic adverse effects related to APs.

Abstract Epigenetic modifications influenced by environmental exposures are molecular sources of phenotypic heterogeneity found in schizophrenia and bipolar disorder and may contribute to shared etiopathogenetic mechanisms of these two disorders. Newborns who experienced perinatal asphyxia have suffered reduced oxygen delivery to the brain around the time of birth, which increases the risk of later psychiatric diagnosis. This study aimed to investigate DNA methylation in blood cells for associations with a history of perinatal asphyxia, a neurologically harmful condition occurring within the biological environment of birth. We utilized prospective data from the Medical Birth Registry of Norway to identify incidents of perinatal asphyxia in 643 individuals with schizophrenia or bipolar disorder and 676 healthy controls. We performed an epigenome wide association study to distinguish differentially methylated positions associated with perinatal asphyxia. We found an interaction between methylation and exposure to perinatal asphyxia on case–control status, wherein having a history of perinatal asphyxia was associated with an increase of methylation in healthy controls and a decrease of methylation in patients on 4 regions of DNA important for brain development and function. The differentially methylated regions were observed in genes involved in oligodendrocyte survival and axonal myelination and functional recovery (LINGO3); assembly, maturation and maintenance of the brain (BLCAP;NNAT and NANOS2) and axonal transport processes and neural plasticity (SLC2A14). These findings are consistent with the notion that an opposite epigenetic response to perinatal asphyxia, in patients compared with controls, may contribute to molecular mechanisms of risk for schizophrenia and bipolar disorder.

Abstract Background A child's socioeconomic environment can shape central aspects of their life, including vulnerability to mental disorders. Negative environmental influences in youth may interfere with the extensive and dynamic brain development occurring at this time. Indeed, there are numerous yet diverging reports of associations between parental socioeconomic status (SES) and child cortical brain morphometry. Most of these studies have used single metric‐ or unimodal analyses of standard cortical morphometry that downplay the probable scenario where numerous biological pathways in sum account for SES‐related cortical differences in youth. Methods To comprehensively capture such variability, using data from 9758 children aged 8.9–11.1 years from the ABCD Study®, we employed linked independent component analysis (LICA) and fused vertex‐wise cortical thickness, surface area, curvature and grey‐/white‐matter contrast (GWC). LICA revealed 70 uni‐ and multimodal components. We then assessed the linear relationships between parental education, parental income and each of the cortical components, controlling for age, sex, genetic ancestry, and family relatedness. We also assessed whether cortical structure moderated the negative relationships between parental SES and child general psychopathology. Results Parental education and income were both associated with larger surface area and higher GWC globally, in addition to local increases in surface area and to a lesser extent bidirectional GWC and cortical thickness patterns. The negative relation between parental income and child psychopathology were attenuated in children with a multimodal pattern of larger frontal‐ and smaller occipital surface area, and lower medial occipital thickness and GWC. Conclusion Structural brain MRI is sensitive to SES diversity in childhood, with GWC emerging as a particularly relevant marker together with surface area. In low‐income families, having a more developed cortex across MRI metrics, appears beneficial for mental health.

Abstract The placenta plays a role in fetal brain development, and pregnancy and birth complications can be signs of placental dysfunction. Birth asphyxia is associated with smaller head size and higher risk of developing schizophrenia (SZ), but whether birth asphyxia and placental genomic risk factors associated with SZ are related and how they might impact brain development is unclear. 433 adult patients with SZ and 870 healthy controls were clinically evaluated and underwent brain magnetic resonance imaging. Pregnancy and birth information were obtained from the Medical Birth Registry of Norway. Polygenic risk scores (PRS) from the latest genome-wide association study in SZ were differentiated into placental PRS (PlacPRS) and non-placental PRS. If the interaction between PRSs and birth asphyxia on case-control status was significant, neonatal head circumference (nHC) and adult intracranial volume (ICV) were further evaluated with these variables using multiple regression. PlacPRS in individuals with a history of birth asphyxia was associated with a higher likelihood of being a patient with SZ (t = 2.10, p = 0.018). We found a significant interaction between PlacPRS and birth asphyxia on nHC in the whole sample (t = −2.43, p = 0.008), with higher placental PRS for SZ associated with lower nHC in those with birth asphyxia. This relationship was specific to males (t = −2.71, p = 0.005) and also found with their adult ICV (t = −1.97, p = 0.028). These findings suggest that placental pathophysiology and birth asphyxia may affect early and late trajectories of brain development, particularly in males with a higher vulnerability to SZ. This knowledge might lead to new strategies of treatment and prevention in SZ.

Research has demonstrated associations between pubertal development and brain maturation. However, existing studies have been limited by small samples, cross-sectional designs, and inconclusive findings regarding directionality of effects and sex differences.We examined the longitudinal temporal coupling of puberty status assessed using the Pubertal Development Scale (PDS) and magnetic resonance imaging (MRI)-based grey and white matter brain structure. Our sample consisted of 8896 children and adolescents at baseline (mean age = 9.9) and 6099 at follow-up (mean age = 11.9) from the Adolescent Brain and Cognitive Development (ABCD) Study cohort.Applying multigroup Bivariate Latent Change Score (BLCS) models, we found that baseline PDS predicted the rate of change in cortical thickness among females and rate of change in cortical surface area for both males and females. We also found a correlation between baseline PDS and surface area and co-occurring changes over time in males. Diffusion tensor imaging (DTI) analyses revealed correlated change between PDS and fractional anisotropy (FA) for both males and females, but no significant associations for mean diffusivity (MD).Our results suggest that pubertal status predicts cortical maturation, and that the strength of the associations differ between sex. Further research spanning the entire duration of puberty is needed to understand the extent and contribution of pubertal development on the youth brain.

Abstract Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the ‘normativeness’ of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.

