X chromosomal genetic variants are associated with childhood obesity
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001002738 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Asthma is caused by a combination of poorly understood genetic and environmental factors. We found multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in EBV-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P <10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encode transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma. Experiment Overall Design: Gene expression levels were evaluated in 404 children. We then evaluated the relationship between SNPs in the 17q21 region (which show association to asthma in the same children) with gene expression levels. See http://www.sph.umich.edu/csg/liang/asthma/
2007-11-09 | E-GEOD-8052 | biostudies-arrayexpress
Project description:Obesity is considered a multifactorial disorder with high heritability (50-75%), probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including CNVs, have been defined, the genetic causes underlying the disease still remain largely unknown. We aimed to identify novel genetic and genomic abnormalities in a cohort of Spanish children with severe non-syndromic early-onset obesity (EOO). We obtained molecular karyotypes of 157 children with EOO. Large and rare CNVs were validated and segregated in the family. A higher burden of duplication-type CNVs was detected in EOO patients versus controls (OR=1.85, p-value=0.008).
2017-04-28 | E-MTAB-5680 | biostudies-arrayexpress
Project description:Asthma is caused by a combination of poorly understood genetic and environmental factors. We found multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in EBV-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P <10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encode transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma. Keywords: association study, global gene expression, asthma, ORMDL3
2007-07-01 | GSE8052 | GEO
Project description:Genome-wide association studies (GWAS) have boosted our knowledge of genetic risk variants in autoimmune diseases (AIDs). Most of the risk variants are located within or near genes with immunological functions, and the majority is found to be non-coding, pointing towards a regulatory role. We have performed a cis expression quantitative trait locus (eQTL) screen to investigate whether single nucleotide polymorphisms (SNPs) associated with AIDs influence gene expression in thymus. Genotyping was performed using the Immunochip and 353 AID associated SNPs were tested against expression of surrounding genes (+/- 1 Mb) from human thymic tissue (N=42). We identified eight genes where the expression was associated with AID risk SNPs at a study-wide level of significance (P < 2.57x10-5). Five genes (FCRL3, RNASET2, C2orf74, SIRPG and SYS1) displayed cis eQTL signals also in other tissues, while for two loci (NPIPB8 and LOC388814), the eQTL signal appear to be thymus-specific. Since many AID risk variants from GWAS have been subsequently fine-mapped in recent Immunochip projects, we explored the overlap between these novel AID risk variants and the thymic eQTL regions. Moreover, we examined the functional annotation of the seven expression altering SNPs (eSNPs). Our study reveals autoimmune risk variants that act as eQTLs in thymus. We have highlighted functional variants within these genetic regions that potentially can represent causal autoimmune risk variants. Total RNA from 42 human thymic samples were obtained from children undergoing cardiac surgery.
2016-01-21 | E-GEOD-77052 | biostudies-arrayexpress
Project description:To identify SNPs predisposing to systemic mastocytosis (SM) we performed a two stage GWAs consisting of two cohorts from the UK and Germany at stage 1 and three cohorts from Spain, Italy and Denmark at stage 2. At both stages, the SM cases were compared with publicly available controls. The control cohorts used were WTCCC and KORA at stage 1 and the Spanish National DNA bank, InChianti and Inter99 at stage 2. The data available are raw intensity files for 480 SM cases that were genotyped at stage 1. Please see our publication (Galata et al 2020) for details regarding QC of the stage 1 samples.
2020-08-03 | E-MTAB-9358 | biostudies-arrayexpress
Project description:Background: The mechanisms of how genetic variants (SNPs) identified in genome-wide association studies act to influence body mass remain unknown for most of these SNPs, which continue to puzzle the scientific community. Recent evidence points to epigenetic and chromatin state of the genome to have an important role. Methods: 355 healthy young individuals were genotyped for 52 known obesity-associated SNPs and we obtained DNA methylation levels in their blood using the Illumina 450K BeadChip. Associations between alleles and methylation at proximal cytosine residues were tested using a linear model adjusted for age, sex, weight category and a proxy for blood cell type counts. For replication in other tissues, we used two open-access datasets (skin fibroblasts, n=62; four brain regions, n=121-133) and an additional dataset in subcutaneous and visceral fat (n=149). Results: We found that alleles at 28 of these obesity-associated SNPs associate with methylation levels at 107 proximal CpG sites. Out of 107 CpG sites, 38 are located in gene promoters, including genes strongly implicated in obesity (MIR148A, BDNF, PTPMT1, NR1H3, MGAT1, SCGB3A1, HOXC12, PMAIP1, PSIP1, RPS10-NUDT3, RPS10, SKOR1, MAP2K5, SIX5, AGRN, IMMP1L, ELP4, ITIH4, SEMA3G, POMC, ADCY3, SSPN, LGR4, TUFM, MIR4721, SULT1A1, SULT1A2, APOBR, CLN3, SPNS1,SH2B1, ATXN2L, and IL27). Interestingly, the associated SNPs are in known eQTLs for some of these genes. We also found that the 107 CpGs are enriched in enhancers in peripheral blood mononuclear cells. Finally, our results indicate that some of these associations are not be blood-specific as we successfully replicated four associations in skin fibroblasts. Conclusions: Our results strongly suggest that many obesity-associated SNPs are associated with proximal gene regulation, which was reflected by association of obesity risk allele genotypes with differential DNA methylation. This study highlights the importance of DNA methylation and other chromatin marks as a way to understand the molecular basis of genetic variants associated to human diseases and traits. Bisulphite converted DNA from 355 individuals aged 14-34 were hybridised to the Illumina Infinium 450k Human Methylation Beadchip.
