Institution
Wellcome Trust Centre for Human Genetics
Facility•Oxford, United Kingdom•
About: Wellcome Trust Centre for Human Genetics is a facility organization based out in Oxford, United Kingdom. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 2122 authors who have published 4269 publications receiving 433899 citations.
Topics: Population, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Linkage disequilibrium
Papers published on a yearly basis
Papers
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University of Helsinki1, National Institutes of Health2, University of Oulu3, Wellcome Trust Sanger Institute4, Broad Institute5, Harvard University6, University of Tartu7, University of Melbourne8, Stanford University9, Boston Children's Hospital10, University of Michigan11, Lund University12, University of Turku13, Duke University14, Intermountain Medical Center15, University of Ottawa16, University of Pennsylvania17, Wellcome Trust Centre for Human Genetics18, University of Verona19, University of Washington20, Washington University in St. Louis21, University of Tampere22, University of Eastern Finland23, Churchill Hospital24, University of Oxford25, Semel Institute for Neuroscience and Human Behavior26, Turku University Hospital27
TL;DR: In this paper, the authors compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that the average Finn has more low-frequency loss-of-function variants and complete gene knockouts.
Abstract: Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻⁸) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹⁷). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻⁴), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.
367 citations
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TL;DR: How whole-genome sequencing studies have advanced understanding of the mechanisms and principles of within-host genome evolution is described, and the consequences of findings such as a potent adaptive potential for pathogenicity are considered.
Abstract: Whole-genome sequencing has opened the way for investigating the dynamics and genomic evolution of bacterial pathogens during the colonization and infection of humans. The application of this technology to the longitudinal study of adaptation in an infected host--in particular, the evolution of drug resistance and host adaptation in patients who are chronically infected with opportunistic pathogens--has revealed remarkable patterns of convergent evolution, suggestive of an inherent repeatability of evolution. In this Review, we describe how these studies have advanced our understanding of the mechanisms and principles of within-host genome evolution, and we consider the consequences of findings such as a potent adaptive potential for pathogenicity. Finally, we discuss the possibility that genomics may be used in the future to predict the clinical progression of bacterial infections and to suggest the best option for treatment.
365 citations
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TL;DR: In this paper, the authors investigated the association between myocardial infarction and the insertion/deletion (I/D) polymorphism of the gene for the angiotensin-1-converting enzyme (ACE).
364 citations
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TL;DR: Genetic association data are now providing new routes to understanding the aetiology of disease, as well as new footholds on the long and difficult path to better treatment and disease prevention.
Abstract: After more than a decade of hope and hype, researchers are finally making inroads into understanding the genetic basis of many common human diseases. The use of genome-wide association studies has broken the logjam, enabling genetic variants at specific loci to be associated with particular diseases. Genetic association data are now providing new routes to understanding the aetiology of disease, as well as new footholds on the long and difficult path to better treatment and disease prevention.
364 citations
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Texas Biomedical Research Institute1, University of Dundee2, Wellcome Trust Centre for Human Genetics3, National Institute for Health Research4, University of Oxford5, King's College London6, South London and Maudsley NHS Foundation Trust7, University of Queensland8, Princess Alexandra Hospital9, University College London10, University of London11, Trinity College, Dublin12, Cardiff University13, Wellcome Trust14, Wellcome Trust Sanger Institute15, Queen Mary University of London16, Leicester Royal Infirmary17, St George's, University of London18, University of Cambridge19, University of Leicester20, Glenfield Hospital21, University of Edinburgh22, Peninsula College of Medicine and Dentistry23, University of Exeter24, Ninewells Hospital25
TL;DR: It is concluded that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to meetformin.
Abstract: Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.
362 citations
Authors
Showing all 2127 results
Name | H-index | Papers | Citations |
---|---|---|---|
Mark I. McCarthy | 200 | 1028 | 187898 |
John P. A. Ioannidis | 185 | 1311 | 193612 |
Gonçalo R. Abecasis | 179 | 595 | 230323 |
Simon I. Hay | 165 | 557 | 153307 |
Robert Plomin | 151 | 1104 | 88588 |
Ashok Kumar | 151 | 5654 | 164086 |
Julian Parkhill | 149 | 759 | 104736 |
James F. Wilson | 146 | 677 | 101883 |
Jeremy K. Nicholson | 141 | 773 | 80275 |
Hugh Watkins | 128 | 524 | 91317 |
Erik Ingelsson | 124 | 538 | 85407 |
Claudia Langenberg | 124 | 452 | 67326 |
Adrian V. S. Hill | 122 | 589 | 64613 |
John A. Todd | 121 | 515 | 67413 |
Elaine Holmes | 119 | 560 | 58975 |