Abstract Schizophrenia and bipolar disorder are severe mental illnesses (SMI) linked to both genetic and environmental factors. Herpes simplex virus 1 (HSV1) is a common neurotropic pathogen which after the primary infection establishes latency with periodic reactivations. We hypothesized that the latent HSV1 infection is associated with brain structural abnormalities and cognitive impairment, especially in SMI. We included 420 adult patients with SMI (schizophrenia or bipolar spectrum) and 481 healthy controls. Circulating HSV1 immunoglobulin G concentrations were measured with immunoassays. We measured the total grey matter volume (TGMV), cortical, subcortical, cerebellar and regional cortical volumes based on T1-weighted MRI scans processed in FreeSurfer v6.0.0. Intelligence quotient (IQ) was assessed with the Wechsler Abbreviated Scale of Intelligence. Seropositive patients had significantly smaller TGMV than seronegative patients (642 cm3 and 654 cm3, respectively; p = 0.019) and lower IQ (104 and 107, respectively; p = 0.018). No TGMV or IQ differences were found between seropositive and seronegative healthy controls. Post-hoc analysis showed that (a) in both schizophrenia and bipolar spectrum, seropositive patients had similarly smaller TGMV than seronegative patients, whereas the HSV1-IQ association was driven by the schizophrenia spectrum group, and (b) among all patients, seropositivity was associated with smaller total cortical (p = 0.016), but not subcortical or cerebellar grey matter volumes, and with smaller left caudal middle frontal, precentral, lingual, middle temporal and banks of superior temporal sulcus regional cortical grey matter volumes. The results of this cross-sectional study indicate that HSV1 may be an environmental factor associated with brain structural abnormalities and cognitive impairment in SMI.

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Abstract Several lines of evidence implicate immune abnormalities in the pathophysiology of severe mental disorders (SMD) and comorbid mental disorders. Here, we use the data from genome-wide association studies (GWAS) of autoimmune diseases and mental phenotypes associated with SMD to disentangle genetic susceptibilities of immune abnormalities in SMD. We included 1004 patients with SMD and 947 healthy controls (HC) and measured plasma levels of IL-1Ra, sIL-2R, gp130, sTNFR-1, IL-18, APRIL, and ICAM-1. Polygenic risk scores (PRS) of six autoimmune disorders, CRP, and 10 SMD-related mental phenotypes were calculated from GWAS. General linear models were applied to assess the association of PRS with immune marker abnormalities. We found negative associations between PRS of educational attainment and IL-1Ra (P = 0.01) and IL-18 (P = 0.01). There were nominal positive associations between PRS of psoriasis and sgp130 (P = 0.02) and PRS of anxiety and IL-18 (P = 0.03), and nominal negative associations between PRS of anxiety and sIL-2R (P = 0.02) and PRS of educational attainment and sIL-2R (P = 0.03). Associations explained minor amounts of the immune marker plasma-level difference between SMD and HC. Different PRS and immune marker associations in the SMD group compared to HC were shown for PRS of extraversion and IL-1Ra ([interaction effect (IE), P = 0.002), and nominally for PRS of openness and IL-1Ra (IE, P = 0.02) and sTNFR-1 (IE, P = 0.04). Our findings indicate polygenic susceptibilities to immune abnormalities in SMD involving genetic overlap with SMD-related mental phenotypes and psoriasis. Associations might suggest immune genetic factors of SMD subgroups characterized by autoimmune or specific mental features.

IntroductionRelative to men, women are at a higher risk of developing age-related neurocognitive disorders including Alzheimer’s disease. While women’s health has historically been understudied, emerging evidence suggests that reproductive life events such as pregnancy and hormone use may influence women’s cognition later in life.MethodsWe investigated the associations between reproductive history, exogenous hormone use, apolipoprotein (APOE) ε4 genotype and cognition in 221,124 middle- to older-aged (mean age 56.2 ± 8.0 years) women from the UK Biobank. Performance on six cognitive tasks was assessed, covering four cognitive domains: episodic visual memory, numeric working memory, processing speed, and executive function.ResultsA longer reproductive span, older age at menopause, older age at first and last birth, and use of hormonal contraceptives were positively associated with cognitive performance later in life. Number of live births, hysterectomy without oophorectomy and use of hormone therapy showed mixed findings, with task-specific positive and negative associations. Effect sizes were generally small (Cohen’s d < 0.1). While APOE ε4 genotype was associated with reduced processing speed and executive functioning, in a dose-dependent manner, it did not influence the observed associations between female-specific factors and cognition.DiscussionOur findings support previous evidence of associations between a broad range of female-specific factors and cognition. The positive association between a history of hormonal contraceptive use and cognition later in life showed the largest effect sizes (max. d = 0.1). More research targeting the long-term effects of female-specific factors on cognition and age-related neurocognitive disorders including Alzheimer’s disease is crucial for a better understanding of women’s brain health and to support women’s health care.

BackgroundStructural neuroimaging studies have identified similarities in the brains of individuals diagnosed with schizophrenia (SZ) and bipolar I disorder (BP), with overlap in regions of gray matter (GM) deficits between the two disorders. Recent studies have also shown that the symptom phenotypes associated with SZ and BP may allow for a more precise categorization than the current diagnostic criteria. In this study, we sought to identify GM alterations that were unique to each disorder and whether those alterations were also related to unique symptom profiles.Materials and methodsWe analyzed the GM patterns and clinical symptom presentations using independent component analysis (ICA), hierarchical clustering, and n-way biclustering in a large (N ∼ 3,000), merged dataset of neuroimaging data from healthy volunteers (HV), and individuals with either SZ or BP.ResultsComponent A showed a SZ and BP < HV GM pattern in the bilateral insula and cingulate gyrus. Component B showed a SZ and BP < HV GM pattern in the cerebellum and vermis. There were no significant differences between diagnostic groups in these components. Component C showed a SZ < HV and BP GM pattern bilaterally in the temporal poles. Hierarchical clustering of the PANSS scores and the ICA components did not yield new subgroups. N-way biclustering identified three unique subgroups of individuals within the sample that mapped onto different combinations of ICA components and symptom profiles categorized by the PANSS but no distinct diagnostic group differences.ConclusionThese multivariate results show that diagnostic boundaries are not clearly related to structural differences or distinct symptom profiles. Our findings add support that (1) BP tend to have less severe symptom profiles when compared to SZ on the PANSS without a clear distinction, and (2) all the gray matter alterations follow the pattern of SZ < BP < HV without a clear distinction between SZ and BP.

