We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.

Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.

Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. We identify a hemizygous SHANK1 deletion that segregates in a four-generation family in which male carriers--but not female carriers--have ASD with higher functioning. A de novo SHANK1 deletion was also detected in an unrelated male individual with ASD with higher functioning, and no equivalent SHANK1 mutations were found in >15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1.

The cerebellum is implicated in social cognition and is likely to be involved in the pathophysiology of autism spectrum disorder (ASD). The goal of our study was to explore cerebellar morphology in adults with ASD and its relationship to eye contact, as measured by fixation time allocated on the eye region using an eye-tracking device. Two-hundred ninety-four subjects with ASD and controls were included in our study and underwent a structural magnetic resonance imaging scan. Global segmentation and cortical parcellation of the cerebellum were performed. A sub-sample of 59 subjects underwent an eye tracking protocol in order to measure the fixation time allocated to the eye region. We did not observe any difference in global cerebellar volumes between ASD patients and controls; however, regional analyses found a decrease of the volume of the right anterior cerebellum in subjects with ASD compared to controls. There were significant correlations between fixation time on eyes and the volumes of the vermis and Crus I. Our results suggest that cerebellar morphology may be related to eye avoidance and reduced social attention. Eye tracking may be a promising neuro-anatomically based stratifying biomarker of ASD.

The present study was designed to investigate the effects of reputational priors and direct reciprocity on the dynamics of trust building in adults with (N = 17) and without (N = 25) autism spectrum disorder (ASD) using a multi-round Trust Game (MTG). On each round, participants, who played as investors, were required to maximize their benefits by updating their prior expectations (the partner's positive or negative reputation), based on the partner's directed reciprocity, and adjusting their own investment decisions accordingly. Results showed that reputational priors strongly oriented the initial decision to trust, operationalized as the amount of investment the investor shares with the counterpart. However, while typically developed participants were mainly affected by the direct reciprocity, and rapidly adopted the optimal Tit-for-Tat strategy, participants with ASD continued to rely on reputational priors throughout the game, even when experience of the counterpart's actual behavior contradicted their prior-based expectations. In participants with ASD, the effect of the reputational prior never disappeared, and affected judgments of trustworthiness and reciprocity of the partner even after completion of the game. Moreover, the weight of prior reputation positively correlated with the severity of the ASD participant's social impairments while the reciprocity score negatively correlated with the severity of repetitive and stereotyped behaviors, as measured by the Autism Diagnostic Interview-Revised (ADI-R). In line with Bayesian theoretical accounts, the present findings indicate that individuals with ASD have difficulties encoding incoming social information and using it to revise and flexibly update prior social expectations, and that this deficit might severely hinder social learning and everyday life interactions.

There is growing concern about measuring patient experience with mental health care. There are currently numerous patient-reported experience measures (PREMs) available for mental health care, but there is little guidance for selecting the most suitable instruments. The objective of this systematic review was to provide an overview of the psychometric properties and the content of available PREMs.

Circulating autoantibodies directed against extracellular domains of the glutamatergic N-methyl-D-aspartate receptors (NMDAR-Ab) elicit psychotic symptoms in humans and behavioral deficits in animal models. Recent advances suggest that NMDAR-Ab exert their pathogenic action by altering the trafficking of NMDAR, which results in a synaptic NMDAR hypofunction consistent with the consensual glutamatergic hypothesis of psychotic disorders. Yet, dysfunction in the dopaminergic signaling is also proposed to be at the core of psychotic disorders. Since NMDAR and dopamine D1 receptors (D1R) form membrane signaling complexes, we investigated whether NMDAR-Ab purified from patients with NMDAR-encephalitis or schizophrenia impaired D1R surface dynamics. As previous data demonstrated that NMDAR-Ab, at least from NMDAR-encephalitis patients, mainly bind to hippocampal NMDAR, we used single nanoparticle imaging to track D1R specifically at the surface of hippocampal neurons that were exposed to either purified G type immunoglobulins (IgGs) from NMDAR-Ab seropositive patients suffering from NMDAR-encephalitis or schizophrenia, or control IgGs from healthy NMDAR-Ab seropositive or seronegative subjects. We report that overnight incubation with NMDAR-Ab from patients, but not from healthy carriers, decreased the surface dynamics of D1R compared with NMDAR-Ab seronegative IgGs. This decrease was abolished, and even reversed, in D1R mutant that cannot physically interact with NMDAR. Overall, our data indicate that NMDAR-Ab from patients with psychotic symptoms alter the trafficking of D1R, likely through the surface crosstalk between NMDAR and D1R.

