Susceptibility Locus For Schizophrenia Research Articles

Identification of Schizophrenia Susceptibility Loci in the Urban Taiwanese Population.

Background and Objectives: Genomic studies have identified several SNP loci associated with schizophrenia in East Asian populations. Environmental factors, particularly urbanization, play a significant role in schizophrenia development. This study aimed to identify schizophrenia susceptibility loci and characterize their biological functions and molecular pathways in Taiwanese urban Han individuals. Materials and Methods: Participants with schizophrenia were recruited from the Taiwan Precision Medicine Initiative at Tri-Service General Hospital. Genotype-phenotype association analysis was performed, with significant variants annotated and analyzed for functional relevance. Results: A total of 137 schizophrenia patients and 26,129 controls were enrolled. Ten significant variants (p < 1 × 10-5) and 15 expressed genes were identified, including rs1010840 (SOWAHC and RGPD6), rs11083963 (TRPM4), rs11619878 (LINC00355 and LINC01052), rs117010638 (AGBL1 and MIR548AP), rs1170702 (LINC01680 and LINC01720), rs12028521 (KAZN and PRDM2), rs12859097 (DMD), rs1556812 (ATP11A), rs78144262 (LINC00977), and rs9997349 (ENPEP). These variants and associated genes are involved in immune response, blood pressure regulation, muscle function, and the cytoskeleton. Conclusions: Identified variants and associated genes suggest a potential genetic predisposition to schizophrenia in the Taiwanese urban Han population, highlighting the importance of potential comorbidities, considering population-specific genetic and environmental interactions.

Complement C4 associations with altered microbial biomarkers exemplify gene-by-environment interactions in schizophrenia

Schizophrenia is a complex brain disorder with genetic and environmental factors contributing to its etiology. Complement C4 genes are schizophrenia susceptibility loci and are activated in response to infections and gut microbiome imbalances. We hypothesize that C4 genetic susceptibility predisposes individuals to neuropathological effects from pathogen exposures or a microbiome in dysbiosis. In 214 individuals with schizophrenia and 123 non-psychiatric controls, we examined C4 gene copy number and haplotype groups for associations with schizophrenia and microbial plasma biomarkers. C4A copy number and haplotypes containing HERV-K insertions (C4A-long; C4AL-C4AL) conferred elevated odds ratios for schizophrenia diagnoses (OR 1.58–2.56, p < 0.0001), while C4B-short (C4BS) haplogroups conferred decreased odds (OR 0.43, p < 0.0001). Haplogroup-microbe combinations showed extensive associations with schizophrenia including C4AL with Candida albicans IgG (OR 2.16, p < 0.0005), C4AL-C4BL with cytomegalovirus (CMV) IgG (OR 1.79, p < 0.008), C4BS with lipopolysaccharide-binding protein (LBP) (OR 1.18, p < 0.0001), and C4AL-C4AL with Toxoplasma gondii IgG (OR = 17.67, p < 0.0001). In controls, only one haplogroup-microbe combination was significant: C4BS with CMV IgG (OR 0.52, p < 0.02). In schizophrenia only, LBP and CMV IgG levels were inversely correlated with C4A and C4S copy numbers, respectively (R2 = 0.13–0.16, p < 0.0001). C4 haplogroups were associated with altered scores of cognitive functioning in both cases and controls and with psychiatric symptom scores in schizophrenia. Our findings link complement C4 genes with a susceptibility to infections and a dysbiotic microbiome in schizophrenia. These results support immune system mechanisms by which gene-environmental interactions may be operative in schizophrenia.

DSNetwork: An Integrative Approach to Visualize Predictions of Variants' Deleteriousness.

One of the most challenging tasks of the post-genome-wide association studies (GWAS) research era is the identification of functional variants among those associated with a trait for an observed GWAS signal. Several methods have been developed to evaluate the potential functional implications of genetic variants. Each of these tools has its own scoring system, which forces users to become acquainted with each approach to interpret their results. From an awareness of the amount of work needed to analyze and integrate results for a single locus, we proposed a flexible and versatile approach designed to help the prioritization of variants by aggregating the predictions of their potential functional implications. This approach has been made available through a graphical user interface called DSNetwork, which acts as a single point of entry to almost 60 reference predictors for both coding and non-coding variants and displays predictions in an easy-to-interpret visualization. We confirmed the usefulness of our methodology by successfully identifying functional variants in four breast cancer and nine schizophrenia susceptibility loci.