Gradients in parental socioeconomic status (SES) are closely linked to important life outcomes in children and adolescents, such as cognitive abilities, school achievement, and mental health. Parental SES may also influence brain development, with several magnetic resonance imaging (MRI) studies reporting associations with youth brain morphometry. However, MRI signal intensity metrics have not been assessed, but could offer a microstructural correlate, thereby increasing our understanding of SES influences on neurobiology. We computed a parental SES score from family income, parental education and parental occupation, and assessed relations with cortical microstructure as measured by T1w/T2w ratio (n = 504, age = 3–21 years). We found negative age-stabile relations between parental SES and T1w/T2w ratio, indicating that youths from lower SES families have higher ratio in widespread frontal, temporal, medial parietal and occipital regions, possibly indicating a more developed cortex. Effect sizes were small, but larger than for conventional morphometric properties i.e. cortical surface area and thickness, which were not significantly associated with parental SES. Youths from lower SES families had poorer language related abilities, but microstructural differences did not mediate these relations. T1w/T2w ratio appears to be a sensitive imaging marker for further exploring the association between parental SES and child brain development.

The discrepancy between chronological age and the apparent age of the brain based on neuroimaging data — the brain age delta — has emerged as a reliable marker of brain health. With an increasing wealth of data, approaches to tackle heterogeneity in data acquisition are vital. To this end, we compiled raw structural magnetic resonance images into one of the largest and most diverse datasets assembled (n=53542), and trained convolutional neural networks (CNNs) to predict age. We achieved state-of-the-art performance on unseen data from unknown scanners (n=2553), and showed that higher brain age delta is associated with diabetes, alcohol intake and smoking. Using transfer learning, the intermediate representations learned by our model complemented and partly outperformed brain age delta in predicting common brain disorders. Our work shows we can achieve generalizable and biologically plausible brain age predictions using CNNs trained on heterogeneous datasets, and transfer them to clinical use cases.

Abstract Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

The genetic architecture underlying brainstem regions and how this links to common brain disorders is not well understood. Here, the authors use MRI and GWAS data from 27,034 individuals to identify genetic and morphological brainstem features that influence common brain disorders.

Background: Early-onset psychosis (EOP) is among the leading causes of disease burden in adolescents. Negative symptoms and cognitive deficits predicts poorer functional outcome. A better understanding of the association between negative symptoms and cognitive impairment may inform theories on underlying mechanisms and elucidate targets for development of new treatments. Two domains of negative symptoms have been described in adult patients with schizophrenia: apathy and diminished expression, however, the factorial structure of negative symptoms has not been investigated in EOP. We aimed to explore the factorial structure of negative symptoms and investigate associations between cognitive performance and negative symptom domains in adolescents with EOP. We hypothesized that (1) two negative symptom factors would be identifiable, and that (2) diminished expression would be more strongly associated with cognitive performance, similar to adult psychosis patients.Methods: Adolescent patients with non-affective EOP (n = 169) were included from three cohorts: Youth-TOP, Norway (n = 45), Early-Onset Study, Norway (n = 27) and Adolescent Schizophrenia Study, Mexico (n = 97). An exploratory factor analysis was performed to investigate the underlying structure of negative symptoms (measured with the Positive and Negative Syndrome Scale (PANSS)). Factor-models were further assessed using confirmatory factor analyses. Associations between negative symptom domains and six cognitive domains were assessed using multiple linear regression models controlling for age, sex and cohort. The neurocognitive domains from the MATRICS Consensus Cognitive Battery included: speed of processing, attention, working memory, verbal learning, visual learning, and reasoning and problem solving.Results: The exploratory factor analysis of PANSS negative symptoms suggested retaining only a single factor, but a forced two factor solution corroborated previously described factors of apathy and diminished expression in adult-onset schizophrenia. Results from confirmatory factor analysis indicated a better fit for the two-factor model than for the one-factor model. For both negative symptom domains, negative symptom scores were inversely associated with verbal learning scores.Conclusion: The results support the presence of two domains of negative symptoms in EOP; apathy and diminished expression. Future studies on negative symptoms in EOP should examine putative differential effects of these symptom domains. For both domains, negative symptom scores were significantly inversely associated with verbal learning.

Abnormal default mode network (DMN) connectivity has been found in schizophrenia and other psychotic disorders. However, there are limited studies on early onset psychosis (EOP), and their results show lack of agreement. Here, we investigated within-network DMN connectivity in EOP compared to healthy controls (HC), and its relationship to clinical characteristics.A sample of 68 adolescent patients with EOP (mean age 16.53 ± 1.12 [SD] years, females 66%) and 95 HC (mean age 16.24 ± 1.50 [SD], females 60%) from two Scandinavian cohorts underwent resting state functional magnetic resonance imaging (rsfMRI). A group independent component analysis (ICA) was performed to identify the DMN across all participants. Dual regression was used to estimate spatial maps reflecting each participant’s DMN network, which were compared between EOP and HC using voxel-wise general linear models and permutation-based analyses. Subgroup analyses were performed within the patient group, to explore associations between diagnostic subcategories and current use of psychotropic medication in relation to connectivity strength.The analysis revealed significantly reduced DMN connectivity in EOP compared to HC in the posterior cingulate cortex, precuneus, fusiform cortex, putamen, pallidum, amygdala, and insula. The subgroup analysis in the EOP group showed strongest deviations for affective psychosis, followed by other psychotic disorders and schizophrenia. There was no association between DMN connectivity strength and the current use of psychotropic medication.In conclusion, the findings demonstrate weaker DMN connectivity in adolescent patients with EOP compared to healthy peers, and differential effects across diagnostic subcategories, which may inform our understanding of underlying disease mechanisms in EOP.