Precision psychiatry is attracting increasing attention lately as a recognized priority. One of the goals of precision psychiatry is to develop tools capable of aiding a clinically informed psychiatric diagnosis objectively. Cognitive, inflammatory and immunological factors are altered in both bipolar disorder (BD) and schizophrenia (SZ), however, most of these alterations do not respect diagnostic boundaries from a phenomenological perspective and possess great variability in different individuals with the same phenotypic diagnosis and, consequently, none so far has proven to have the ability of reliably aiding in the differential diagnosis of BD and SZ. We developed a probabilistic multi-domain data integration model consisting of immune and inflammatory biomarkers in peripheral blood and cognitive biomarkers using machine learning to predict diagnosis of BD and SZ. A total of 416 participants, being 323, 372, and 279 subjects for blood, cognition and combined biomarkers analysis, respectively. Our multi-domain model performances for the BD vs. control (sensitivity 80% and specificity 71%) and for the SZ vs. control (sensitivity 84% and specificity 81%) pairs were high in general, however, our multi-domain model had only moderate performance for the differential diagnosis of BD and SZ (sensitivity 71% and specificity 73%). In conclusion, our results show that the diagnosis of BD and of SZ, and that the differential diagnosis of BD and SZ can be predicted with possible clinical utility by a computational machine learning algorithm employing blood and cognitive biomarkers, and that their integration in a multi-domain outperforms algorithms based in only one domain. Independent studies are needed to validate these findings.

Infections and autoimmunity are associated with autism spectrum disorders (ASD), with both strongly influenced by the genetic regulation of the human leukocyte antigen (HLA) system. The relationship between ASD and the HLA genetic diversity requires further investigation. Using a case control design, the distribution of HLA class II-DRB1 and DQB1 alleles, genotypes and haplotypes were investigated in ASD patients, versus healthy controls (HC). ASD patients meeting DSM-IV TR criteria and HC (474 and 350 respectively) were genotyped at medium resolution using a Luminex-based SSO technology. Comparisons of genotypes, allele frequencies associated with a haplotype analysis were performed. Results indicate: (i) the HLA-DRB1 *11-DQB1*07 haplotype was more prevalent in ASD patients, versus HC (Pc = 0.001), partially replicating previous data and possibly linking to gastro-intestinal (GI)-related pro-inflammatory processes, given that this haplotype associates with pediatric celiac disorders; (ii) the HLA-DRB1 *17-DQB1*02 haplotype was higher in HC, versus ASD patients (Pc = 0.002), indicating that this is a protective haplotype. Using the Autism Diagnostic Interview to assess clinical dimensions, higher scores on social (Pc = 0.006) and non-verbal functioning (Pc = 0.004) associated with the DRB1 *11 DQB1*07 haplotype. Our results support HLA involvement in ASD, with possible relevance to GI and gut-brain axis dysregulation.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.

