The Finland-United States Investigation of NIDDM Genetics (FUSION) Study
Ontology highlight
ABSTRACT: The Finland-United States Investigation of NIDDM Genetics (FUSION) study is a long-term effort to identify genetic variants that predispose to type 2 diabetes (T2D) or that impact the variability of T2D-related quantitative traits. The initial effort involved linkage analysis of affected-sibling-pair (ASP) families based on over 5,000 individuals living in Finland, and association fine mapping based on these family members and additional T2D cases and controls. Recently we completed a genome-wide association scan on 1161 T2D cases and 1174 normal glucose tolerant (NGT) controls. Individual-level data is available here for the 919 T2D cases and 787 NGT controls who reconsented to the use of their data or are deceased. Version 3 adds individual-level data for additional phenotypic variables.
PROVIDER: phs000100.v3.p1 | EGA |
REPOSITORIES: EGA
Publications
Mapping genes for NIDDM. Design of the Finland-United States Investigation of NIDDM Genetics (FUSION) Study.
Valle T T Tuomilehto J J Bergman R N RN Ghosh S S Hauser E R ER Eriksson J J Nylund S J SJ Kohtamäki K K Toivanen L L Vidgren G G Tuomilehto-Wolf E E Ehnholm C C Blaschak J J Langefeld C D CD Watanabe R M RM Magnuson V V Ally D S DS Hagopian W A WA Ross E E Buchanan T A TA Collins F F Boehnke M M
Diabetes care 19980601 6
<h4>Objective</h4>To map and identify susceptibility genes for NIDDM and for the intermediate quantitative traits associated with NIDDM.<h4>Research design and methods</h4>We describe the methodology and sample of the Finland-United States Investigation of NIDDM Genetics (FUSION) study. The whole genome search approach is being applied in studies of several different ethnic groups to locate susceptibility genes for NIDDM. Detailed description of the study materials and designs of such studies ar ...[more]
Similar Datasets
Project description:<p>The Finland-United States Investigation of NIDDM Genetics (FUSION) study is a long-term effort to identify genetic variants that predispose to type 2 diabetes (T2D) or that impact the variability of T2D-related quantitative traits. The initial effort involved linkage analysis of affected-sibling-pair (ASP) families based on over 5,000 individuals living in Finland, and association fine mapping based on these family members and additional T2D cases and controls. We completed a genome-wide association scan on 1161 T2D cases and 1174 normal glucose tolerant (NGT) controls. Individual-level data is available for the 919 T2D cases and 787 NGT controls who reconsented to the use of their data or are deceased (<a href="./study.cgi?study_id=phs000100">phs000100</a>). In addition, we selected these 919 T2D cases and a matched set of 919 NGT controls (774 overlapping with GWAS) for targeted sequencing of 78 genes associated with glucose, insulin, and/or lipids. 400 of these T2D cases were also chosen for whole-exome sequencing (<a href="./study.cgi?study_id=phs000702">phs000702</a>).</p>
| phs000867 | dbGaP
Project description:Skeletal myocytes are metabolically active and susceptible to insulin resistance, thus implicated in type 2 diabetes (T2D). This complex disease involves systemic metabolic changes and their elucidation at the systems level requires genome-wide data and biological networks. Genome-scale metabolic models (GEMs) provide a network-context to integrate high-throughput data. We generated myocyte-specific RNA-seq data and investigated their correlation with proteome data. These data were then used to reconstruct a comprehensive myocyte GEM. Next, we performed a meta-analysis of six studies comparing muscle transcription in T2D versus healthy subjects. Transcriptional changes were mapped on the myocyte GEM, revealing extensive transcriptional regulation in T2D, particularly around pyruvate oxidation, branched-chain amino acid catabolism, and tetrahydrofolate metabolism, connected through the down-regulated dihydrolipoamide dehydrogenase. Strikingly, the gene signature underlying this metabolic regulation successfully classifies the disease state of individual samples, suggesting that regulation of these pathways is a ubiquitous feature of myocytes in response to T2D. Isolated skeletal muscle precursor cells from six normal glucose tolerant and non-obese males and females were differentiated in vitro. RNA from fully differentiated myotubes was sequenced using RNA-seq.