Young chronological age is one of the strongest predictors for antisocial behaviour in the general population and for violent offending in individuals with psychotic disorders. An individual's age can be predicted with high accuracy using neuroimaging and machine-learning. The deviation between predicted and chronological age, i.e., brain age gap (BAG) has been suggested to reflect brain health, likely relating partly to neurodevelopmental and aging-related processes and specific disease mechanisms. Higher BAG has been demonstrated in patients with psychotic disorders. However, little is known about the brain-age in violent offenders with psychosis and the possible associations with psychopathy traits.We estimated brain-age in 782 male individuals using T1-weighted MRI scans. Three machine learning models (random forest, extreme gradient boosting with and without hyper parameter tuning) were first trained and tested on healthy controls (HC, n = 586). The obtained BAGs were compared between HC and age matched violent offenders with psychosis (PSY-V, n = 38), violent offenders without psychosis (NPV, n = 20) and non-violent psychosis patients (PSY-NV, n = 138). We ran additional comparisons between BAG of PSY-V and PSY-NV and associations with Positive and Negative Syndrome Scale (PANSS) total score as a measure of psychosis symptoms. Psychopathy traits in the violence groups were assessed with Psychopathy Checklist-revised (PCL-R) and investigated for associations with BAG.We found significantly higher BAG in PSY-V compared with HC (4.9 years, Cohen's d = 0.87) and in PSY-NV compared with HC (2.7 years, d = 0.41). Total PCL-R scores were negatively associated with BAG in the violence groups (d = 1.17, p

Background: The ratio of T1-weighted (T1w) and T2-weighted (T2w) magnetic resonance imaging (MRI) images is often used as a proxy measure of cortical myelin. However, the T1w/T2w-ratio is based on signal intensities that are inherently non-quantitative and known to be affected by extrinsic factors. To account for this a variety of processing methods have been proposed, but a systematic evaluation of their efficacy is lacking. Given the dependence of the T1w/T2w-ratio on scanner hardware and T1w and T2w protocols, it is important to ensure that processing pipelines perform well also across different sites. Methods: We assessed a variety of processing methods for computing cortical T1w/T2w-ratio maps, including correction methods for nonlinear field inhomogeneities, local outliers, and partial volume effects as well as intensity normalisation. These were implemented in 33 processing pipelines which were applied to four test-retest datasets, with a total of 170 pairs of T1w and T2w images acquired on four different MRI scanners. We assessed processing pipelines across datasets in terms of their reproducibility of expected regional distributions of cortical myelin, lateral intensity biases, and test-retest reliability regionally and across the cortex. Regional distributions were compared both qualitatively with histology and quantitatively with two reference datasets, YA-BC and YA-B1+, from the Human Connectome Project. Results: Reproducibility of raw T1w/T2w-ratio distributions was overall high with the exception of one dataset. For this dataset, Spearman rank correlations increased from 0.27 to 0.70 after N3 bias correction relative to the YA-BC reference and from -0.04 to 0.66 after N4ITK bias correction relative to the YA-B1+ reference. Partial volume and outlier corrections had only marginal effects on the reproducibility of T1w/T2w-ratio maps and test-retest reliability. Before intensity normalisation, we found large coefficients of variation (CVs) and low intraclass correlation coefficients (ICCs), with total whole-cortex CV of 10.13% and whole-cortex ICC of 0.58 for the raw T1w/T2w-ratio. Intensity normalisation with WhiteStripe, RAVEL, and Z-Score improved total whole-cortex CVs to 5.91%, 5.68%, and 5.19% respectively, whereas Z-Score and Least Squares improved whole-cortex ICCs to 0.96 and 0.97 respectively. Conclusions: In the presence of large intensity nonuniformities, bias field correction is necessary to achieve acceptable correspondence with known distributions of cortical myelin, but it can be detrimental in datasets with less intensity inhomogeneity. Intensity normalisation can improve test-retest reliability and inter-subject comparability. However, both bias field correction and intensity normalisation methods vary greatly in their efficacy and may affect the interpretation of results. The choice of T1w/T2w-ratio processing method must therefore be informed by both scanner and acquisition protocol as well as the given study objective. Our results highlight limitations of the T1w/T2w-ratio, but also suggest concrete ways to enhance its usefulness in future studies.

Abstract Introduction Successful inhibition of distracting emotions is important for preserving well‐being and daily functioning. There is conflicting evidence regarding the impact of healthy aging on emotional inhibition, and possible age‐related alterations in the neuronal underpinnings of emotional interference processing are unexplored. Methods Thirty younger (mean age 26 years; 15 women) and 30 older (mean age 71 years; 13 women) healthy adults performed a face–word emotional Stroop task while undergoing functional magnetic resonance imaging of the brain. A resting‐state scan was acquired for calculating the amplitude of low‐frequency fluctuations as an estimate of vascular reactivity. Comparisons of brain activation during the task were assessed in a whole‐brain, voxel‐wise analysis, contrasting congruent, and incongruent conditions. The canonical regions of the frontoparietal, salience, dorsal attention, and default mode networks were used as seed regions for assessing functional connectivity within and between large‐scale brain networks. Task performance was evaluated using response accuracy and response time. Results The older adults had longer response times and lower task accuracy than the younger adults, but the emotional interference effect was not significantly different between the groups. Whole‐brain analysis revealed no significant age‐related differences in brain activation patterns. Rescaling the data for estimated variability in vascular reactivity did not affect the results. In older adults, there was relatively stronger functional connectivity with the default mode network, the sensorimotor network, and the dorsal attention network for the frontoparietal and salience network seeds during the task. Conversely, younger adults had relatively stronger connections within and between the frontoparietal and salience networks. Conclusion In this first fMRI study of emotional Stroop interference in older and younger adults, we found that the emotional interference effect was unchanged in healthy aging and replicated the finding from non‐emotional task studies that older adults have greater between‐network and less within‐network connectivity compared to younger adults.

