Schizophrenia Loci Research Articles

Multitrait Genetic Analysis Identifies Novel Pleiotropic Loci for Depression and Schizophrenia in East Asians.

While genetic correlations, pleiotropic loci, and shared genetic mechanisms of psychiatric disorders have been extensively studied in European populations, the investigation of these factors in East Asian populations has been relatively limited. To identify novel pleiotropic risk loci for depression and schizophrenia (SCZ) in East Asians. We utilized the most comprehensive dataset available for East Asians and quantified the genetic overlap between depression, SCZ, and their related traits via a multitrait genome-wide association study. Global and local genetic correlations were estimated by LDSC and ρ-HESS. Pleiotropic loci were identified by the multitrait analysis of GWAS (MTAG). Besides the significant correlation between depression and SCZ, our analysis revealed genetic correlations between depression and obesity-related traits, such as weight, BMI, T2D, and HDL. In SCZ, significant correlations were detected with HDL, heart diseases and use of various medications. Conventional meta-analysis of depression and SCZ identified a novel locus at 1q25.2 in East Asians. Further multitrait analysis of depression, SCZ and related traits identified ten novel pleiotropic loci for depression, and four for SCZ. Our findings demonstrate shared genetic underpinnings between depression and SCZ in East Asians, as well as their associated traits, providing novel candidate genes for the identification and prioritization of therapeutic targets specific to this population.

Shared Genetic Architecture Between Schizophrenia and Anorexia Nervosa: A Cross-trait Genome-Wide Analysis.

Schizophrenia (SCZ) and anorexia nervosa (AN) are 2 severe and highly heterogeneous disorders showing substantial familial co-aggregation. Genetic factors play a significant role in both disorders, but the shared genetic etiology between them is yet to be investigated. Using summary statistics from recent large genome-wide association studies on SCZ (Ncases = 53 386) and AN (Ncases = 16 992), a 2-sample Mendelian randomization analysis was conducted to explore the causal relationship between SCZ and AN. MiXeR was employed to quantify their polygenic overlap. A conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was adopted to identify loci jointly associated with both disorders. Functional annotation and enrichment analyses were performed on the shared loci. We observed a cross-trait genetic enrichment, a suggestive bidirectional causal relationship, and a considerable polygenic overlap (Dice coefficient = 62.2%) between SCZ and AN. The proportion of variants with concordant effect directions among all shared variants was 69.9%. Leveraging overlapping genetic associations, we identified 6 novel loci for AN and 33 novel loci for SCZ at condFDR <0.01. At conjFDR <0.05, we identified 10 loci jointly associated with both disorders, implicating multiple genes highly expressed in the cerebellum and pituitary and involved in synapse organization. Particularly, high expression of the shared genes was observed in the hippocampus in adolescence and orbitofrontal cortex during infancy. This study provides novel insights into the relationship between SCZ and AN by revealing a shared genetic component and offers a window into their complex etiology.

Polygenic Resilience Scores are Associated with Lower Penetrance of Schizophrenia Risk Genes, Protection Against Psychiatric and Medical Disorders, and Enhanced Mental Well-Being and Cognition.

In the past decade, significant advances have been made in finding genomic risk loci for schizophrenia (SCZ). This, in turn, has enabled the search for SCZ resilience loci that mitigate the impact of SCZ risk genes. Recently, we discovered the first genomic resilience profile for SCZ, completely independent from the established risk loci for SCZ. We posited that these resilience loci protect against SCZ for those having a heighted genomic risk for SCZ. Nevertheless, our understanding of genetic resilience remains limited. It remains unclear whether resilience loci foster protection against adverse states associated with SCZ risk related to clinical, cognitive, and brain-structural phenotypes. To address this knowledge gap, we analyzed data from 487,409 participants from the UK Biobank, and found that resilience loci for SCZ afforded protection against lifetime psychiatric (schizophrenia, bipolar disorder, anxiety, and depression) and non-psychiatric medical disorders (such as asthma, cardiovascular disease, digestive disorders, metabolic disorders, and external causes of morbidity and mortality). Resilience loci also protected against self-harm behaviors, improved fluid intelligence, and larger whole-brain and brain-regional sizes. Overall, this study sheds light on the range of phenotypes that are significantly associated with resilience loci within the general population, revealing distinct patterns separate from those associated with SCZ risk loci. Our findings indicate that resilience loci may offer protection against serious psychiatric and medical outcomes, co-morbidities, and cognitive impairment. Therefore, it is conceivable that resilience loci facilitate adaptive processes linked to improved health and life expectancy.

