Genome-wide association studies and beyond.
Ontology highlight
ABSTRACT:
SUBMITTER: Witte JS
PROVIDER: S-EPMC3997166 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Obesity and related complications are major health burdens. Almost 700 million adults are currently obese globally and the prevalence is predicted to rise towards 2030. The sudden change of lifestyle with physical inactivity and excessive calorie intake undoubtedly have a major part of the epidemic development; however, some individuals seem to be more prone to be affected by an unhealthy lifestyle than others. Hence, genetic predisposition also has an essential role in determining disease susceptibility and response to lifestyle factors. Since the introduction of genome-wide association studies (GWAS), the success of identifying obesity susceptibility variants have increased, and a total of 32 variants have been identified associating genome-wide significantly with body mass index (BMI) and 18 with measures of fat distribution during four overall obesity GWAS waves. However, the immediate success of the GWAS approach has eased off, but the proportion of explained variance for BMI by the identified obesity variants remains low. This review suggests and discusses new initiatives to take GWAS of obesity to the next level, including gene-environment interactions as modulating/masking factors, low-frequent or rare variants and ways to address such analyses, and finally reflections about the applicability of epigenetic modifications when elucidating the genetic background of obesity.
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Project description:Genetic linkage and association methods have long been the most important tools for gene identification in humans. These approaches can either be hypothesis-based (i.e., candidate-gene studies) or hypothesis-free (i.e., genome-wide studies). The first part of this review offers an overview of the latest successes in gene finding for blood pressure (BP) and essential hypertension using these DNA sequence-based discovery techniques. We further emphasize the importance of post-genome-wide association study (post-GWAS) analysis, which aims to prioritize genetic variants for functional follow-up. Whole-genome next-generation sequencing will eventually be necessary to provide a more comprehensive picture of all DNA variants affecting BP and hypertension. The second part of this review discusses promising novel approaches that move beyond the DNA sequence and aim to discover BP genes that are differentially regulated by epigenetic mechanisms, including microRNAs, histone modification, and methylation.
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Project description:Genome-wide, imputed, sequence, and structural data are now available for exceedingly large sample sizes. The needs for data management, handling population structure and related samples, and performing associations have largely been met. However, the infrastructure to support analyses involving complexity beyond genome-wide association studies is not standardized or centralized. We provide the PLatform for the Analysis, Translation, and Organization of large-scale data (PLATO), a software tool equipped to handle multi-omic data for hundreds of thousands of samples to explore complexity using genetic interactions, environment-wide association studies and gene-environment interactions, phenome-wide association studies, as well as copy number and rare variant analyses. Using the data from the Marshfield Personalized Medicine Research Project, a site in the electronic Medical Records and Genomics Network, we apply each feature of PLATO to type 2 diabetes and demonstrate how PLATO can be used to uncover the complex etiology of common traits.
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Project description:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of complex etiology that primarily affects women of childbearing age. The development of SLE is attributed to the breach of immunological tolerance and the interaction between SLE-susceptibility genes and various environmental factors, resulting in the production of pathogenic autoantibodies. Working in concert with the innate and adaptive arms of the immune system, lupus-related autoantibodies mediate immune-complex deposition in various tissues and organs, leading to acute and chronic inflammation and consequent end-organ damage. Over the past two decades or so, the impact of genetic susceptibility on the development of SLE has been well demonstrated in a number of large-scale genetic association studies which have uncovered a large fraction of genetic heritability of SLE by recognizing about a hundred SLE-susceptibility loci. Integration of genetic variant data with various omics data such as transcriptomic and epigenomic data potentially provides a unique opportunity to further understand the roles of SLE risk variants in regulating the molecular phenotypes by various disease-relevant cell types and in shaping the immune systems with high inter-individual variances in disease susceptibility. In this review, the catalogue of SLE susceptibility loci will be updated, and biological signatures implicated by the SLE-risk variants will be critically discussed. It is optimistically hoped that identification of SLE risk variants will enable the prognostic and therapeutic biomarker armamentarium of SLE to be strengthened, a major leap towards precision medicine in the management of the condition.
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Project description:This paper provides details on the necessary steps to assess and control data in genome wide association studies (GWAS) using genotype information on a large number of genetic markers for large number of individuals. Due to varied study designs and genotyping platforms between multiple sites/projects as well as potential genotyping errors, it is important to ensure high quality data. Scripts and directions are provided to facilitate others in this process.