Abstract Objective Early‐onset psychosis (EOP) and bipolar disorder (EOBP) (at

BackgroundAutoantibodies to the N-methyl-D-aspartate receptor (NMDAR-Abs) in autoimmune encephalitis have been associated with prominent psychiatric symptoms. The aims of the present study are to identify the prevalence of NMDAR-Abs in adolescents with early onset psychosis disorders (EOP) and healthy controls (HC) and examine its clinical significance.MethodPlasma samples were acquired from 46 adolescent EOP patients and 69 age- and sex matched HC, and assessed for the presence of immunoglobulin G NMDAR-Abs. All participants underwent psychiatric evaluation, neurological examination and head magnetic resonance imaging.ResultsNMDAR-Abs were detected in three of 46 (6.5%) EOP patients and in two of 69 (2.9%) HC. One NMDAR-Abs EOP patient presented with unusual psychopathology and minor T1 weighted lesions of vasculopathological origin located bi-frontally and in the basal ganglia, and had a recent diagnosis of a separate autoimmune disease. One NMDAR-Ab HC displayed a T2 weighted FLAIR hyperintensity lesion in the left frontal lobe. The remaining three NMDAR-Ab participants were two EOP patients without neurological or radiological findings, and one HC without any clinical findings.ConclusionsWe report that a small number of EOP patients and HC have NMDAR-Abs with a similar frequency in both groups. The presence of the antibodies was not associated with any distinctive clinical or radiological features. Detection of the antibodies had no diagnostic implication, and a positive NMDAR antibody test must be carefully interpreted and reviewed within the individual clinical context.

Schizophrenia is a severe mental disorder with often a chronic course. Neuroimaging studies report brain abnormalities in both white and gray matter structures. However, the relationship between microstructural white matter differences and volumetric subcortical structures is not known. We investigated 30 long-term treated patients with schizophrenia and schizoaffective disorder (mean age 51.1 ± 7.9 years, mean illness duration 27.6 ± 8.0 years) and 42 healthy controls (mean age 54.1 ± 9.1 years) using 3 T diffusion and structural magnetic resonance imaging. The free-water imaging method was used to model the diffusion signal, and subcortical volumes were obtained from FreeSurfer. We applied multiple linear regression to investigate associations between (i) patient status and regional white matter microstructure, (ii) medication dose or clinical symptoms on white matter microstructure in patients, and (iii) for interactions between subcortical volumes and diagnosis on microstructural white matter regions showing significant patient-control differences. The patients had significantly decreased free-water corrected fractional anisotropy (FAt), explained by decreased axial diffusivity and increased radial diffusivity (RDt) bilaterally in the anterior corona radiata (ACR) and the left anterior limb of the internal capsule (ALIC) compared to controls. In the fornix, the patients had significantly increased RDt. In patients, positive symptoms were associated with localized increased free-water and negative symptoms with localized decreased FAt and increased RDt. There were significant interactions between patient status and several subcortical structures on white matter microstructure and the free-water compartment for left ACR and fornix, and limited to the free-water compartment for right ACR and left ALIC. The Cohen's d effect sizes were medium to large (0.61 to 1.20, absolute values). The results suggest a specific pattern of frontal white matter axonal degeneration and demyelination and fornix demyelination that is attenuated in the presence of larger structures of the limbic system in patients with chronic schizophrenia and schizoaffective disorder. Findings warrant replication in larger samples.

White matter abnormalities are well-established in adult patients with psychosis. Less is known about abnormalities in the rarely occurring adolescent early onset psychosis (EOP). In particular, whether antipsychotic medication might impact white matter microstructure is not known. Using 3T diffusion weighted imaging, we investigated differences in white matter microstructure and the impact of antipsychotic medication status in medicated (n = 11) and unmedicated (n = 11) EOP patients relative to healthy controls (n = 33), aged between 12-18 years. Using Tract-based Spatial Statistics, we calculate case-control differences in scalar diffusion measures, i.e. fractional anisotropy (FA), axial diffusion (AD) and radial diffusion (RD), and investigated their association with antipsychotic medication in patients. We found significantly lower FA in the left genu of the corpus callosum, the left anterior corona radiata (ACR) and the right superior longitudinal fasciculus in EOP patients relative to healthy controls. AD values were also lower in the left ACR, largely overlapping with the FA findings. Mean FA in the left ACR was significantly associated with antipsychotic medication status (Cohen's d = 1.37, 95% CI [0.01, 2.68], p = 0.008), showing higher FA values in medicated compared to unmedicated EOP patients. The present study is the first to link antipsychotic medication status to altered regional FA in the left ACR, a region hypothesized to contribute to the etiology of psychosis. Replications are warranted to draw firm conclusions about putatively enhancing effects of antipsychotic medication on white matter microstructure in adolescent-onset psychosis.