Copy number variant risk loci for schizophrenia converge on the BDNF pathway

Objectives Schizophrenia genetics is intricate, with common and rare variants’ contributions not fully understood. Certain copy number variations (CNVs) elevate risk, pivotal for understanding mental disorder models. Despite CNVs’ genome-wide distribution and variable gene and protein effects, we must explore beyond affected genes to interaction partners and molecular pathways. Methods In this study, we developed machine-readable interactive pathways to enable analysis of functional effects of genes within CNV loci and identify ten common pathways across CNVs with high schizophrenia risk using the WikiPathways database, schizophrenia risk gene collections from GWAS studies, and a gene-disease association database. Results For CNVs that are pathogenic for schizophrenia, we found overlapping pathways, including BDNF signalling, cytoskeleton, and inflammation. Common schizophrenia risk genes identified by different studies are found in all CNV pathways, but not enriched. Conclusions Our findings suggest that specific pathways - BDNF signalling - are critical contributors to schizophrenia risk conferred by rare CNVs. Our approach highlights the importance of not only investigating deleted or duplicated genes within pathogenic CNV loci, but also study their direct interaction partners, which may explain pleiotropic effects of CNVs on schizophrenia risk and offer a broader field for interventions.

Genetic susceptibility for schizophrenia after adjustment by genetic susceptibility for smoking: implications in identification of risk genes and genetic correlation with related traits.

Prevalence of smoking in schizophrenia (SCZ) is larger than in general population. Genetic studies provided some evidence of a causal effect of smoking on SCZ. We aim to characterize the genetic susceptibility to SCZ affected by genetic susceptibility to smoking. Multi-trait-based conditional and joint analysis was applied to the largest European SCZ genome-wide association studies (GWAS) to remove genetic effects on SCZ driven by smoking, estimated by generalized summary data-based Mendelian randomization. Enrichment analysis was performed to compare original v. conditional GWAS. Change in genetic correlation between SCZ and relevant traits after conditioning was assessed. Colocalization analysis was performed to identify specific loci confirming general findings. Conditional analysis identified 19 new risk loci for SCZ and 42 lost loci whose association with SCZ may be partially driven by smoking. These results were strengthened by colocalization analysis. Enrichment analysis indicated a higher association of differentially expressed genes at prenatal brain stages after conditioning. Genetic correlation of SCZ with substance use and dependence, attention deficit-hyperactivity disorder, and several externalizing traits significantly changed after conditioning. Colocalization of association signal between SCZ and these traits was identified for some of the lost loci, such as CHRNA2, CUL3, and PCDH7. Our approach led to identification of potential new SCZ loci, loci partially associated to SCZ through smoking, and a shared genetic susceptibility between SCZ and smoking behavior related to externalizing phenotypes. Application of this approach to other psychiatric disorders and substances may lead to a better understanding of the role of substances on mental health.

The relationship between case-control differential gene expression from brain tissue and genetic associations in schizophrenia.