Novel genetic susceptibility loci identified by family based whole exome sequencing in Han Chinese schizophrenia patients

Schizophrenia (SCZ) is a highly heritable psychiatric disorder that affects approximately 1% of population around the world. However, early relevant studies did not reach clear conclusions of the genetic mechanisms of SCZ, suggesting that additional susceptibility loci that exert significant influence on SCZ are yet to be revealed. So, in order to identify novel susceptibility genes that account for the genetic risk of SCZ, we performed a systematic family-based study using whole exome sequencing (WES) in 65 Han Chinese families. The analysis of 51 SCZ trios with both unaffected parents identified 22 exonic and 1 splice-site de novo mutations (DNMs) on a total of 23 genes, and showed that 12 genes carried rare protein-altering compound heterozygous mutations in more than one trio. In addition, we identified 26 exonic or splice-site single nucleotide polymorphisms (SNPs) on 18 genes with nominal significance (P < 5 × 10−4) using a transmission disequilibrium test (TDT) in all the families. Moreover, TDT result confirmed a SCZ susceptibility locus on 3p21.1, encompassing the multigenetic region NEK4-ITIH1-ITIH3-ITIH4. Through several different strategies to predict the potential pathogenic genes in silico, we revealed 4 previous discovered susceptibility genes (TSNARE1, PBRM1, STAB1 and OLIG2) and 4 novel susceptibility loci (PSEN1, TLR5, MGAT5B and SSPO) in Han Chinese SCZ patients. In summary, we identified a list of putative candidate genes for SCZ using a family-based WES approach, thus improving our understanding of the pathology of SCZ and providing critical clues to future functional validation.

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.

Comprehensive functional annotation of susceptibility SNPs prioritized 10 genes for schizophrenia

Nearly 95% of susceptibility SNPs identified by genome-wide association studies (GWASs) are located in non-coding regions, which causes a lot of difficulty in deciphering their biological functions on disease pathogenesis. Here, we aimed to conduct a comprehensive functional annotation for all the schizophrenia susceptibility loci obtained from GWASs. Considering varieties of epigenomic regulatory elements, we annotated all 22,688 acquired susceptibility SNPs according to their genomic positions to obtain functional SNPs. The comprehensive annotation indicated that these functional SNPs are broadly involved in diverse biological processes. Histone modification enrichment showed that H3K27ac, H3K36me3, H3K4me1, and H3K4me3 were related to the development of schizophrenia. Transcription factors (TFs) prediction, methylation quantitative trait loci (meQTL) analyses, expression quantitative trait loci (eQTL) analyses, and proteomic quantitative trait loci analyses (pQTL) identified 447 target protein-coding genes. Subsequently, differential expression analyses between schizophrenia cases and controls, nervous system phenotypes from mouse models, and protein–protein interaction with known schizophrenia-related pathways and genes were carried out with our target genes. We finaly prioritized 10 target genes for schizophrenia (CACNA1C, CLU, CSNK2B, GABBR1, GRIN2A, MAPK3, NOTCH4, SRR, TNF, and SYNGAP1). Our results may serve as an encyclopedia of schizophrenia susceptibility SNPs and offer holistic guides for post-GWAS functional experiments.

Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.

Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.

Association of the Synapse-Associated Protein 97 (SAP97) Gene Polymorphism With Neurocognitive Function in Schizophrenic Patients.

The SAP97 gene is located in the schizophrenia susceptibility locus 3q29, and it encodes the synaptic scaffolding protein that interacts with the N-methyl-D-aspartate (NMDA) receptor, which is presumed to be dysregulated in schizophrenia. In this study, we genotyped a single-nucleotide polymorphism (SNP) (rs3915512) in the SAP97 gene in 1114 patients with schizophrenia and 1036 healthy-matched controls in a Han Chinese population through the improved multiplex ligation detection reaction (imLDR) technique. Then, we analyzed the association between this SNP and the patients' clinical symptoms and neurocognitive function. Our results showed that there were no significant differences in the genotype and allele frequencies between the patients and the controls for the rs3915512 polymorphism. However, patients with the rs3915512 polymorphism TT genotype had higher neurocognitive function scores (list learning scores, symbol coding scores, category instances scores and controlled oral word association test scores) than the subjects with the A allele (P = 4.72 × 10−5, 0.027, 0.027, 0.013, respectively). Our data are the first to suggest that the SAP97 rs3915512 polymorphism may affect neurocognitive function in patients with schizophrenia.

