Sweden-Schizophrenia Population-Based Case-Control Exome Sequencing
Ontology highlight
ABSTRACT: Current findings of the genetic risk of schizophrenia and bipolar disorder emerging from genome wide association studies (GWAS) support a highly polygenic model displaying the full spectrum of causal alleles that includes the extremes of rare, penetrant alleles as well as common alleles of small effect. Lower frequency polymorphism, rare variants and private mutations have eluded measurement by GWAS studies and thus association with disease. In order to create a comprehensive catalogue of low frequency or rare coding variation in individuals with psychiatric disease and to build a foundation for future genetic studies of schizophrenia and bipolar disorder, we have obtained whole exome DNA sequence from a population-based schizophrenia and bipolar disorder Swedish case-control cohort.
PROVIDER: phs000473.v1.p1 | EGA |
REPOSITORIES: EGA
Publications
Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth.
Fromer Menachem M Moran Jennifer L JL Chambert Kimberly K Banks Eric E Bergen Sarah E SE Ruderfer Douglas M DM Handsaker Robert E RE McCarroll Steven A SA O'Donovan Michael C MC Owen Michael J MJ Kirov George G Sullivan Patrick F PF Hultman Christina M CM Sklar Pamela P Purcell Shaun M SM
American journal of human genetics 20121001 4
Sequencing of gene-coding regions (the exome) is increasingly used for studying human disease, for which copy-number variants (CNVs) are a critical genetic component. However, detecting copy number from exome sequencing is challenging because of the noncontiguous nature of the captured exons. This is compounded by the complex relationship between read depth and copy number; this results from biases in targeted genomic hybridization, sequence factors such as GC content, and batching of samples du ...[more]
Similar Datasets
Project description:<p>Current findings of the genetic risk of schizophrenia and bipolar disorder emerging from genome wide association studies (GWAS) support a highly polygenic model displaying the full spectrum of causal alleles that includes the extremes of rare, penetrant alleles as well as common alleles of small effect. Lower frequency polymorphism, rare variants and private mutations have eluded measurement by GWAS studies and thus association with disease. In order to create a comprehensive catalogue of low frequency or rare coding variation in individuals with psychiatric disease and to build a foundation for future genetic studies of schizophrenia and bipolar disorder, we have obtained whole exome DNA sequence from a population-based schizophrenia and bipolar disorder Swedish case-control cohort.</p>
| phs000473 | dbGaP
Project description:Background: Autism spectrum disorder (ASD) is a severe early onset neurodevelopmental disorder with high heritability but significant heterogeneity. Traditional genome-wide approaches to test for association of common variants with autism susceptibility risk has met with limited success. However, novel methods to identify moderate risk alleles in attainable sample sizes are now gaining momentum. Methods:M-BM- In this study, we utilized publically available GWAS data from the Autism Genome Project (AGP) and annotated the results (p < 0.001) for eQTLs present in the parietal lobe, cerebellum, and lymphoblastoid cell lines. We then performed a test of enrichment by comparing these results to simulated data conditioned on minor allele frequency in order to generate an empirical p-value indicating statistically significant enrichment of eQTLs in top results from the autism GWAS. Results:M-BM- Our findings show a global enrichment of brain eQTLs, but not LCL eQTLs, among top SNPs from an autism GWAS. Additionally, the data implicates individual genesM-BM- SLC25A12,M-BM- PANX1M-BM- andM-BM- PANX2, as well as pathways previously implicated in autism. Conclusions:M-BM- These findings provide supportive rationale for the use of annotation-based approaches to GWAS. We use microarray technology to understand the etiology and pathology of psychiatric diseases at the transcriptomic level. Postmortem human brain samples came from the Stanley Medical Research InstituteM-bM-^@M-^Ys Neuropathology Consortium and Array collections, including schizophrenia, bipolar disorder and control samples.