Large numbers of genetic loci have been identified that are known to contain common risk alleles for schizophrenia, but linking associated alleles to specific risk genes remains challenging. Given that most alleles that influence liability to schizophrenia are thought to do so by altered gene expression, intuitively, case-control differential gene expression studies should highlight genes with a higher probability of being associated with schizophrenia and could help identify the most likely causal genes within associated loci. Here, we test this hypothesis by comparing transcriptome analysis of the dorsolateral prefrontal cortex from 563 schizophrenia cases and 802 controls with genome-wide association study (GWAS) data from the third wave study of the Psychiatric Genomics Consortium. Genes differentially expressed in schizophrenia were not enriched for common allelic association statistics compared with other brain-expressed genes, nor were they enriched for genes within associated loci previously reported to be prioritized by genetic fine-mapping. Genes prioritized by Summary-based Mendelian Randomization were underexpressed in cases compared to other genes in the same GWAS loci. However, the overall strength and direction of expression change predicted by SMR were not related to that observed in the differential expression data. Overall, this study does not support the hypothesis that genes identified as differentially expressed from RNA sequencing of bulk brain tissue are enriched for those that show evidence for genetic associations. Such data have limited utility for prioritizing genes in currently associated loci in schizophrenia.

Genome-wide tandem repeat expansions contribute to schizophrenia risk

Tandem repeat expansions (TREs) can cause neurological diseases but their impact in schizophrenia is unclear. Here we analyzed genome sequences of adults with schizophrenia and found that they have a higher burden of TREs that are near exons and rare in the general population, compared with non-psychiatric controls. These TREs are disproportionately found at loci known to be associated with schizophrenia from genome-wide association studies, in individuals with clinically-relevant genetic variants at other schizophrenia loci, and in families where multiple individuals have schizophrenia. We showed that rare TREs in schizophrenia may impact synaptic functions by disrupting the splicing process of their associated genes in a loss-of-function manner. Our findings support the involvement of genome-wide rare TREs in the polygenic nature of schizophrenia.

Regulatory Variant rs2535629 in ITIH3 Intron Confers Schizophrenia Risk By Regulating CTCF Binding and SFMBT1 Expression.

Genome‐wide association studies have identified 3p21.1 as a robust risk locus for schizophrenia. However, the underlying molecular mechanisms remain elusive. Here a functional regulatory variant (rs2535629) is identified that disrupts CTCF binding at 3p21.1. It is confirmed that rs2535629 is also significantly associated with schizophrenia in Chinese population and the regulatory effect of rs2535629 is validated. Expression quantitative trait loci analysis indicates that rs2535629 is associated with the expression of three distal genes (GLT8D1, SFMBT1, and NEK4) in the human brain, and CRISPR‐Cas9‐mediated genome editing confirmed the regulatory effect of rs2535629 on GLT8D1, SFMBT1, and NEK4. Interestingly, differential expression analysis of GLT8D1, SFMBT1, and NEK4 suggested that rs2535629 may confer schizophrenia risk by regulating SFMBT1 expression. It is further demonstrated that Sfmbt1 regulates neurodevelopment and dendritic spine density, two key pathological characteristics of schizophrenia. Transcriptome analysis also support the potential role of Sfmbt1 in schizophrenia pathogenesis. The study identifies rs2535629 as a plausibly causal regulatory variant at the 3p21.1 risk locus and demonstrates the regulatory mechanism and biological effect of this functional variant, indicating that this functional variant confers schizophrenia risk by altering CTCF binding and regulating expression of SFMBT1, a distal gene which plays important roles in neurodevelopment and synaptic morphogenesis.

Schizophrenia Genetics and Neuropsychiatric Features in Childhood-onset Systemic Lupus Erythematosus.