Cross-tissue eQTL enrichment of associations in schizophrenia.

The genome-wide association study of the Psychiatric Genomics Consortium identified over one hundred schizophrenia susceptibility loci. The number of non-coding variants discovered suggests that gene regulation could mediate the effect of these variants on disease. Expression quantitative trait loci (eQTLs) contribute to variation in levels of mRNA. Given the co-occurrence of schizophrenia and several traits not involving the central nervous system (CNS), we investigated the enrichment of schizophrenia associations among eQTLs for four non-CNS tissues: adipose tissue, epidermal tissue, lymphoblastoid cells and blood. Significant enrichment was seen in eQTLs of all tissues: adipose (β = 0.18, p = 8.8 × 10−06), epidermal (β = 0.12, p = 3.1 × 10−04), lymphoblastoid (β = 0.19, p = 6.2 × 10−08) and blood (β = 0.19, p = 6.4 × 10−06). For comparison, we looked for enrichment of association with traits of known relevance to one or more of these tissues (body mass index, height, rheumatoid arthritis, systolic blood pressure and type-II diabetes) and found that schizophrenia enrichment was of similar scale to that observed when studying diseases in the context of a more likely causal tissue. To further investigate tissue specificity, we looked for differential enrichment of eQTLs with relevant Roadmap affiliation (enhancers and promoters) and varying distance from the transcription start site. Neither factor significantly contributed to the enrichment, suggesting that this is equally distributed in tissue-specific and cross-tissue regulatory elements. Our analyses suggest that functional correlates of schizophrenia risk are prevalent in non-CNS tissues. This could be because of pleiotropy or the effectiveness of variants affecting expression in different contexts. This suggests the utility of large, single-tissue eQTL experiments to increase eQTL discovery power in the study of schizophrenia, in addition to smaller, multiple-tissue approaches. Our results conform to the notion that schizophrenia is a systemic disorder involving many tissues.

An association study of ATXN2 gene rs7969300 polymorphism with schizophrenia

Objective To assess the association between rs7969300 polymorphism of ATXN2 gene and schizophrenia. Methods Totally 1 207 schizophrenia patients diagnosed in accordance with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition(DSM-Ⅳ) and 1 120 healthy controls were involved.The rs7969300 gene SNP locus of ATXN2 gene was detected by ligase detection reaction polymerase chain reaction (PCR). PLINK software was used for statistical analysis. Results The results showed that there were no significantly different genotype frequencies(Schizophrenia patients(C/C: 240, C/T: 537, T/T: 394), health controls(C/C: 208, C/T: 521, T/T: 368), χ2=1.001, P=0.606) and allele frequencies(Schizophrenia patients(C1017, T1325), health controls(C937, T1257), χ2=0.238, P=0.626)of rs7969300 polymorphism between schizophrenia patients and healthy controls. Conclusion This study does not support that ATXN2 rs7969300 is a susceptibility locus for schizophrenia. Key words: Ataxins; SNP; Schizophrenia

The Proteome of BLOC-1 Genetic Defects Identifies the Arp2/3 Actin Polymerization Complex to Function Downstream of the Schizophrenia Susceptibility Factor Dysbindin at the Synapse.

The mechanisms associated with schizophrenia are mostly unknown despite the increasing number of genetic loci identified that increase disease risk. We present an experimental strategy that impartially and comprehensively interrogates the proteome of neurons to identify effects of genetic mutations in a schizophrenia risk factor, dysbindin. We find that the expression of the actin polymerization complex Arp2/3 is reduced in dysbindin-deficient cells, thus affecting actin-dependent phenotypes in two cellular compartments where dysbindin resides, endosomes and presynapses. Our studies indicate that a central cellular structure affected by schizophrenia susceptibility loci is the actin cytoskeleton, an organelle necessary for synaptic function in the presynaptic and postsynaptic compartment.

Common variants on 2p16.1, 6p22.1 and 10q24.32 are associated with schizophrenia in Han Chinese population.