Bipolar disorder (BD) is a severe manic-depressive illness. Patients with BD have been shown to have gray matter (GM) deficits in prefrontal, frontal, parietal, and temporal regions; however, the relationship between structural effects and clinical profiles has proved elusive when considered on a region by region or voxel by voxel basis. In this study, we applied parallel independent component analysis (pICA) to structural neuroimaging measures and the positive and negative syndrome scale (PANSS) in 110 patients (mean age 34.9 ± 11.65) with bipolar disorder, to examine networks of brain regions that relate to symptom profiles. The pICA revealed two distinct symptom profiles and associated GM concentration alteration circuits. The first PANSS pICA profile mainly involved anxiety, depression and guilty feelings, reflecting mood symptoms. Reduced GM concentration in right temporal regions predicted worse mood symptoms in this profile. The second PANSS pICA profile generally covered blunted affect, emotional withdrawal, passive/apathetic social withdrawal, depression and active social avoidance, exhibiting a withdrawal or apathy dominating component. Lower GM concentration in bilateral parietal and frontal regions showed worse symptom severity in this profile. In summary, a pICA decomposition suggested BD patients showed distinct mood and apathy profiles differing from the original PANSS subscales, relating to distinct brain structural networks.

BackgroundPatients with psychiatric conditions are often referred for a brain scan during the course of their diagnostic workup.AimsThe aim of our study is to determine frequency and type of organic brain pathology, the relationship to age, gender and psychiatric diagnosis.MethodWe investigated magnetic resonance imaging and computed tomography brain scans from consecutively referred patients over a 10-year period (January 2002-December 2011). The reasons for referral, estimated psychiatric diagnosis, and the pathology discovered for each patient were registered.ResultsA total of 34% of patients demonstrated organic brain pathology, of which 32.8% were considered clinically relevant. This represents a higher frequency of relevant pathology than reported in healthy subjects. Age (P

Abstract Background Personality is considered as an important aspect in persons with psychotic disorders. Several studies have investigated personality in schizophrenia. However, no study has investigated stability of personality traits exceeding three years in patients with schizophrenia. This study aims to investigate the stability of personality traits over a five-year period among patients with schizophrenia and non-psychotic individuals and to evaluate case-control differences. Methods Patients with psychotic disorders (n = 36) and non-psychotic individuals (n = 76) completed Swedish universities Scales of Personality (SSP) at two occasions five years apart. SSP scores were analysed for effect of time and case-control differences by multiple analysis of covariance (MANCOVA) and within-subjects correlation. Results MANCOVA within-subjects analysis did not show any effect of time. Thus, SSP mean scale scores did not significantly vary during the five-year interval. Within subject correlations (Spearman) ranged 0.30–0.68 and 0.54–0.75 for the different SSP scales in patients and controls, respectively. Patients scored higher than controls in SSP scales Somatic Trait Anxiety, Psychic Trait Anxiety, Stress Susceptibility, Lack of Assertiveness, Detachment, Embitterment, and Mistrust. Conclusion The stability of the SSP personality trait was reasonably high among patients with psychotic disorder, although lower than among non-psychotic individuals, which is in accordance with previous research.

After publication of the original article [1], it was brought to our attention that some of the numbers in Table 3were incorrect.

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

The brain underpinnings of schizophrenia and bipolar disorders are multidimensional, reflecting complex pathological processes and causal pathways, requiring multivariate techniques to disentangle. Furthermore, little is known about the complementary clinical value of brain structural phenotypes when combined with data on cognitive performance and genetic risk. Using data-driven fusion of cortical thickness, surface area, and gray matter density maps (GMD), we found six biologically meaningful patterns showing strong group effects, including four statistically independent multimodal patterns reflecting co-occurring alterations in thickness and GMD in patients, over and above two other independent patterns of widespread thickness and area reduction. Case-control classification using cognitive scores alone revealed high accuracy, and adding imaging features or polygenic risk scores increased performance, suggesting their complementary predictive value with cognitive scores being the most sensitive features. Multivariate pattern analyses reveal distinct patterns of brain morphology in mental disorders, provide insights on the relative importance between brain structure, cognitive and polygenetic risk score in classification of patients, and demonstrate the importance of multivariate approaches in studying the pathophysiological substrate of these complex disorders. Keywords: Multimodal MRI, Clinical prediction, Classification, Brain structure, Schizophrenia, Bipolar disorder, Cognition, Polygenic risk

Background: Alzheimer’s disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits.Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer’s Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework.Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect).Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP.

BACKGROUND:Lower vitamin D levels are found in people with schizophrenia and depressive disorders, and also associated with neuroimaging abnormalities such as reduced brain volume in both animals and humans. Reduced whole brain and increased ventricular volume are also systematically reported in schizophrenia. Even though vitamin D deficiency has been proposed as a risk mechanism for schizophrenia there exist no studies to date of the association between vitamin D levels and brain volume in this population. Therefore, we investigated the relationship between vitamin D levels and brain phenotypes in psychotic disorders, and assessed possible interactions with genetic variants in vitamin D receptor (VDR) and other genetic variants that play a role in vitamin D levels in the body. METHODS:Our sample consisted of 83 psychosis patients and 101 healthy controls. We measured vitamin D levels as serum 25-hydroxyvitamin D. All participants were genotyped and neuroimaging conducted by structural magnetic resonance imaging. RESULTS:Vitamin D levels were significantly positively associated with peripheral grey matter volume in patients (β 860.6; 95% confidence interval (CI) 333.4-1466, p < .003). A significant interaction effect of BSML marker (rs1544410) was observed to mediate the association between patient status and both white matter volume (β 23603.3; 95% CI 2732.8-48708.6, p < .05) and whole brain volume (β 46670.6, 95% CI 8817.8-93888.3, p < .04). Vitamin D did not predict ventricular volume, which rather was associated with patient status (β 4423.3, 95% CI 1583.2-7267.8p < .002) and CYP24A1 marker (rs6013897) (β 2491.5, 95% CI 269.7-4978.5, p < .04). CONCLUSIONS:This is the first study of the association between vitamin D levels and brain volume in patients with psychotic disorders that takes into account possible interaction with genetic polymorphisms. The present findings warrant replication in independent samples.