We examined the association between schizophrenia genetic susceptibility loci and neuropsychiatric systemic lupus erythematosus (NPSLE) features in childhood-onset SLE (cSLE) participants. Study participants from the Lupus Clinic at the Hospital for Sick Children, Toronto, met ≥ 4 of the American College of Rheumatology and/or SLE International Collaborating Clinics SLE classification criteria and were genotyped using the Illumina Multi-Ethnic Global Array or the Global Screening Array. Ungenotyped single-nucleotide polymorphisms (SNPs) were imputed, and ancestry was genetically inferred. We calculated 2 additive schizophrenia-weighted polygenic risk scores (PRS) using (1) genome-wide significant SNPs (P < 5 × 10-8), and (2) an expanded list of SNPs with significance at P < 0.05. We defined 2 outcomes compared to absence of NPSLE features: (1) any NPSLE feature, and (2) subtypes of NPSLE features (psychosis and nonpsychosis NPSLE). We completed logistic and multinomial regressions, first adjusted for inferred ancestry only and then added for variables significantly associated with NPSLE in our cohort (P < 0.05). We included 513 participants with cSLE. Median age at diagnosis was 13.8 years (IQR 11.2-15.6), 83% were female, and 31% were of European ancestry. An increasing schizophrenia genome-wide association PRS was not associated with NPSLE (OR 1.04, 95% CI 0.87-1.26, P = 0.62), nor with the NPSLE subtypes, psychosis (OR 0.97, 95% CI 0.73-1.29, P = 0.84) and other nonpsychosis NPSLE (OR 1.08, 95% CI 0.88-1.34, P = 0.45), in ancestry-adjusted models. Results were similar for the model including covariates (ancestry, malar rash, oral/nasal ulcers, arthritis, lymphopenia, Coombs-positive hemolytic anemia, lupus anticoagulant, and anticardiolipin antibodies) and for the expanded PRS estimates. We did not observe an association between known risk loci for schizophrenia and NPSLE in a multiethnic cSLE cohort. This work warrants further validation.

Genome-wide association study followed by trans-ancestry meta-analysis identify 17 new risk loci for schizophrenia

BackgroundOver 200 schizophrenia risk loci have been identified by genome-wide association studies (GWASs). However, the majority of risk loci were identified in populations of European ancestry (EUR), potentially missing important biological insights. It is important to perform 5 GWASs in non-European populations.MethodsTo identify novel schizophrenia risk loci, we conducted a GWAS in Han Chinese population (3493 cases and 4709 controls). We then performed a large-scale meta-analysis (a total of 143,438 subjects) through combining our results with previous GWASs conducted in EAS and EUR. In addition, we also carried out comprehensive post-GWAS analysis, including heritability partitioning, enrichment of schizophrenia associations in tissues and cell types, trancscriptome-wide association study (TWAS), expression quantitative trait loci (eQTL) and differential expression analysis.ResultsWe identified two new schizophrenia risk loci, including associations in SHISA9 (rs7192086, P = 4.92 × 10-08) and PES1 (rs57016637, P = 2.33 × 10−11) in Han Chinese population. A fixed-effect meta-analysis (a total of 143,438 subjects) with summary statistics from EAS and EUR identifies 15 novel genome-wide significant risk loci. Heritability partitioning with linkage disequilibrium score regression (LDSC) reveals a significant enrichment of schizophrenia heritability in conserved genomic regions, promoters, and enhancers. Tissue and cell-type enrichment analyses show that schizophrenia associations are significantly enriched in human brain tissues and several types of neurons, including cerebellum neurons, telencephalon inhibitory, and excitatory neurons. Polygenic risk score profiling reveals that GWAS summary statistics from trans-ancestry meta-analysis (EAS + EUR) improves prediction performance in predicting the case/control status of our sample. Finally, transcriptome-wide association study (TWAS) identifies risk genes whose cis-regulated expression change may have a role in schizophrenia.ConclusionsOur study identifies 17 novel schizophrenia risk loci and highlights the importance and necessity of conducting genetic study in different populations. These findings not only provide new insights into genetic etiology of schizophrenia, but also facilitate to delineate the pathophysiology of schizophrenia and develop new therapeutic targets.