Many schizophrenia susceptibility loci have been identified through genome-wide association studies (GWASs) in European populations. However, until recently, schizophrenia GWASs in non-European populations were limited to small sample sizes and have yielded few loci associated with schizophrenia. To identify genetic risk variations for schizophrenia in the Han Chinese population, we performed a two-stage GWAS of schizophrenia comprising 4384 cases and 5770 controls, followed by independent replications of 13 single-nucleotide polymorphisms in an additional 4339 schizophrenia cases and 7043 controls of Han Chinese ancestry. Furthermore, we conducted additional analyses based on the results in the discovery stage. The combined analysis confirmed evidence of genome-wide significant associations in the Han Chinese population for three loci, at 2p16.1 (rs1051061, in an exon of VRK2, P=1.14 × 10-12, odds ratio (OR)=1.17), 6p22.1 (rs115070292 in an intron of GABBR1, P=4.96 × 10-10, OR=0.77) and 10q24.32 (rs10883795 in an intron of AS3MT, P=7.94 × 10-10, OR=0.87; rs10883765 at an intron of ARL3, P=3.06 × 10-9, OR=0.87). The polygenic risk score based on Psychiatric Genomics Consortium schizophrenia GWAS data modestly predicted case-control status in the Chinese population (Nagelkerke R2: 1.7% ~5.7%). Our pathway analysis suggested that neurological biological pathways such as GABAergic signaling, dopaminergic signaling, cell adhesion molecules and myelination pathways are involved in schizophrenia. These findings provide new insights into the pathogenesis of schizophrenia in the Han Chinese population. Further studies are needed to establish the biological context and potential clinical utility of these findings.

Neuregulin-1 Gene and Schizophrenia, and its Negative Symptoms in an Iranian Population

Background: During the last two decades, much effort is put to better understand the etiology of schizophrenia. Studying negative symptoms such as endophenotypes is a plausible approach to elucidate the genetic basis of schizophrenia. Neuregulin-1 (NRG1) is a key candidate gene to develop schizophrenia and its negative symptoms. The NRG1 variant rs6988339 was previously characterized as a schizophrenia susceptibility locus in different Scottish populations. Objectives: The current study aimed to examine the association of rs6988339 with schizophrenia and its negative symptoms in an Iranian population. Methods: The current case-controlled study enrolled 469 subjects (276 unrelated schizophrenia patients and 193 healthy controls). The study investigated the association of rs6988339 with schizophrenia and its negative symptoms (assessed with the positive and negative syndrome scale; PANSS) in an Iranian population. Results: The obtained results showed that rs6988339 was a schizophrenia susceptibility locus in the Iranian population, the minor allele G was the risk allele and A the protective allele (P = 0.0007). Of the four subscales of the PANSS test, the negative score showed the strongest association with this variant (P = 0.001). Conclusions: The results further supported the implication of NRG1 in the pathogenesis of negative symptoms in schizophrenia.

Neuregulin-1 Gene and Schizophrenia, and its Negative Symptoms in an Iranian Population

Background: During the last two decades, much effort is put to better understand the etiology of schizophrenia. Studying negative symptoms such as endophenotypes is a plausible approach to elucidate the genetic basis of schizophrenia. Neuregulin-1 (NRG1) is a key candidate gene to develop schizophrenia and its negative symptoms. The NRG1 variant rs6988339 was previously characterized as a schizophrenia susceptibility locus in different Scottish populations. Objectives: The current study aimed to examine the association of rs6988339 with schizophrenia and its negative symptoms in an Iranian population. Methods: The current case-controlled study enrolled 469 subjects (276 unrelated schizophrenia patients and 193 healthy controls). The study investigated the association of rs6988339 with schizophrenia and its negative symptoms (assessed with the positive and negative syndrome scale; PANSS) in an Iranian population. Results: The obtained results showed that rs6988339 was a schizophrenia susceptibility locus in the Iranian population, the minor allele G was the risk allele and A the protective allele (P = 0.0007). Of the four subscales of the PANSS test, the negative score showed the strongest association with this variant (P = 0.001). Conclusions: The results further supported the implication of NRG1 in the pathogenesis of negative symptoms in schizophrenia.

G72 primate-specific gene: a still enigmatic element in psychiatric disorders.

Numerous studies have demonstrated a link between genetic markers on chromosome 13 and schizophrenia, bipolar affective disorder, and other psychiatric phenotypes. The G72/G30 genes (transcribed in opposite directions) are located on chromosome 13q33, a region demonstrating strong evidence for linkage with various neuropsychiatric disorders. G72/G30 was identified in 2002 as a schizophrenia susceptibility locus; however, subsequent association studies did not reach consensus on single SNPs within the locus. Simultaneously, a new vision for the genetic architecture of psychiatric disorders suggested that schizophrenia was a quantitative trait, therefore ascribable to potentially hundreds of genes and subjected to the vagaries of the environment. The main protein product of G72 gene is named pLG72 or D-amino acid oxidase activator DAOA (153 amino acids) and its function is still debated. Functional analyses, also showing controversial results, indicate that pLG72 contributes to N-methyl-D-aspartate receptor modulation by affecting activity of the flavoprotein D-amino acid oxidase, the enzyme responsible for degrading the neuromodulator D-serine. In this review we, for the first time, summarize findings from molecular genetic linkage and association studies concerning G72 gene, cellular and molecular studies on pLG72, and investigations performed on G72/G30 transgenic mice. This will help elucidate the role of psychosis susceptibility genes, which will have a major impact on our understanding of disease pathophysiology and thus change classification and treatment.