2015-04-07 | E-GEOD-63887 | biostudies-arrayexpress
Project description:The GoDARTS T2D-GENES exome sequencing study includes 1924 samples, 965 T2D cases and 959 T2D controls, from European ancestry. This cohort is part of a larger exome sequencing effort from the T2D-GENES project and contains the exome sequencing vcf from the GoDARTS samples. The other data generated from the T2D-GENES project can be found in dbGAP. Samples underwent deep exome sequencing, with SNVs and INDEls called according to GATK best practices.
| EGAD00001004311 | EGA
Project description:<p>The Finland-United States Investigation of NIDDM Genetics (FUSION) study is a long-term effort to identify genetic variants that predispose to type 2 diabetes (T2D) or that impact the variability of T2D-related quantitative traits (QTs). Skeletal muscle and adipose are major insulin target tissues and play key roles in insulin resistance. We hypothesize that a subset of T2D and related QT variants alter gene expression in skeletal muscle and adipose tissue. For this FUSION Tissue Biopsy Study, we have obtained and are analyzing RNA-Seq, microRNA (miRNA)-Seq, and DNA methylation (methyl)-Seq data on biopsy samples from 331 individuals from across the range of glucose tolerance: 124 normal glucose tolerance (NGT), 77 impaired glucose tolerance (IGT), 44 impaired fasting glucose (IFG), and 86 newly-diagnosed T2Ds. Participants completed two study visits, two weeks apart. First visits comprised most of the clinical phenotyping, including four-point OGTT (fasting, and 30, 60, and 120 minute post-load); BMI, WHR; lipids; blood pressure; and many other variables. Participants also completed FUSION health history, medication, and lifestyle questionnaires. At second visit, we obtained ~250mg <i>vastus lateralis</i> skeletal muscle, ~750mg abdominal subcutaneous adipose, and a ~5x15mm section of abdominal skin. Visits were completed in March 2013. RNA isolation is ongoing in the Collins laboratory at the NIH, RNA and miRNA sequencing at the NIH Intramural Sequencing Center (NISC), and genotyping at the Center for Inherited Disease Research (CIDR). Individual-level data is available here for the 306 individuals who consented to data deposit.</p> <p>To focus on evaluation of gene expression and its regulation in skeletal muscle, we analyzed mRNA extracted from <i>vastus lateralis</i> skeletal muscle obtained from 271 of the 331 individual subjects from Finland, along with genome-wide genotypes. Individual-level data is available here for the 250 subjects who reconsented to the use of their data. Release phs001048.v2.p1 adds muscle data for an additional 42 subjects and data from adipose tissue for 276 subjects. Total RNA was isolated using Trizol extraction in the Collins laboratory at the NIH. The mRNA was poly-A selected, 24-plex libraries were generated using the Illumina TruSeq directional mRNA-seq library protocol and RNA sequencing was performed on HiSeq2000 sequencers using 101bp paired-end reads at NISC. miRNA libraries were prepared from total RNA from 296 muscle and 270 adipose samples, pooled and sequenced 50bp single-end reads on Illumina HiSeq2500. Data for 272 muscle and 251 adipose samples are available here for individuals with consent for data deposit. DNA was extracted from blood in the Collins laboratory, and genotyping on the Illumina Omni2.5M array was performed at CIDR. Genotypes were imputed using the HRC 2016 reference panel. In order to assess regions of open chromatin in skeletal muscle, we obtained muscle tissue from a commercial provider to perform ATAC-seq; these samples were sequenced at the University of Michigan DNA Sequencing Core.</p> <p>Greater than 90% of the approximately 80 loci associated with T2D and the 100s of loci associated with T2D-related traits (glucose and insulin, anthropometrics, lipids) through genome-wide association studies occur in non-coding regions, suggesting a strong regulatory component to disease susceptibility. Regulatory element activity is often tissue-specific, which further complicates discovery of the causal/functional variation. Therefore, there is a critical need to understand the full spectrum of genetic variation and regulatory element usage in T2D-relevant tissues. To that end, this study contains whole genome sequence and whole genome bisulfite sequence, and/or Illumina MethylationEPIC Array data, of two tissues relevant to T2D: skeletal muscle and adipose tissue from individuals with glucose tolerance categories ranging from normal to T2D, providing a comprehensive survey of both individual genetic variation as well as DNA methylation across different tissues from multiple individuals.</p>
