Dynamic complexity of genetic regulatory effects in response to a high cholesterol, high fat diet in baboons
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ABSTRACT:
ORGANISM(S): Papio anubis
PROVIDER: GSE227346 | GEO | 2023/12/27
REPOSITORIES: GEO
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Project description:Profiles of sequence variants that influence gene transcription are very important for understanding mechanisms that affect phenotypic variation and disease susceptibility. Using genotypes at 1.4 million SNPs and a comprehensive transcriptional profile of 15,454 coding genes and 6,113 lincRNA genes obtained from peripheral blood cells of 298 Japanese individuals, we mapped expression quantitative trait loci (eQTLs). We identified 3,804 cis-eQTLs (within 500 kb from target genes) and 165 trans-eQTLs (>500 kb away or on different chromosomes). Cis-eQTLs were often located in transcribed or adjacent regions of genes; among these regions, 5’ untranslated regions and 5’ flanking regions had the largest effects. Epigenetic evidence for regulatory potential accumulated in public databases explained the magnitude of the effects of our eQTLs. Cis-eQTLs were often located near the respective target genes, if not within genes. Large effect sizes were observed with eQTLs near target genes, and effect sizes were obviously attenuated as the eQTL distance from the gene increased. Using a very stringent significance threshold, we identified 165 large-effect trans-eQTLs. We used our eQTL map to assess 8,069 disease-associated SNPs identified in 1,436 genome-wide association studies (GWAS). We identified genes that might be truly causative, but GWAS might have failed to identify for 148 out of the GWAS-identified SNPs; for example, TUFM (P=3.3E-48) was identified for inflammatory bowel disease (early onset); ZFP90 (P=4.4E-34) for ulcerative colitis; and IDUA (P=2.2E-11) for Parkinson's disease. We identified four genes (P<2.0E-14) that might be related to three diseases and two hematological traits; each expression is regulated by trans-eQTLs on a different chromosome than the gene. The study subjects were 301 apparently healthy individuals residing in Nagahama City, Japan. Whole blood was collected from each participant when in a non-stimulated state.
2014-06-23 | E-GEOD-53351 | biostudies-arrayexpress
Project description:Profiles of sequence variants that influence gene transcription are very important for understanding mechanisms that affect phenotypic variation and disease susceptibility. Using genotypes at 1.4 million SNPs and a comprehensive transcriptional profile of 15,454 coding genes and 6,113 lincRNA genes obtained from peripheral blood cells of 298 Japanese individuals, we mapped expression quantitative trait loci (eQTLs). We identified 3,804 cis-eQTLs (within 500 kb from target genes) and 165 trans-eQTLs (>500 kb away or on different chromosomes). Cis-eQTLs were often located in transcribed or adjacent regions of genes; among these regions, 5’ untranslated regions and 5’ flanking regions had the largest effects. Epigenetic evidence for regulatory potential accumulated in public databases explained the magnitude of the effects of our eQTLs. Cis-eQTLs were often located near the respective target genes, if not within genes. Large effect sizes were observed with eQTLs near target genes, and effect sizes were obviously attenuated as the eQTL distance from the gene increased. Using a very stringent significance threshold, we identified 165 large-effect trans-eQTLs. We used our eQTL map to assess 8,069 disease-associated SNPs identified in 1,436 genome-wide association studies (GWAS). We identified genes that might be truly causative, but GWAS might have failed to identify for 148 out of the GWAS-identified SNPs; for example, TUFM (P=3.3E-48) was identified for inflammatory bowel disease (early onset); ZFP90 (P=4.4E-34) for ulcerative colitis; and IDUA (P=2.2E-11) for Parkinson's disease. We identified four genes (P<2.0E-14) that might be related to three diseases and two hematological traits; each expression is regulated by trans-eQTLs on a different chromosome than the gene.
2014-06-23 | GSE53351 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent form of hepatic disease and feeding mice a High-Fat, High-Caloric (HFHC) diet is a standard model of NAFLD. In order to better understand the genetic basis of NAFLD, we conducted an expression quantitative trait locus (eQTL) analysis of mice fed a HFHC diet. 265 (A/J × C57BL/6J) F2 male mice were fed a HFHC diet for 8 weeks. QTL analysis was utilized to identify genomic regions that regulate hepatic gene expression of Xbp1s and Socs3. We identified two overlapping loci for Xbp1 and Socs3 on Chr 1 (164.0-185.4 Mb and 174.4-190.5 Mb, respectively) and Chr 11 (41.1-73.1 Mb and 44.0-68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9-117.4 Mb). C57BL/6J-Chr 11A/J/ NaJ mice fed a HFHC diet manifested the A/J phenotype of increased Xbp1s and Socs3 gene expression (p<0.05), while C57BL/6J-Chr 1A/J/ NaJ mice retained the C57BL/6 phenotype. In addition, we replicated the eQTLs on Chr 1 and 12 (LOD scores ? 3.5) using mice from the BXD murine reference panel challenged with CCl4 to induce chronic liver injury and fibrosis. We have identified overlapping eQTLs for Xbp1 and Socs3 on Chr 1 and 11, and consomic mice confirmed that replacing the C57BL/6 with the A/J Chr 11 resulted in an A/J phenotype for Xbp1 and Socs3 gene expression. Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases. Liver samples from eight-week-old AJ and C57BL6J males fed a High Fat High Calorie diet.