Schizophrenia (SZ) is a psychotic disorder with significant cognitive dysfunction. Abnormal brain activation during cognitive processing has been reported, both in task-positive and task-negative networks. Further, structural cortical and subcortical brain abnormalities have been documented, but little is known about how task-related brain activation is associated with brain anatomy in SZ compared to healthy controls (HC). Utilizing linked independent component analysis (LICA), a data-driven multimodal analysis approach, we investigated structure–function associations in a large sample of SZ (n = 96) and HC (n = 142). We tested for associations between task-positive (fronto-parietal) and task-negative (default-mode) brain networks derived from fMRI activation during an n-back working memory task, and brain structural measures of surface area, cortical thickness, and gray matter volume, and to what extent these associations differed in SZ compared to HC. A significant association (p

Clinical and cognitive symptoms domain-based subtyping in schizophrenia (Sz) has been critiqued due to the lack of neurobiological correlates and heterogeneity in symptom scores. We, therefore, present a novel data-driven framework using biclustered independent component analysis to detect subtypes from the reliable and stable gray matter concentration (GMC) of patients with Sz. The developed methodology consists of the following steps: source-based morphometry (SBM) decomposition, selection and sorting of two component loadings, subtype component reconstruction using group information-guided ICA (GIG-ICA). This framework was applied to the top two group discriminative components namely the insula/superior temporal gyrus/inferior frontal gyrus (I-STG-IFG component) and the superior frontal gyrus/middle frontal gyrus/medial frontal gyrus (SFG-MiFG-MFG component) from our previous SBM study, which showed diagnostic group difference and had the highest effect sizes. The aggregated multisite dataset consisted of 382 patients with Sz regressed of age, gender, and site voxelwise. We observed two subtypes (i.e., two different subsets of subjects) each heavily weighted on these two components, respectively. These subsets of subjects were characterized by significant differences in positive and negative syndrome scale (PANSS) positive clinical symptoms (p = 0.005). We also observed an overlapping subtype weighing heavily on both of these components. The PANSS general clinical symptom of this subtype was trend level correlated with the loading coefficients of the SFG-MiFG-MFG component (r = 0.25; p = 0.07). The reconstructed subtype-specific component using GIG-ICA showed variations in voxel regions, when compared to the group component. We observed deviations from mean GMC along with conjunction of features from two components characterizing each deciphered subtype. These inherent variations in GMC among patients with Sz could possibly indicate the need for personalized treatment and targeted drug development.

Ketamine administration is a well-established approach to mimic experimentally some aspects of schizophrenia. Adult neurogenesis dysregulation is associated with psychiatric disorders, including schizophrenia. The potential role of neurogenesis in the ketamine-induced phenotype is largely unknown. Recent results from human genetic studies have shown the pituitary adenylate cyclase-activating polypeptide (PACAP) gene is a risk factor for schizophrenia. Its potential role on the regulation of neurogenesis in experimental model of schizophrenia remains to be investigated. We aimed to determine whether ketamine affects the viability of adult neural stem cells (NSC). We also investigated whether the detrimental effect mediated by ketamine could be counteracted by PACAP. NSCs were isolated from the subventricular zone of the mouse and exposed to ketamine with/without PACAP. After 24 hours, cell viability, potential involvement of apoptosis, endoplasmic reticulum (ER) stress, mTOR and AMPA pathway activation were assessed by quantitative RT-PCR and Western blot analysis. We show that ketamine impairs NSC viability in correlation with increased apoptosis, ER stress and mTOR activation. The results also suggest that the effect of ketamine occurs via AMPA receptor activation. Finally, we show that PACAP counteracted the decreased NSC viability induced by ketamine via the specific activation of the PAC-1 receptor subtype. Our study shows that the NSC viability may be negatively affected by ketamine with putative importance for the development of a schizophrenia phenotype in the ketamine induced animal model of schizophrenia. The neuroprotective effect via PAC-1 activation suggests a potentially novel pharmacological target for the treatment of schizophrenia, via neurogenesis normalization.

The many subcomponents of the human cortex are known to follow an anatomical pattern and functional relationship that appears to be highly conserved between individuals. This suggests that this pattern and the relationship among cortical regions are important for cortical function and likely shaped by genetic factors, although the degree to which genetic factors contribute to this pattern is unknown. We assessed the genetic relationships among 12 cortical surface areas using brain images and genotype information on 2,364 unrelated individuals, brain images on 466 twin pairs, and transcriptome data on 6 postmortem brains in order to determine whether a consistent and biologically meaningful pattern could be identified from these very different data sets. We find that the patterns revealed by each data set are highly consistent (p

Altered neurodevelopment and plasticity are implicated in schizophrenia pathology. Based on the important role of neurotrophic factors in brain development and plasticity as well as their extensive expression in hippocampal areas, we hypothesized that a variation in the neurotrophin receptor 3 gene (NTRK-3) is associated to hippocampal function and schizophrenia. Thirty-three tagging NTRK-3 single nucleotide polymorphisms (SNPs) were genotyped in 839 schizophrenia patients and 1473 healthy controls. SNPs that were significantly associated with schizophrenia were evaluated in subgroups of the sample with neuropsychological test battery (n=104 patients and 175 controls) and functional magnetic resonance imaging tests of hippocampal function (n=36 controls). rs999905 was nominally significantly associated with schizophrenia and the haplotype block that included markers rs999905 and rs4887348 remained significant after permutation tests. These gene variants are also related to in vivo brain function in healthy control subjects, shown by a significant association with hippocampal activation during an encoding task. The present results, although not robust, suggest that the NTRK-3 gene influences hippocampal function and may modify the risk for schizophrenia.