Genome wide association study identifies four loci for early onset schizophrenia

Early onset schizophrenia (EOS, defined as first onset of schizophrenia before age 18) is a rare form of schizophrenia (SCZ). Though genome-wide association studies (GWASs) have identified multiple risk variants for SCZ, most of the cases included in these GWASs were not stratified according to their first age at onset. To date, the genetic architecture of EOS remains largely unknown. To identify the risk variants and to uncover the genetic basis of EOS, we conducted a two-stage GWAS of EOS in populations of Han Chinese ancestry in this study. We first performed a GWAS using 1,256 EOS cases and 2,661 healthy controls (referred as discovery stage). The genetic variants with a P < 1.0 × 10−04 in discovery stage were replicated in an independent sample (903 EOS cases and 3,900 controls). We identified four genome-wide significant risk loci for EOS in the combined samples (2,159 EOS cases and 6,561 controls), including 1p36.22 (rs1801133, Pmeta = 4.03 × 10−15), 1p31.1 (rs1281571, Pmeta = 4.14 × 10−08), 3p21.31 (rs7626288, Pmeta = 1.57 × 10−09), and 9q33.3 (rs592927, Pmeta = 4.01 × 10−11). Polygenic risk scoring (PRS) analysis revealed substantial genetic overlap between EOS and SCZ. These discoveries shed light on the genetic basis of EOS. Further functional characterization of the identified risk variants and genes will help provide potential targets for therapeutics and diagnostics.

CCmed: cross-condition mediation analysis for identifying replicable trans-associations mediated by cis-gene expression.

Trans-acting expression quantitative trait loci (eQTLs) collectively explain a substantial proportion of expression variation, yet are challenging to detect and replicate since their effects are often individually weak. A large proportion of genetic effects on distal genes are mediated through cis-gene expression. Cis-association (between SNP and cis-gene) and gene-gene correlation conditional on SNP genotype could establish trans-association (between SNP and trans-gene). Both cis-association and gene-gene conditional correlation have effects shared across relevant tissues and conditions, and trans-associations mediated by cis-gene expression also have effects shared across relevant conditions. We proposed a Cross-Condition Mediation analysis method (CCmed) for detecting cis-mediated trans-associations with replicable effects in relevant conditions/studies. CCmed integrates cis-association and gene-gene conditional correlation statistics from multiple tissues/studies. Motivated by the bimodal effect-sharing patterns of eQTLs, we proposed two variations of CCmed, CCmedmost and CCmedspec for detecting cross-tissue and tissue-specific trans-associations, respectively. We analyzed data of 13 brain tissues from the Genotype-Tissue Expression (GTEx) project, and identified trios with cis-mediated trans-associations across brain tissues, many of which showed evidence of trans-association in two replication studies. We also identified trans-genes associated with schizophrenia loci in at least two brain tissues. CCmed software is available at http://github.com/kjgleason/CCmed. Supplementary data are available at Bioinformatics online.

Functional variants fine‐mapping and gene function characterization provide insights into the role of ZNF323 in schizophrenia pathogenesis

Schizophrenia is a severe mental disease characterized with positive symptoms, negative symptoms, and cognitive impairments. Although recent genome-wide association studies (GWASs) have identified over 145 risk loci for schizophrenia, pinpointing the causal variants and genes at the reported loci and elucidating their roles in schizophrenia remain major challenges. Here we identify a functional single-nucleotide polymorphism (SNP; rs213237) in ZNF323 promoter by using functional fine-mapping. We found that allelic differences at rs213237 affected the ZNF323 promoter activity significantly. Consistently, expression quantitative trait loci (eQTL) analysis showed that rs213237 was significantly associated with ZNF323 expression in diverse human brain tissues, suggesting that rs213237 may contribute to schizophrenia risk through regulating ZNF323 expression. Interestingly, we found that ZNF323 protein was localized in the nucleus and knockdown of ZNF323 in macaque neural stem cells (mNSCs) significantly impaired proliferation and survival of mNSCs. We further showed that stable knockdown of ZNF323 in SH-SY5Y cells resulted in significant decrease of the tyrosine hydroxylase (TH) protein expression. Finally, transcriptome analysis revealed that ZNF323 may regulate pivotal schizophrenia risk genes (including VIPR2 and NPY) and schizophrenia-associated pathways (including PI3K-AKT and NOTCH signaling pathways), suggesting that ZNF323 may be a major regulator of schizophrenia risk genes. Our study reveals how a genetic variant in ZNF323 promoter contributes to schizophrenia risk through regulating ZNF323 expression. More importantly, our findings demonstrate that ZNF323 may have a pivotal role in schizophrenia pathogenesis through regulating schizophrenia risk genes and schizophrenia-associated biological processes (including neurodevelopment, PI3K-AKT, and NOTCH signaling pathways).