2012-12-31 | E-GEOD-35974 | biostudies-arrayexpress
Project description:Background: Autism spectrum disorder (ASD) is a severe early onset neurodevelopmental disorder with high heritability but significant heterogeneity. Traditional genome-wide approaches to test for association of common variants with autism susceptibility risk has met with limited success. However, novel methods to identify moderate risk alleles in attainable sample sizes are now gaining momentum. Methods:M-BM- In this study, we utilized publically available GWAS data from the Autism Genome Project (AGP) and annotated the results (p < 0.001) for eQTLs present in the parietal lobe, cerebellum, and lymphoblastoid cell lines. We then performed a test of enrichment by comparing these results to simulated data conditioned on minor allele frequency in order to generate an empirical p-value indicating statistically significant enrichment of eQTLs in top results from the autism GWAS. Results:M-BM- Our findings show a global enrichment of brain eQTLs, but not LCL eQTLs, among top SNPs from an autism GWAS. Additionally, the data implicates individual genesM-BM- SLC25A12,M-BM- PANX1M-BM- andM-BM- PANX2, as well as pathways previously implicated in autism. Conclusions:M-BM- These findings provide supportive rationale for the use of annotation-based approaches to GWAS. We use microarray technology to understand the etiology and pathology of psychiatric diseases at the transcriptomic level. Postmortem human brain samples came from the Stanley Medical Research InstituteM-bM-^@M-^Ys Neuropathology Consortium and Array collections, including schizophrenia, bipolar disorder and control samples.
2012-12-31 | E-GEOD-35977 | biostudies-arrayexpress
Project description:RNA-seq of three brain regions from schizophrenia and bipolar disorder patients and psychiatrically normal individuals
2025-01-24 | E-GEOD-78936 | ExpressionAtlas
Project description:Suicide and suicide attempts are complex behaviors that result from the interaction of different factors, including genetic variants that increase the predisposition to suicidal behaviors. Copy number variations (CNVs) are deletions or duplications of a segment of DNA usually larger than one kilobase. These structural genetic changes, although quite rare, have been associated with genetic liability to mental disorders, such as autism, schizophrenia, and bipolar disorder. No genome-wide level studies have been published investigating the potential role of CNVs in suicidal behaviors. Based on single-nucleotide polymorphism array data, we followed the Penn-CNV standards to detect CNVs in 1,608 subjects, comprising 475 suicide and suicide attempt cases and 1,133 controls. Although the initial algorithms determined the presence of CNVs on chromosomes 6 and 12 in seven and eight cases, respectively, compared with none of the controls, visual inspection of the raw data did not support this finding. Furthermore we were unable to validate these findings by CNV-specific real-time polymerase chain reaction. Additionally, rare CNV burden analysis did not find an association between the frequency or length of rare CNVs and suicidal behavior in our sample population. Although our findings suggest CNVs do not play an important role in the etiology of suicidal behaviors, they are not inconsistent with the strong evidence from the literature suggesting that other genetic variants account for a portion of the total phenotypic variability in suicidal behavior.
2015-04-17 | E-MTAB-3519 | biostudies-arrayexpress
Project description:GSK3b signaling has been implicated in the pathophysiology of bipolar affective disorder based on the inhibitory effect of lithium salts on this pathway. This has been supported by a recent genome wide association study. In addition, GSK3b signaling may also play a role in schizophrenia, an idea that is based on the finding that the protein encoded by the schizophrenia candidate gene DISC1 inhibits GSK3b. Gene expression is affected by GSK3b signaling through the activation of the transcription factor b-catenin, which modulates expression through a protein-protein binding interaction with members of the TCF/LEF family. To identify genes targeted by GSK3b/b-catenin, investigators have used expression profiling in lithium treated cells and animals. Gene knockdown and transfection are other experimental methodologies one can employ. However, these approaches are not possible using human brain tissue. Consequently, we used ChIP-chip to identify promoters bound by b-catenin as an indirect method for identifying genes targeted by GSK3b. Fetal brain was used because schizophrenia is viewed as a neurodevelopmental disorder. In addition, fetal brain tissue is not affected by the confounding factors associated with postmortem tissue (postmortem delay, cause of death, brain pH, use of medication and other environmental factors). We carried out two complete promoter array hybridizations on different biological isolates using the 385K two-Array Human Promoter Set developed by Nimblegen/Roche. Significant enrichment