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Project description:Recent advances in the field of genetics have dramatically changed our understanding of autoimmune disease. Candidate gene and, more recently, genome-wide association (GWA) studies have led to an explosion in the number of loci and pathways known to contribute to autoimmune phenotypes. Since the 1970s, researchers have known that several alleles in the MHC region play a role in the pathogenesis of many autoimmune diseases. More recent work has identified numerous risk loci involving both the innate and adaptive immune responses. However, much remains to be learned about the heritability of autoimmune conditions. Most regions found through GWA scans have yet to isolate the association to the causal allele(s) responsible for conferring disease risk. A role for rare variants (allele frequencies of <1%) has begun to emerge. Future research will use next-generation sequencing (NGS) technology to comprehensively evaluate the human genome for risk variants. Whole-transcriptome sequencing is now possible, which will provide much more detailed gene expression data. The dramatic drop in the cost and time required to sequence the entire human genome will ultimately make it possible for this technology to be used as a clinical diagnostic tool.
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Project description:BackgroundGenome-wide association studies (GWAS) have identified 30 risk loci for primary sclerosing cholangitis (PSC). Variants within these loci are found predominantly in noncoding regions of DNA making their mechanisms of conferring risk hard to define. Epigenomic studies have shown noncoding variants broadly impact regulatory element activity. The possible association of noncoding PSC variants with regulatory element activity has not been studied. We aimed to (1) determine if the noncoding risk variants in PSC impact regulatory element function and (2) if so, assess the role these regulatory elements have in explaining the genetic risk for PSC.MethodsAvailable epigenomic datasets were integrated to build a comprehensive atlas of cell type-specific regulatory elements, emphasizing PSC-relevant cell types. RNA-seq and ATAC-seq were performed on peripheral CD4+ T cells from 10 PSC patients and 11 healthy controls. Computational techniques were used to (1) study the enrichment of PSC-risk variants within regulatory elements, (2) correlate risk genotype with differences in regulatory element activity, and (3) identify regulatory elements differentially active and genes differentially expressed between PSC patients and controls.ResultsNoncoding PSC-risk variants are strongly enriched within immune-specific enhancers, particularly ones involved in T-cell response to antigenic stimulation. In total, 250 genes and >10,000 regulatory elements were identified that are differentially active between patients and controls.ConclusionsMechanistic effects are proposed for variants at 6 PSC-risk loci where genotype was linked with differential T-cell regulatory element activity. Regulatory elements are shown to play a key role in PSC pathophysiology.
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Project description:Genome-wide association studies (GWAS) analyze the genetic component of a phenotype or the etiology of a disease. Despite the success of many GWAS, little progress has been made in uncovering the underlying mechanisms for many diseases. The use of metabolomics as a readout of molecular phenotypes has enabled the discovery of previously undetected associations between diseases and signaling and metabolic pathways. In addition, combining GWAS and metabolomic information allows the simultaneous analysis of the genetic and environmental impacts on homeostasis. Most success has been seen in metabolic diseases such as diabetes, obesity and dyslipidemia. Recently, associations between loci such as FADS1, ELOVL2 or SLC16A9 and lipid concentrations have been explained by GWAS with metabolomics. Combining GWAS with metabolomics (mGWAS) provides the robust and quantitative information required for the development of specific diagnostics and targeted drugs. This review discusses the limitations of GWAS and presents examples of how metabolomics can overcome these limitations with the focus on metabolic diseases.
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Project description:Since the first reports in 2009, genome-wide association studies (GWAS) have been successful in identifying germline variants associated with glioma susceptibility. In this review, we describe a chronological history of glioma GWAS, culminating in the most recent study comprising 12,496 cases and 18,190 controls. We additionally summarize associations at the 27 glioma-risk SNPs that have been reported so far. Future efforts are likely to be principally focused on assessing association of germline-risk SNPs with particular molecular subgroups of glioma, as well as investigating the functional basis of the risk loci in tumor formation. These ongoing studies will be important to maximize the impact of research into glioma susceptibility, both in terms of insight into tumor etiology as well as opportunities for clinical translation. Cancer Epidemiol Biomarkers Prev; 27(4); 418-28. ©2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer."
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Project description:Genome-wide association studies (GWAS) have evolved over the last ten years into a powerful tool for investigating the genetic architecture of human disease. In this work, we review the key concepts underlying GWAS, including the architecture of common diseases, the structure of common human genetic variation, technologies for capturing genetic information, study designs, and the statistical methods used for data analysis. We also look forward to the future beyond GWAS.
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