The Finland-United States Investigation of NIDDM Genetics (FUSION) - GWAS Study
Ontology highlight
ABSTRACT:
SECONDARY ACCESSION(S): PRJNA75935PRJNA75933
REPOSITORIES: dbGaP
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| README.txt | Txt | |||
| phs000100.v1.p1.FUSION.analysis-PI.MULTI.tar.gz | Other | |||
| phs000100.pha002839.txt.gz | Txt | |||
| 00readme.txt | Txt | |||
| datadict.xsl | Other |
Items per page: 5 1 - 5 of 36 |
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Project description:The global epidemic of type 2 diabetes mellitus (T2D) is one of the most challenging problems of the 21(st) century leading cause of and the fifth death worldwide. Substantial evidence suggests that T2D is a multifactorial disease with a strong genetic component. Recent genome-wide association studies (GWAS) have successfully identified and replicated nearly 75 susceptibility loci associated with T2D and related metabolic traits, mostly in Europeans, and some in African, and South Asian populations. The GWAS serve as a starting point for future genetic and functional studies since the mechanisms of action by which these associated loci influence disease is still unclear and it is difficult to predict potential implication of these findings in clinical settings. Despite extensive replication, no study has unequivocally demonstrated their clinical role in the disease management beyond progression to T2D from impaired glucose tolerance. However, these studies are revealing new molecular pathways underlying diabetes etiology, gene-environment interactions, epigenetic modifications, and gene function. This review highlights evolving progress made in the rapidly moving field of T2D genetics that is starting to unravel the pathophysiology of a complex phenotype and has potential to show clinical relevance in the near future.
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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. 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.</p>
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Project description:Genome-wide association studies (GWAS) of asthma have yielded exciting results and identified novel risk alleles and loci. But, like other common complex diseases, asthma-associated alleles have small effect sizes and account for little of the prevalence of asthma. In this review, I discuss the limitations of GWAS approaches and the major challenges facing geneticists in the post-GWAS era and propose alternative strategies to address these challenges. In particular, I propose that focusing on genetic variations that influences gene expression and using cell models of gene-environment interactions in cell types that are relevant to asthma will allow us to more completely characterize the genetic architecture of asthma.
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Project description:The study of complex genetics in autoimmune diseases has progressed at a tremendous pace over the last 4 years, as a direct result of the enormous gains made by genome wide association studies (GWAS). Novel genetic findings are continuously being reported alongside the rapid development of genetic technologies, sophisticated statistical analysis, and larger sample collections. It is now becoming clear that multiple genes contribute to disease risk in many complex genetic disorders including rheumatoid arthritis (RA) and that there are common genetic risk factors that underlie a spectrum of autoimmune diseases. This review details the current genetic landscape of RA, and describes what GWAS has taught us in terms of missing heritability, subsets of disease, existence of genetic heterogeneity, and shared autoimmune risk loci. Finally, this review addresses the initial challenges faced in translating the wealth of genetic findings into determining the biological mechanisms that contribute to the relationship between genotype and phenotype. Unraveling the mechanism of how genes directly influence the cause of RA will lead to a better understanding of the disease and will ultimately have a direct clinical impact, informing the development of new therapies that can be utilized in the treatment of RA.