for b-catenin immunoprecipitates was determined in each experiment if the log2 ratio of signal obtained for the b-catenin antibody compared with control was below an FDR<0.2 using NimbleScan. NimbleScan reports three different levels of enrichment (peaks) based on the FDR score, as described in methods. Since whole brain tissue was used in these experiments, we chose the least conservative FDR (<0.2) to reduce the type II error (false negative) rate, which could be caused by enrichment at some promoters in a subset of cells being diluted by the absence of b-catenin immunoprecipitates at those loci in other cells. A total of 640 gene promoters showed evidence for b-catenin binding on two arrays. We validated enrichment at 9 gene promoters using real time PCR. The 640 genes are analyzed using SLEP (Sullivan Lab Evidence Project, http://slep.unc.edu). Analysis of the SLEP database was restricted to genome wide association studies (GWAS) and copy number variants (CNVs) in ASD, BD and SZ. In addition, a gene was scored as a potential candidate if it fell within a linkage peak or if multiple positive association studies were found upon a candidate gene analysis. Promoters for 24 genes implicated in these disorders were targeted by b-catenin. Of these, a total of 16 genes are very strong candidates based on unbiased genome-wide surveys (GWAS and CNV screening). The other 8 have been implicated by linkage analysis and candidate gene analysis, which are the least robust genetic methods for targeting specific genes in psychiatric disorders. We carried out a similar analysis on 640 genes that did not show evidence for enrichment in the b-catenin ChIP-chip. Only 5 genes were found, none of which are GWAS or CNV targets. Based on the finding that five candidate genes were found in a group of 640 randomly selected genes, while 24 were identified in the ChIP-chip experiment, the binding of b-catenin to schizophrenia and bipolar disorder candidate gene promoters is highly significant (p = 6.5 x 10-12). The findings suggest that many seemingly disparate candidate genes for psychiatric disorders can be grouped into the GSK3b/b-catenin signaling pathway. The results could also have therapeutic implications in helping to identify bipolar patients who respond best to lithium, as well as identify patients with schizophrenia who might benefit from the drug. Immunoprecipitates were generated with an antibody to b-Catenin
2010-04-01 | E-GEOD-21151 | biostudies-arrayexpress
Project description:Genome wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by an exon microarray study. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders. There were 20 anterior cingulate postmortem brain samples that were extracted for total RNA, and analyzed using Affymetrix Exon Array (bipolar disorder subjects n = 9, controls n = 11).
2016-02-25 | E-GEOD-78246 | biostudies-arrayexpress
Project description:Schizophrenia is a complex psychiatric disorder encompassing a range of symptoms and etiology dependent upon the interaction of genetic and environmental factors. Several risk genes, such as DISC1, have been associated with schizophrenia as well as bipolar disorder (BPD) and major depressive disorder (MDD), consistent with the hypothesis that a shared genetic architecture could contribute to divergent clinical syndromes. The present study compared gene expression profiles across three brain regions in post-mortem tissue from matched subjects with schizophrenia, BPD or MDD and unaffected controls. Post-mortem brain tissue was collected from control subjects and well-matched subjects with schizophrenia, BPD, and MDD (n=19 from each group). RNA was isolated from hippocampus, Brodmann Area 46, and associative striatum and hybridized to U133_Plus2 Affymetrix chips. Data were normalized by RMA, subjected to pairwise comparison followed by Benjamini and Hochberg False Discovery Rate correction (FDR). Samples derived from patients with schizophrenia exhibited many more changes in gene expression across all brain regions than observed in BPD or MDD. Several genes showed changes in both schizophrenia and BPD, though the magnitude of change was usually larger in schizophrenia. Several genes that have variants associated with schizophrenia were found to have altered expression in multiple regions of brains from subjects with schizophrenia. Continued evaluation of circuit-level alterations in gene expression and gene-network relationships may further our understanding of how genetic variants may be influencing biological processes to contribute to psychiatric disease. Pre-frontal cortex, striatum and hippocampus were obtained from subjects with schizophrenia, bipolar disorder, major depressive disorder and matched controls.
2014-01-11 | E-GEOD-53987 | biostudies-arrayexpress
Project description:We used microarrays to identify the differently expressed genes in disease model for bipolar disorder and schizophrenia.
2018-07-10 | GSE116820 | GEO
Project description:Mitochondrial Abnormalities in Schizophrenia and Bipolar Disorder
| PRJNA719179 | ENA