Both brain structural abnormalities and neurocognitive impairments are core features of schizophrenia. We have previously reported enlargements in subcortical brain structure volumes and impairment of neurocognitive functioning as measured by the MATRICS Cognitive Consensus Battery (MCCB) in early onset schizophrenia spectrum disorders (EOS). To our knowledge, no previous study has investigated whether neurocognitive performance and volumetric abnormalities in subcortical brain structures are related in EOS.Twenty-four patients with EOS and 33 healthy controls (HC) were included in the study. Relationships between the caudate nucleus, the lateral and fourth ventricles volumes and neurocognitive performance were investigated with multivariate linear regression analyses. Intracranial volume, age, antipsychotic medication and IQ were included as independent predictor-variables.The caudate volume was negatively correlated with verbal learning performance uniquely in the EOS group (r=-.454, p=.034). There were comparable positive correlations between the lateral ventricular volume and the processing speed, attention and reasoning and problem solving domains for both the EOS patients and the healthy controls. Antipsychotic medication was related to ventricular enlargements, but did not affect the brain structure-function relationship.Enlargement of the caudate volume was related to poorer verbal learning performance in patients with EOS. Despite a 32% enlargement of the lateral ventricles in the EOS group, associations to processing speed, attention and reasoning and problem solving were similar for both the EOS and the HC groups.

The human Y chromosome is almost always excluded from genome-wide investigations of copy number variants (CNVs) due to its highly repetitive structure. This chromosome should not be forgotten, not only for its well-known relevance in male fertility, but also for its involvement in clinical phenotypes such as cancers, heart failure and sex specific effects on brain and behaviour.We analysed Y chromosome data from Affymetrix 6.0 SNP arrays and found that the signal intensities for most of 8179 SNP/CN probes in the male specific region (MSY) discriminated between a male, background signals in a female and an isodicentric male containing a large deletion of the q-arm and a duplication of the p-arm of the Y chromosome. Therefore, this SNP/CN platform is suitable for identification of gain and loss of Y chromosome sequences. In a set of 1718 males, we found 25 different CNV patterns, many of which are novel. We confirmed some of these variants by PCR or qPCR. The total frequency of individuals with CNVs was 14.7%, including 9.5% with duplications, 4.5% with deletions and 0.7% exhibiting both. Hence, a novel observation is that the frequency of duplications was more than twice the frequency of deletions. Another striking result was that 10 of the 25 detected variants were significantly overrepresented in one or more haplogroups, demonstrating the importance to control for haplogroups in genome-wide investigations to avoid stratification. NO-M214(xM175) individuals presented the highest percentage (95%) of CNVs. If they were not counted, 12.4% of the rest included CNVs, and the difference between duplications (8.9%) and deletions (2.8%) was even larger.Our results demonstrate that currently available genome-wide SNP platforms can be used to identify duplications and deletions in the human Y chromosome. Future association studies of the full spectrum of Y chromosome variants will demonstrate the potential involvement of gain or loss of Y chromosome sequence in different human phenotypes.

Bipolar disorder (BD) is a highly heritable disorder with polygenic inheritance. Among the most consistent findings from functional magnetic imaging (fMRI) studies are limbic hyperactivation and dorsal hypoactivation. However, the relation between reported brain functional abnormalities and underlying genetic risk remains elusive. This is the first cross-sectional study applying a whole-brain explorative approach to investigate potential influence of BD case-control status and polygenic risk on brain activation.A BD polygenic risk score (PGRS) was estimated from the Psychiatric Genomics Consortium BD case-control study, and assigned to each individual in our independent sample (N=85 BD cases and 121 healthy controls (HC)), all of whom participated in an fMRI emotional faces matching paradigm. Potential differences in BOLD response across diagnostic groups were explored at whole-brain level in addition to amygdala as a region of interest. Putative effects of BD PGRS on brain activation were also investigated.At whole-brain level, BD cases presented with significantly lower cuneus/precuneus activation than HC during negative face processing (Z-threshold=2.3 as cluster-level correction). The PGRS was associated positively with increased right inferior frontal gyrus (rIFG) activation during negative face processing. For amygdala activation, there were no correlations with diagnostic status or PGRS.These findings are in line with previous reports of reduced precuneus and altered rIFG activation in BD. While these results demonstrate the ability of PGRS to reveal underlying genetic risk of altered brain activation in BD, the lack of convergence of effects at diagnostic and PGRS level suggests that this relation is a complex one.

ObjectivesSeveral genetic studies have implicated the CACNA1C SNP rs1006737 in bipolar disorder (BD) and schizophrenia (SZ) pathology. This polymorphism was recently found associated with increased amygdala activity in healthy controls and patients with BD. We performed a functional Magnetic Resonance Imaging (fMRI) study in a sample of BD and SZ cases and healthy controls to test for altered amygdala activity in carriers of the rs1006737 risk allele (AA/AG), and to investigate if there were differences across the diagnostic groups.MethodsRs1006737 was genotyped in 250 individuals (N = 66 BD, 61 SZ and 123 healthy controls), all of Northern European origin, who underwent an fMRI negative faces matching task. Statistical tests were performed with a model correcting for sex, age, diagnostic category and medication status in the total sample, and then in each diagnostic group.ResultsIn the total sample, carriers of the risk allele had increased activation in the left amygdala. Group-wise analyses showed that this effect was significant in the BD group, but not in the other diagnostic groups. However, there was no significant interaction effect for the risk allele between BD and the other groups.ConclusionsThese results indicate that CACNA1C SNP rs1006737 affects amygdala activity during emotional processing across all diagnostic groups. The current findings add to the growing body of knowledge of the pleiotropic effect of this polymorphism, and further support that ion channel dysregulation is involved in the underlying mechanisms of BD and SZ.

BACKGROUND: Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation. METHODOLOGY/PRINCIPAL FINDINGS: We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia. CONCLUSIONS/SIGNIFICANCE: We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.