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Project description:BackgroundAlcohol dependence (AD) is a complex psychiatric disorder and a significant public health problem. Twin and family-based studies have consistently estimated its heritability to be approximately 50%, and many studies have sought to identify specific genetic variants associated with susceptibility to AD. These studies have been primarily linkage or candidate gene based and have been mostly unsuccessful in identifying replicable risk loci. Genome-wide association studies (GWAS) have improved the detection of specific loci associated with complex traits, including AD. However, findings from GWAS explain only a small proportion of phenotypic variance, and alternative methods have been proposed to investigate the associations that do not meet strict genome-wide significance criteria.MethodsThis review summarizes all published AD GWAS and post-GWAS analyses that have sought to exploit GWAS data to identify AD-associated loci.ResultsFindings from AD GWAS have been largely inconsistent, with the exception of variants encoding the alcohol-metabolizing enzymes. Analyses of GWAS data that go beyond standard association testing have demonstrated the polygenic nature of AD and the large contribution of common variants to risk, nominating novel genes and pathways for AD susceptibility.ConclusionsFindings from AD GWAS and post-GWAS analyses have greatly increased our understanding of the genetic etiology of AD. However, it is clear that larger samples will be necessary to detect loci in addition to those that encode alcohol-metabolizing enzymes, which may only be possible through consortium-based efforts. Post-GWAS approaches to studying the genetic influences on AD are increasingly common and could greatly increase our knowledge of both the genetic architecture of AD and the specific genes and pathways that influence risk.
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Project description:The β-hemoglobinopathies are inherited disorders resulting from altered coding potential or expression of the adult β-globin gene. Impaired expression of β-globin reduces adult hemoglobin (α2β2) production, the hallmark of β-thalassemia. A single-base mutation at codon 6 leads to formation of HbS (α2βS2) and sickle cell disease. While the basis of these diseases is known, therapy remains largely supportive. Bone marrow transplantation is the only curative therapy. Patients with elevated levels of fetal hemoglobin (HbF, α2γ2) as adults exhibit reduced symptoms and enhanced survival. The β-globin gene locus is a paradigm of cell- and developmental stage-specific regulation. Although the principal erythroid cell transcription factors are known, mechanisms responsible for silencing of the γ-globin gene were obscure until application of genome-wide association studies (GWAS). Here, we review findings in the field. GWAS identified BCL11A as a candidate negative regulator of γ-globin expression. Subsequent studies have established BCL11A as a quantitative repressor. GWAS-related single-nucleotide polymorphisms lie within an essential erythroid enhancer of the BCL11A gene. Disruption of a discrete region within the enhancer reduces BCL11A expression and induces HbF expression, providing the basis for gene therapy using gene editing tools. A recently identified, second silencing factor, leukemia/lymphoma-related factor/Pokemon, shares features with BCL11A, including interaction with the nucleosome remodeling deacetylase repressive complex. These findings suggest involvement of a common pathway for HbF silencing. In addition, we discuss other factors that may be involved in γ-globin gene silencing and their potential manipulation for therapeutic benefit in treating the β-hemoglobinopathies.
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Project description:Type 2 diabetes mellitus is a complex disorder encompassing multiple metabolic defects. We report results from an autosomal genome scan for type 2 diabetes-related quantitative traits in 580 Finnish families ascertained for an affected sibling pair and analyzed by the variance components-based quantitative-trait locus (QTL) linkage approach. We analyzed diabetic and nondiabetic subjects separately, because of the possible impact of disease on the traits of interest. In diabetic individuals, our strongest results were observed on chromosomes 3 (fasting C-peptide/glucose: maximum LOD score [MLS] = 3.13 at 53.0 cM) and 13 (body-mass index: MLS = 3.28 at 5.0 cM). In nondiabetic individuals, the strongest results were observed on chromosomes 10 (acute insulin response: MLS = 3.11 at 21.0 cM), 13 (2-h insulin: MLS = 2.86 at 65.5 cM), and 17 (fasting insulin/glucose ratio: MLS = 3.20 at 9.0 cM). In several cases, there was evidence for overlapping signals between diabetic and nondiabetic individuals; therefore we performed joint analyses. In these joint analyses, we observed strong signals for chromosomes 3 (body-mass index: MLS = 3.43 at 59.5 cM), 17 (empirical insulin-resistance index: MLS = 3.61 at 0.0 cM), and 19 (empirical insulin-resistance index: MLS = 2.80 at 74.5 cM). Integrating genome-scan results from the companion article by Ghosh et al., we identify several regions that may harbor susceptibility genes for type 2 diabetes in the Finnish population.
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