2015-09-17 | E-GEOD-73103 | biostudies-arrayexpress
Project description:The identification of multiple signals at individual loci could explain additional phenotypic variance ('missing heritability') of common traits, and help identify causal genes. We examined gene expression levels as a model trait because of the large number of strong genetic effects acting in cis. Using expression profiles from 613 individuals, we performed genome-wide single nucleotide polymorphism (SNP) analyses to identify cis-expression quantitative trait loci (eQTLs), and conditional analysis to identify second signals. We examined patterns of association when accounting for multiple SNPs at a locus and when including additional SNPs from the 1000 Genomes Project. We identified 1298 cis-eQTLs at an approximate false discovery rate 0.01, of which 118 (9%) showed evidence of a second independent signal. For this subset of 118 traits, accounting for two signals resulted in an average 31% increase in phenotypic variance explained (Wilcoxon P< 0.0001). The association of SNPs with cis gene expression could increase, stay similar or decrease in significance when accounting for linkage disequilibrium with second signals at the same locus. Pairs of SNPs increasing in significance tended to have gene expression increasing alleles on opposite haplotypes, whereas pairs of SNPs decreasing in significance tended to have gene expression increasing alleles on the same haplotypes. Adding data from the 1000 Genomes Project showed that apparently independent signals could be potentially explained by a single association signal. Our results show that accounting for multiple variants at a locus will increase the variance explained in a substantial fraction of loci, but that allelic heterogeneity will be difficult to define without resequencing loci and functional work. Gene expression data was determined of peripheral blood samples (n=705) from InChianti cohort.
2013-06-21 | E-GEOD-48152 | biostudies-arrayexpress
Project description:Background: The mechanisms of how genetic variants (SNPs) identified in genome-wide association studies act to influence body mass remain unknown for most of these SNPs, which continue to puzzle the scientific community. Recent evidence points to epigenetic and chromatin state of the genome to have an important role. Methods: 355 healthy young individuals were genotyped for 52 known obesity-associated SNPs and we obtained DNA methylation levels in their blood using the Illumina 450K BeadChip. Associations between alleles and methylation at proximal cytosine residues were tested using a linear model adjusted for age, sex, weight category and a proxy for blood cell type counts. For replication in other tissues, we used two open-access datasets (skin fibroblasts, n=62; four brain regions, n=121-133) and an additional dataset in subcutaneous and visceral fat (n=149). Results: We found that alleles at 28 of these obesity-associated SNPs associate with methylation levels at 107 proximal CpG sites. Out of 107 CpG sites, 38 are located in gene promoters, including genes strongly implicated in obesity (MIR148A, BDNF, PTPMT1, NR1H3, MGAT1, SCGB3A1, HOXC12, PMAIP1, PSIP1, RPS10-NUDT3, RPS10, SKOR1, MAP2K5, SIX5, AGRN, IMMP1L, ELP4, ITIH4, SEMA3G, POMC, ADCY3, SSPN, LGR4, TUFM, MIR4721, SULT1A1, SULT1A2, APOBR, CLN3, SPNS1,SH2B1, ATXN2L, and IL27). Interestingly, the associated SNPs are in known eQTLs for some of these genes. We also found that the 107 CpGs are enriched in enhancers in peripheral blood mononuclear cells. Finally, our results indicate that some of these associations are not blood-specific as we successfully replicated four associations in skin fibroblasts. Conclusions: Our results strongly suggest that many obesity-associated SNPs are associated with proximal gene regulation, which was reflected by association of obesity risk allele genotypes with differential DNA methylation. This study highlights the importance of DNA methylation and other chromatin marks as a way to understand the molecular basis of genetic variants associated to human diseases and traits.
2015-09-17 | GSE73103 | GEO
Project description:Background & Aims: Most inflammatory bowel diseases (IBDs) are classic polygenic disorders represented by common alleles. However, multiple determinants of very early-onset IBD characterized by a more extensive disease course remain largely unknown. The present study aimed to define the genetic architecture of pediatric and adult-onset IBDs in the Polish population. Results: Of 82 SNPs validated/replicated for association with IBD, a novel BRD2 (rs1049526) association was found in both pediatric (OR= 2.35) and adult (OR= 2.66) patients. Thirty SNPs were shared between pediatric and adult patients; 22 and 30 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare/infrequent, potentially deleterious variants in IBD-associated or innate immunity-associated genes. Both groups of variants were over-represented in affected children. Two highly deleterious homozygous variants, HLA-DRB1 c.565_566insC and NCF4 p.Arg8Trp, were found in two affected children, and WAS p.Glu131Lys was found in one child and one adult patient. Conclusions: Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare/low frequency deleterious variants in affected children suggests a contribution by yet unexplained genetic components.
2017-01-01 | GSE79094 | GEO
Project description:Tacrolimus (TAC) is an immunosuppressant widely used in kidney transplantation. TAC displays considerable inter-individual variability in pharmacokinetics (PK). Genetic and clinical factors play important roles in TAC PK. To define genetic factors associated with tacrolimus blood trough concentration, we performed a genome-wide association study of renal transplant samples from 251 Chinese renal transplant recipients. We identified 23 single nucleotide polymorphisms (SNPs) related to TAC PK variability. All 23 genome-wide significant SNPs (p<5E-8) were located on chromosome 7, including rs776746. These findings suggest that these SNPs may be associated with the unexlained TAC PK variability in renal transplant recipients and require further investigation.
2022-02-24 | GSE196772 | GEO