2014-08-02 | E-GEOD-56987 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent form of hepatic disease and feeding mice a High-Fat, High-Caloric (HFHC) diet is a standard model of NAFLD. In order to better understand the genetic basis of NAFLD, we conducted an expression quantitative trait locus (eQTL) analysis of mice fed a HFHC diet. 265 (A/J × C57BL/6J) F2 male mice were fed a HFHC diet for 8 weeks. QTL analysis was utilized to identify genomic regions that regulate hepatic gene expression of Xbp1s and Socs3. We identified two overlapping loci for Xbp1 and Socs3 on Chr 1 (164.0-185.4 Mb and 174.4-190.5 Mb, respectively) and Chr 11 (41.1-73.1 Mb and 44.0-68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9-117.4 Mb). C57BL/6J-Chr 11A/J/ NaJ mice fed a HFHC diet manifested the A/J phenotype of increased Xbp1s and Socs3 gene expression (p<0.05), while C57BL/6J-Chr 1A/J/ NaJ mice retained the C57BL/6 phenotype. In addition, we replicated the eQTLs on Chr 1 and 12 (LOD scores ? 3.5) using mice from the BXD murine reference panel challenged with CCl4 to induce chronic liver injury and fibrosis. We have identified overlapping eQTLs for Xbp1 and Socs3 on Chr 1 and 11, and consomic mice confirmed that replacing the C57BL/6 with the A/J Chr 11 resulted in an A/J phenotype for Xbp1 and Socs3 gene expression. Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases.
2014-08-02 | GSE56987 | GEO
Project description:Dysregulation of microRNAs (miRNAs) expression has been implicated in molecular genetics events leading to the progression and development of atherosclerosis. We hypothesized that miRNA expression profiles differ between baboons with low and high serum low-density lipoprotein cholesterol (LDL-C) concentrations in response to diet, and that a subset of these miRNAs regulate genes relevant to dyslipidemia and risk of atherosclerosis. We generated small RNA libraries from baboons differing in their LDL-C response to dietary fat and cholesterol (low LDL-C, n = 3; high LDL-C, n = 3) using liver biopsies collected before and after a high-cholesterol, high-fat (HCHF) challenge diet. We sequenced the libraries using Next-Generation Illumina sequencing methods, analyzed the data using mirTools software and identified 517 baboon miRNAs: 490 homologous to human and 27 novel miRNAs. HCHF diet elicited expression of more miRNAs compared to baseline (chow) diet for both low and high LDL-C baboons. Seventeen miRNAs exhibited significant differential expression in response to HCHF diet in high LDL-C baboons compared to nine miRNAs in low LDL-C baboons. Putative miRNA targets were identified with TargetScan/Base tools. miRNAs significantly targeted more genes in high LDL-C baboons compared to low LDL-C responders. Further, we identified miRNA isomers and other non-coding RNAs that were differentially expressed in response to the challenge diet.Our discovery of differentially expressed baboon miRNAs and their targets is a fundamental step in understanding the role of non-coding RNAs in the modulation of dsylipidemia.
2012-07-14 | E-GEOD-37249 | 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-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:Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2,112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters, and enrichment of co-localised functional elements. We found eQTLs for about 85% of analysed genes, 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 MB to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might often be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels, and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. We show for strongly heritable transcripts that a considerable gap still exists between total heritability resulting from all trans-chromosomes and explained variance of all identified trans-eSNPs. In contrast, the vast majority of most cis-heritability of these genes is already explained. Dissection of co-localised functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene-expression, pathways and disease related processes. Gene expression from human blood mononuclear cells from individuals of the Leipzig LIFE Heart Study was analyzed applying Illumina HT-12 v4 Expression BeadChips. After preprocessing, 28,295 expression probes for 2,112 individuals remained for analysis. In a population-based analysis, we identified associations between DNA variants and RNA expression levels and characterized these findings.
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