Влияние генотипа и среды на метилирование ДНК в пересекающихся индексных локусах шизофрении и интеллекта

Целью работы была оценка вклада гаплотипов и полисредового риска (ПСР) в вариативность метилирования ДНК в локусах риска шизофрении. В периферической крови 70 пациентов методом одномолекулярного секвенирования Pacbio бисульфитно-конвертированной ДНК исследовали фрагменты внутри генов MIR137HR и CYP17A1 и вблизи SLC39A8. Из почти 1000 изученных цитозинов восемь были вариативно метилированы. Для семи из них обнаружено влияние генотипа. Дополнительно в одном случае найден эффект взаимодействия генотипа и ПСР и в одном - главный эффект ПСР. Таким образом, у больных в изученных участках вариативность метилирования преимущественно обусловлена структурой ДНК. The study aimed to assess the contribution of haplotypes and polyenvironmental risk scores (PERS) to DNA methylation variability in schizophrenia index loci. In peripheral blood of 70 patients, fragments within the MIR137HR and CYP17A1 genes and near SLC39A8 were studied by Pacbio-based single-molecule real-time bisulfite sequencing. Of about 1000 cytosines, only eight were variably methylated. Genotypes influenced seven of them. Additionally, in one case an interaction effect of haplotype and PERS and in another case a main effect of PERS were found. Thus, in the studied schizophrenia loci, variable methylation is mainly due to DNA structure.

Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia.

Genome-wide association studies have implicated thousands of noncoding variants across common human phenotypes. However, they cannot directly inform the cellular context in which disease-associated variants act. Here, we use open chromatin profiles from discrete mouse cell populations to address this challenge. We applied stratified linkage disequilibrium score regression and evaluated heritability enrichment in 64 genome-wide association studies, emphasizing schizophrenia. We provide evidence that mouse-derived human open chromatin profiles can serve as powerful proxies for difficult to obtain human cell populations, facilitating the illumination of common disease heritability enrichment across an array of human phenotypes. We demonstrate that signatures from discrete subpopulations of cortical excitatory and inhibitory neurons are significantly enriched for schizophrenia heritability with maximal enrichment in cortical layer V excitatory neurons. We also show that differences between schizophrenia and bipolar disorder are concentrated in excitatory neurons in cortical layers II-III, IV, and V, as well as the dentate gyrus. Finally, we leverage these data to fine-map variants in 177 schizophrenia loci nominating variants in 104/177. We integrate these data with transcription factor binding site, chromatin interaction, and validated enhancer data, placing variants in the cellular context where they may modulate risk.

Genome-wide Association Analysis of Parkinson’s Disease and Schizophrenia Reveals Shared Genetic Architecture and Identifies Novel Risk Loci

BackgroundParkinson’s disease (PD) and schizophrenia (SCZ) are heritable brain disorders that involve dysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between the disorders, and movement disturbances are common in patients with SCZ before treatment with antipsychotic drugs. Despite this, little is known about shared genetic etiology between the disorders. MethodsWe analyzed recent large genome-wide association studies on patients with SCZ (N = 77,096) and PD (N = 417,508) using a conditional/conjunctional false discovery rate (FDR) approach to evaluate overlap in common genetic variants and improve statistical power for genetic discovery. Using a variety of biological resources, we functionally characterized the identified genomic loci. ResultsWe observed genetic enrichment in PD conditional on associations with SCZ and vice versa, indicating polygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified 9 novel PD risk loci and 1 novel SCZ locus at conditional FDR < .01. Furthermore, we identified 9 genomic loci jointly associated with PD and SCZ at conjunctional FDR < .05. There was an even distribution of antagonistic and agonistic effect directions among the shared loci, in line with the insignificant genetic correlation between the disorders. Of 67 genes mapped to the shared loci, 65 are expressed in the human brain and show cell type–specific expression profiles. ConclusionsAltogether, the study increases understanding of the genetic architectures underlying SCZ and PD, indicating that common molecular genetic mechanisms may contribute to overlapping pathophysiological and clinical features between the disorders.