| phs001048 | dbGaP
Project description:Genes involved in distinct diabetes types suggest shared disease mechanisms. We show that rare ONECUT1 coding variants cause monogenic recessive diabetes (neonatal or very early-onset, syndromic) in two unrelated patients, and monogenic dominant diabetes (early adult-onset) in heterozygous relatives of these and 13 additional unrelated cases. Patients heterozygous for rare ONECUT1 coding variants define a subgroup of T2D with early-onset diabetes and other features. In addition, common regulatory ONECUT1 variants are associated with multifactorial T2D. Directed differentiation of human pluripotent stem cells to the pancreatic lineage revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. We uncovered that ONECUT1 activates the pro-endocrine genes NKX6.1 and NKX2.2 through binding to their cis-regulatory elements. Globally, ONECUT1-directed gene transcription occurs in association with major islet transcription factors, at clusters of pancreas- and endocrine-specific enhancers within open chromatin. ONECUT1 regulates a transcriptional and epigenetic machinery critical for proper endocrine pancreatic development, involved in a spectrum of diabetes, monogenic recessive and dominant, and multifactorial.
2021-11-03 | PXD018887 | Pride
Project description:Aims: Metformin is a widely used, primary drug of choice to treat individuals with type 2 diabetes (T2D). Clinically, inter-individual variability of drug response is of significant concern. The targets and precise mechanisms of action for metformin is still under interrogation. In the present study, a whole transcriptome analysis was performed with an intent to identify predictive biomarkers of metformin response in T2D individuals. Methods: Twenty drug naïve individuals with T2D and ten healthy controls were enrolled. T2D individuals were administrated with metformin monotherapy and were defined as responders and non-responders based on the changes in their glycated haemoglobin (HbA1c) over a period of three months. Poly(A) RNA Seq was performed using Ion Torrent Proton platform and differentially expressed genes were identified from the transcriptome profiles. The gene prioritization, enrichment analysis, drug-gene interactions, disease gene association analysis were performed using various tools and databases. A correlation analysis was also performed between gene expression and change in HbA1c levels after 3 months of metformin therapy. Results: The expression analysis highlighted differentially expressed genes in metformin responders, non-responders and healthy individuals. The gene prioritization and enrichment analysis highlighted potential targets for predicting metformin response (n=35) as well as T2D disease (n=14). The drug-gene interactions did not show any direct association with diabetes drugs. However, the expression of GDF15, TWISTNB and RPL36A genes showed maximum correlation with change in HbA1c levels after 3 months of metformin therapy. The disease gene association analysis highlighted rs113805659 in MAGI2 gene to be linked with T2D in African Americans. Conclusion: The results of the present study provide evidence for the perturbed transcriptome and pathways associated with metformin drug response in T2D individuals.
2022-06-30 | GSE153315 | GEO
Project description:White adipose tissue (WAT) plays a critical role in whole-body energy homeostasis. In this study, we established the differential proteomic signatures of WAT in glucose-tolerant lean and obese individuals and patients with type 2 diabetes (T2D) and in response to 8 weeks of high intensity interval training (HIIT). We combined a high-throughput and reproducible mass spectrometry-based proteomics pipeline and identified a total of 3773 proteins. We find that a majority of regulated proteins displayed progression from lean to obese and T2D individuals and were highly associated with clinical measures of glucose homeostasis (e.g., insulin sensitivity, HbA1c) and they could, therefore, serve as potential disease biomarkers. Interestingly, HIIT induced a strong increase in WAT ferritin levels independent of group. WAT ferritin levels strongly correlated with individual insulin sensitivity. Thus, we report novel proteomic signatures of WAT related to obesity and T2D and highlight an unrecognized role of human WAT iron metabolism in exercise training adaptations.