A comprehensive analysis of NDST3 for schizophrenia and bipolar disorder in Han Chinese.

A novel susceptibility locus (rs11098403) for schizophrenia and bipolar disorder (BD) was identified in an Ashkenazi Jewish population by a recent large-scale genome-wide association study. The rs11098403 is located in the vicinity of the gene encoding N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 3, (NDST3). This study aimed to replicate the results in a Han Chinese population and then potentially extend these findings. We performed a two-stage study to investigate the association of NDST3 with the schizophrenia and BD risk in the Han Chinese. In stage 1, a total of 632 patients with schizophrenia, 654 patients with BD and 684 healthy controls were recruited from the Shanghai region. In stage 2, 522 schizophrenia patients and 547 normal subjects were enrolled from the Hangzhou region. Then, we conducted a meta-analysis based on the present literature. In stage 1, the single nucleotide polymorphism (SNP) rs11098403 showed a significant association with schizophrenia (corrected P=0.005). The frequency of the rs11098403 G allele was significantly lower among schizophrenia patients than among the controls (odds ratio (OR)=0.68, 95% confidence interval (CI): 0.55−0.84, corrected P=0.002). No significant difference was observed in individual SNP marker genotypes or allele distributions between the BD and control groups. In stage 2, the association of rs11098403 with schizophrenia could be validated (genotypic P=0.001 and allelic P=0.0003). After pooling all data from 1861 patients with schizophrenia and 2081 controls, we observed a significant association of the rs11098403 G allele with schizophrenia (Z=5.56, P<0.001), with an OR=0.70 (95% CI: 0.61−0.79). Then, we performed an expression quantitative trait loci analysis to investigate the functional effect of rs11098403 on NDST3 expression in the brain. We observed a significant association of rs11098403 with NDST3 expression in the hippocampus (P=0.027), although the significance did not survive after multiple testing correction. Our findings provided preliminary evidence that rs11098403 might modify the genetic risk of schizophrenia in the Han Chinese. Further investigations are warranted to identify the precise mechanism regulating brain NDST3 expression in the Han Chinese. These results would help to explain the pathophysiological mechanism of schizophrenia.

A new risk locus in the ZEB2 gene for schizophrenia in the Han Chinese population

The ZEB2 gene encodes the Zinc Finger E-box binding protein. As a key regulator of epithelial mesenchymal differentiation, ZEB2 plays an important role in the pathogenesis of cancer, and its high level expression has been observed in glioma patients. Different mutations in this gene have been identified in patients with Mowat–Wilson syndrome. A previous genome-wide association study (GWAS) of schizophrenia conducted in Caucasians has shown a significant association of rs12991836, located near the ZEB2 gene, with schizophrenia. Thus, we conducted a case control study to further investigate whether this genomic region is also a susceptibility locus for schizophrenia in the Han Chinese population. In total, 1248 schizophrenia (SCZ) cases (mean age±S.D., 36.44±9.0years), 1344 bipolar disorder (BPD) cases (mean age±S.D., 34.84±11.44years), 1056 major depressive disorder (MDD) cases (mean age±S.D., 34.41±12.09years) and 1248 healthy control samples (mean age±S.D., 30.62±11.35years) were recruited. We genotyped 12 SNPs using the Sequenom MassARRAY platform in this study. We found that rs6755392 showed a significant association with SCZ (rs6755392: adjusted Pallele=0.016; adjusted Pgenotype=0.052; OR (95% CI)=1.201 (1.073~1.344)). Additionally, two haplotypes (TCTG, TCTA) were also significantly associated with SCZ. This is the first study claiming the association of the genetic risks of rs6755392 in the ZEB2 gene with schizophrenia.

Genome-wide association study with the risk of schizophrenia in a Korean population.