Molecular Variants in Human Trace Amine-Associated Receptors and Their Implications in Mental and Metabolic Disorders

We provide a comprehensive review of the available evidence on the pathophysiological implications of genetic variants in the human trace amine-associated receptor (TAAR) superfamily. Genes coding for trace amine-associated receptors (taars) represent a multigene family of G-protein-coupled receptors, clustered to a small genomic region of 108 kb located in chromosome 6q23, which has been consistently identified by linkage analyses as a susceptibility locus for schizophrenia and affective disorders. Most TAARs are expressed in brain areas involved in emotions, reward and cognition. TAARs are activated by endogenous trace amines and thyronamines, and evidence for a modulatory action on other monaminergic systems has been reported. Therefore, linkage analyses were followed by fine mapping association studies in schizophrenia and affective disorders. However, none of these reports has received sufficient universal replication, so their status remains uncertain. Single nucleotide polymorphisms in taars have emerged as susceptibility loci from genome-wide association studies investigating migraine and brain development, but none of the detected variants reached the threshold for genome-wide significance. In the last decade, technological advances enabled single-gene or whole-exome sequencing, thus allowing the detection of rare genetic variants, which may have a greater impact on the risk of complex disorders. Using these approaches, several taars (especially taar1) variants have been detected in patients with mental and metabolic disorders, and in some cases, defective receptor function has been demonstrated in vitro. Finally, with the use of transcriptomic and peptidomic techniques, dysregulations of TAARs (especially TAAR6) have been identified in brain disorders characterized by cognitive impairment.

Is psychosis a dysmyelination-related information-processing disorder?

Numerous lines of evidence implicate myelin and oligodendrocyte function as critical processes affecting neuronal connectivity, which is a central abnormality in schizophrenia. Neurodevelopmental models related to dysmyelination have suggested its relation with different schizophrenia-like symptoms. Post-mortem studies in patients with schizophrenia have reported 14-22% reduction in the density and the quantity of oligodendrocytes. Several myelin-related candidate genes have been linked oligodendrocyte and myelin dysfunction with neurocircuitry abnormalities in schizophrenia. A number of myelin gene knockout mice models exhibit schizophrenia-like behaviours, and genomic, especially GWAS, studies identified new schizophrenia loci related to oligodendrocyte genetic polymorphisms. It is known that myelin acts as electrical insulation for the ensheathed axon, which helps to preserve the amplitude and to increase the conduction velocity of the propagating axon potential. A growing body of evidence points towards the involvement of dysmyelination of the prefrontal cortex in the development of the cognitive symptoms of psychosis. Neuroimaging investigations have linked processing speed to brain anatomical connectivity, and have pointed the role of processing speed among the predictors of clinical changes in schizophrenia. The dysmyelination-induced delays in patients with psychosis may cause a discrepancy in sensory feedback mechanisms, which results in prediction error. The myelin abnormalities and the resulting conduction delays vary during the course of the multiple sclerosis and this type of cycles are possibly associated with fluctuations in conduction velocity in psychosis. It is worthy of note that the major histocompatibility complex (MHC) is responsible for the genetic overlap in both multiple sclerosis and schizophrenia. Multiple sclerosis manifests sensory and motor symptoms, and schizophrenia disordered cognition and emotion. Having in mind the interdependent relationship of oligodendrocytes and the axons they myelinate, we could suggest that both multiple sclerosis and schizophrenia may use in central nervous system a common pathway of disordered information-processing. Recent research suggests that adaptive myelination could normalize neuronal electrical excitability, which in turn can modify myelin plasticity, resulting to neural activity and behavior modulation. We may suggest that interventions that preserve white matter integrity or ameliorate white matter disruption may enhance information-processing and functional outcome in psychosis.