Epidemiology has repeatedly associated certain infections with a risk of further developing psychiatric diseases. Such infections can activate retro-transposable genetic elements (HERV) known to trigger immune receptors and impair synaptic plasticity of neuroreceptors. Since the HERV-W ENV protein was recently shown to co-cluster with pro-inflammatory cytokines in a subgroup of patients with schizophrenia or bipolar disorder, we questioned the influence of the COVID-19 pandemic on patients with psychosis spectrum disorders (PSD). Present results revealed that (i) SARS-CoV-2 serology shows high prevalence and titers of antibodies in PSD, (ii) HERV-W ENV is detected in seropositive individuals only and (iii) SARS-CoV-2 and HERV-W ENV positivity co-clustered with high serum levels of pro-inflammatory cytokines in psychotic patients. These results thus suggest that SARS-CoV-2 infection in many patients with psychotic disorders now admitted in the psychiatry department did not cause severe COVID-19. They also confirm the previously reported association of elevated serum pro-inflammatory cytokines and HERV-W ENV in a subgroup of psychotic patients. In the context of the COVID-19 pandemic, this cluster is only found in SARS-CoV-2 seropositive PSD cases, suggesting a dominant influence of this virus on HERV-W ENV and cytokine expression, and/or patients' greater susceptibility to SARS-CoV-2 infection. Further investigation on an interplay between this viral infection and the clinical evolution of such PSD patients is needed. However, this repeatedly defined subgroup of psychotic patients with a pro-inflammatory phenotype and HERV expression calls for a differential therapeutic approach in psychoses, therefore for further precision medicine development.

Repetitive and restricted behaviors and interests (RRBI) are core symptoms of autism with a complex entity and are commonly categorized into 'motor-driven' and 'cognitively driven'. RRBI symptomatology depends on the individual's clinical environment limiting the understanding of RRBI physiology, particularly their associated neuroanatomical structures. The complex RRBI heterogeneity needs to explore the whole RRBI spectrum by integrating the clinical context [autistic individuals, their relatives and typical developing (TD) individuals]. We hypothesized that different RRBI dimensions would emerge by exploring the whole spectrum of RRBI and that these dimensions are associated with neuroanatomical signatures-involving cortical and subcortical areas.

About one fourth of patients with bipolar disorders (BD) have depressive episodes with a seasonal pattern (SP) coupled to a more severe disease. However, the underlying genetic influence on a SP in BD remains to be identified. We studied 269 BD Caucasian patients, with and without SP, recruited from university-affiliated psychiatric departments in France and performed a genetic single-marker analysis followed by a gene-based analysis on 349 single nucleotide polymorphisms (SNPs) spanning 21 circadian genes and 3 melatonin pathway genes. A SP in BD was nominally associated with 14 SNPs identified in 6 circadian genes: NPAS2, CRY2, ARNTL, ARNTL2, RORA and RORB. After correcting for multiple testing, using a false discovery rate approach, the associations remained significant for 5 SNPs in NPAS2 (chromosome 2:100793045-100989719): rs6738097 (pc = 0.006), rs12622050 (pc = 0.006), rs2305159 (pc = 0.01), rs1542179 (pc = 0.01), and rs1562313 (pc = 0.02). The gene-based analysis of the 349 SNPs showed that rs6738097 (NPAS2) and rs1554338 (CRY2) were significantly associated with the SP phenotype (respective Empirical p-values of 0.0003 and 0.005). The associations remained significant for rs6738097 (NPAS2) after Bonferroni correction. The epistasis analysis between rs6738097 (NPAS2) and rs1554338 (CRY2) suggested an additive effect. Genetic variations in NPAS2 might be a biomarker for a seasonal pattern in BD.

The neuropeptide oxytocin (OT) is one of the major targets of research in neuroscience, with respect to social functioning. Oxytocin promotes social skills and improves the quality of face processing in individuals with social dysfunctions such as autism spectrum disorder (ASD). Although one of OT's key functions is to promote social behavior during dynamic social interactions, the neural correlates of this function remain unknown. Here, we combined acute intranasal OT (IN-OT) administration (24 IU) and fMRI with an interactive ball game and a face-matching task in individuals with ASD (N = 20). We found that IN-OT selectively enhanced the brain activity of early visual areas in response to faces as compared to non-social stimuli. OT inhalation modulated the BOLD activity of amygdala and hippocampus in a context-dependent manner. Interestingly, IN-OT intake enhanced the activity of mid-orbitofrontal cortex in response to a fair partner, and insula region in response to an unfair partner. These OT-induced neural responses were accompanied by behavioral improvements in terms of allocating appropriate feelings of trust toward different partners' profiles. Our findings suggest that OT impacts the brain activity of key areas implicated in attention and emotion regulation in an adaptive manner, based on the value of social cues.

Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.