Schizophrenia is regarded as a multifactorial and polygenic brain disorder that is attributed to different combinations of genetic and environmental risk factors. Recently, several genome-wide association studies (GWASs) of schizophrenia have identified numerous risk factors, but the replication results remain controversial and ambiguous. To identify schizophrenia susceptibility loci in the Korean population, we performed a GWAS using the Illumina HumanOmni1-Quad V1.0 Microarray. We genotyped 1,140,419 single nucleotide polymorphisms (SNPs) in 350 Korea schizophrenia patients and 700 control subjects, and approximately 620,001 autosomal SNPs were passed our quality control. In the case-control analysis, the rs9607195 A>G on intergenic area 250 kb away from the ISX gene and the rs12738007 A>G on the intron of the MECR gene were the most strongly associated SNPs with the risk of schizophrenia (P = 6.2 × 10(-8) , OR = 0.50 and P = 3.7 × 10(-7) , OR = 2.39, respectively). In subsequent fine-mapping analysis, 6 SNPs of MECR were genotyped with 310 schizophrenia patients and 604 control subjects. The association of the MECR rs12738007, a top ranked-SNP in GWAS, was replicated (P = 1.5 × 10(-2) , OR = 1.53 in fine mapping analysis, P = 1.5 × 10(-6) , OR = 1.90 in combined analysis). The identification of putative schizophrenia susceptibility loci could provide new insights into genetic factors related with schizophrenia and clues for the development of diagnosis strategies.

Genetic Markers of Human Evolution Are Enriched in Schizophrenia

BackgroundWhy schizophrenia has accompanied humans throughout our history despite its negative effect on fitness remains an evolutionary enigma. It is proposed that schizophrenia is a by-product of the complex evolution of the human brain and a compromise for humans’ language, creative thinking, and cognitive abilities. MethodsWe analyzed recent large genome-wide association studies of schizophrenia and a range of other human phenotypes (anthropometric measures, cardiovascular disease risk factors, immune-mediated diseases) using a statistical framework that draws on polygenic architecture and ancillary information on genetic variants. We used information from the evolutionary proxy measure called the Neanderthal selective sweep (NSS) score. ResultsGene loci associated with schizophrenia are significantly (p = 7.30 × 10−9) more prevalent in genomic regions that are likely to have undergone recent positive selection in humans (i.e., with a low NSS score). Variants in brain-related genes with a low NSS score confer significantly higher susceptibility than variants in other brain-related genes. The enrichment is strongest for schizophrenia, but we cannot rule out enrichment for other phenotypes. The false discovery rate conditional on the evolutionary proxy points to 27 candidate schizophrenia susceptibility loci, 12 of which are associated with schizophrenia and other psychiatric disorders or linked to brain development. ConclusionsOur results suggest that there is a polygenic overlap between schizophrenia and NSS score, a marker of human evolution, which is in line with the hypothesis that the persistence of schizophrenia is related to the evolutionary process of becoming human.

Reduced cortical expression of a newly identified splicing variant of the DLG1 gene in patients with early-onset schizophrenia.

The human discs, large homolog 1 gene (DLG1) is mapped to the schizophrenia-susceptibility locus 3q29, and it encodes a scaffold protein that interacts with the N-methyl-D-aspartate receptor presumably dysregulated in schizophrenia. In the current study, we have newly identified a splicing variant of DLG1, which is transcribed from an unreported 95-base-pair exon (exon 3b) and is labeled 3b(+). We investigated the mRNA expression of 3b(+) in the post-mortem dorsolateral prefrontal cortices of patients with psychiatric disorders, obtained from The Stanley Medical Research Institute, and examined the potential association of the expression with the genotype of the single-nucleotide polymorphism (SNP) rs3915512 located within exon 3b. A real-time quantitative reverse transcriptase-polymerase chain reaction revealed that the mRNA levels of 3b(+) were significantly reduced in patients with early-onset schizophrenia (onset at <18 years old, P=0.0003) but not in those with non-early-onset schizophrenia, early-onset or non-early-onset bipolar disorder or in the controls. Furthermore, the genotype at the rs3915512 SNP was closely associated with the levels of 3b(+) mRNA expression. It is inferred that the T allele fails to meet the exonic splicing enhancer consensus, thus resulting in skipping of exon 3b, leading to the expression of 3b(−) (the previously known DLG1 variant) but not 3b(+). Because all the subjects with early-onset schizophrenia in the current study possess the T/T genotype, the reduced level of the DLG1 3b(+) transcript may be involved in the susceptibility and/or pathophysiology of early-onset schizophrenia.