2024-01-10 | PXD040434 | Pride
Project description:Type 2 diabetes (T2D) is among the leading causes of death in the U.S. Ethnic differences in T2D prevalence are evident, including especially for Native Hawaiians (NHs) who remain disproportionately affected by it. This difference in T2D susceptibility involves an interplay between genetic and environmental factors, of which epigenetic mechanisms, including DNA methylation (DNAm) provide a novel approach to investigating gene-environment interactions of health and disease. Monocytes, an innate immune cell intrinsic to the inflammatory response, are a fundamental immune cell component that likely underlies T2D pathogenesis, given their involvement in inflammation and inflammation-associated insulin resistance and metabolic dysfunction. From participants enrolled into the Multiethnic Cohort Study (MEC), who self-identified as NH (n=152), Japanese American (JA; n=119), or White (n=121), we investigated monocyte-specific DNAm patterns in participants at a baseline visit, when free of T2D, using the HumanMethylation850K (850K) to determine whether monocytes harbor an ethnic-specific epigenetic signature of T2D risk that precedes T2D diagnosis. Using an epigenome-wide association study (EWAS), we found 904 significantly (q < 0.01) differentially methylated loci (DML) at a 5% difference in DNAm between participants who remained T2D free at a 15-year follow-up (i.e., controls) and those that would be diagnosed with T2D by follow-up (i.e., incident T2D) after adjusted for age, sex, and education level. These methylation differences were enriched at regulatory regions of the genome, including intergenic and intragenic regions. Notably, these DML were able to distinctly stratify NHs by T2D risk groups, however, this signature was inapparent in Whites and JAs. Likewise, NHs in the incident T2D group displayed a higher degree of DNAm variability. Sensitivity analysis with traditional risk factors (fasting glucose and body mass index [BMI]) and neighborhood socioeconomic status (nSES) found these risk factors had minimal effect on T2D risk-associated DML. Next, using a similar approach we found ethnic-specific DML in monocytes that was able to uniquely stratify NHs, JAs, and Whites, however, in NHs this epigenetic landscape displayed a higher degree of DNAm variability. Similarly, these DML were enriched at regulatory regions of the genome. In both cases, we found genes associated with biological functions and pathways relevant to monocyte functionality, including immune activation and cellular metabolism. Due to the higher degree of epigenetic variability in NHs, including especially NHs with T2D risk, we investigated differentially variable CpGs associated with T2D risk and ethnic-differences. We found differentially variable CpGs between T2D risk groups were able to stratify NHs with and without T2D risk, whereas it was unresolvable in JAs and Whites. Ethnic-specific DNAm variability clustered each ethnic population distinctly, and NH controls were further partitioned from NHs with T2D risk. Our findings suggest monocytes harbor a unique DNAm signature associated with T2D risk, which may be related to ethnic differences that underlie DNAm variability in monocytes. The increased epigenetic variability in monocytes from NHs may underlie epigenetic plasticity that could allow these cells to readily respond to adverse environmental conditions throughout the life course that may underlie long-term disease risk, whereas in other less susceptible populations with similar environmental exposure, this epigenetic plasticity may not be apparent in monocytes.
2024-06-22 | GSE270223 | GEO
Project description:Endometrial receptivity on genomic level is one of the major cause of implantation failure in IVF patients with unexplained infertility and is a main obstacle in success of IVF. Gene expression profiles of implantation failure cases of unexplained infertility were compared with proven healthy oocyte donors as controls, both undergoing ovarian stimulation. The results provide additional information about gene expression profile related to endometrial receptivity in implantation failure cases especially under the influence of ovarian stimulation during IVF cycle.
2019-06-25 | GSE92324 | GEO
Project description:Endometrial receptivity on genomic level is one of the major cause of implantation failure in IVF patients with unexlained infertility and is a main obstacle in success of IVF. Gene expression profiles of implantation failure cases of unexplained infertility were compared with proven healthy oocyte donors as controls, both undergoing ovarian stimulation. The results provide additional information about gene expression profile related to endometrial receptivity in implantation failure cases especially under the influence of ovarian stimulation during IVF cycle.
2018-08-07 | GSE71835 | GEO