The effect of a genetic variant at the schizophrenia associated AS3MT/BORCS7 locus on striatal dopamine function: A PET imaging study

One of the most statistically significant loci to result from large-scale GWAS of schizophrenia is 10q24.32. However, it is still unclear how this locus is involved in the pathoaetiology of schizophrenia. The hypothesis that presynaptic dopamine dysfunction underlies schizophrenia is one of the leading theories of the pathophysiology of the disorder. Supporting this, molecular imaging studies show evidence for elevated dopamine synthesis and release capacity. Thus, altered dopamine function could be a potential mechanism by which this genetic variant acts to increase the risk of schizophrenia.We therefore tested the hypothesis that the 10q24.32 region confers genetic risk for schizophrenia through an effect on striatal dopamine function. To this aim we investigated the in vivo relationship between a GWAS schizophrenia-associated SNP within this locus and dopamine synthesis capacity measured using [18F]-DOPA PET in healthy controls. 92 healthy volunteers underwent [18F]-DOPA PET scans to measure striatal dopamine synthesis capacity (indexed as Kicer) and were genotyped for the SNP rs7085104. We found a significant association between rs7085104 genotype and striatal Kicer. Our findings indicate that the mechanism mediating the 10q24.32 risk locus for schizophrenia could involve altered dopaminergic function. Future studies are needed to clarify the neurobiological pathway implicated in this association.

Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study

Genome-wide association studies (GWASs) in European populations have identified more than 100 schizophrenia-associated loci. A schizophrenia GWAS in a unique Indian population offers novel findings. To discover and functionally evaluate genetic loci for schizophrenia in a GWAS of a unique Indian population. This GWAS included a sample of affected individuals, family members, and unrelated cases and controls. Three thousand ninety-two individuals were recruited and diagnostically ascertained via medical records, hospitals, clinics, and clinical networks in Chennai and surrounding regions. Affected participants fulfilled DSM-IV diagnostic criteria for schizophrenia. Unrelated control participants had no personal or family history of psychotic disorder. Recruitment, genotyping, and analysis occurred in consecutive phases beginning January 1, 2001. Recruitment was completed on February 28, 2018, and genotyping and analysis are ongoing. Associations of single-nucleotide polymorphisms and gene expression with schizophrenia. The study population included 1321 participants with schizophrenia, 885 family controls, and 886 unrelated controls. Among participants with schizophrenia, mean (SD) age was 39.1 (11.4) years, and 52.7% were male. This sample demonstrated uniform ethnicity, a degree of inbreeding, and negligible rates of substance abuse. A novel genome-wide significant association was observed between schizophrenia and a chromosome 8q24.3 locus (rs10866912, allele A; odds ratio [OR], 1.27 [95% CI, 1.17-1.38]; P = 4.35 × 10-8) that attracted support in the schizophrenia Psychiatric Genomics Consortium 2 data (rs10866912, allele A; OR, 1.04 [95% CI, 1.02-1.06]; P = 7.56 × 10-4). This locus has undergone natural selection, with the risk allele A declining in frequency from India (approximately 72%) to Europe (approximately 43%). rs10866912 directly modifies the abundance of the nicotinate phosphoribosyltransferase gene (NAPRT1) transcript in brain cortex (normalized effect size, 0.79; 95% CI, 0.6-1.0; P = 5.8 × 10-13). NAPRT1 encodes a key enzyme for niacin metabolism. In Indian lymphoblastoid cell lines, (risk) allele A of rs10866912 was associated with NAPRT1 downregulation (AA: 0.74, n = 21; CC: 1.56, n = 17; P = .004). Preliminary zebrafish data further suggest that partial loss of function of NAPRT1 leads to abnormal brain development. Bioinformatic analyses and cellular and zebrafish gene expression studies implicate NAPRT1 as a novel susceptibility gene. Given this gene's role in niacin metabolism and the evidence for niacin deficiency provoking schizophrenialike symptoms in neuropsychiatric diseases such as pellagra and Hartnup disease, these results suggest that the rs10866912 genotype and niacin status may have implications for schizophrenia susceptibility and treatment.