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, Gene, Locus (genetics)
Papers published on a yearly basis
Papers
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Queen Mary University of London1, Medical Research Council2, King's College London3, University of Glasgow4, Glenfield Hospital5, University of Leicester6, University College London7, Imperial College London8, University of Ioannina9, University College Dublin10, St George's, University of London11, University of Cambridge12, University of Dundee13, Centre for Mental Health14, University of Edinburgh15, University of Michigan16, Health Protection Agency17, University Medical Center Groningen18, University of Sassari19, Mount Carmel Health20, University of Milan21, Katholieke Universiteit Leuven22, French Institute of Health and Medical Research23, Paris Descartes University24, University of Tartu25, Tallinn University of Technology26, University of Gothenburg27, University of Oslo28, Lund University29, University of Ottawa30, Clinical Trial Service Unit31, John Radcliffe Hospital32, Wellcome Trust Centre for Human Genetics33, Karolinska University Hospital34, University of Münster35, Wellcome Trust Sanger Institute36, University of London37, GlaxoSmithKline38, AstraZeneca39, Harvard University40, Royal College of Surgeons in Ireland41
TL;DR: An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci and highlighted the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
Abstract: Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
178 citations
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TL;DR: It is shown that perturbation of Z MIZ1 expression in human islets and beta-cells influences exocytosis and insulin secretion, highlighting a novel role for ZMIZ1 in the maintenance of glucose homeostasis.
Abstract: The intersection of genome-wide association analyses with physiological and functional data indicates that variants regulating islet gene transcription influence type 2 diabetes (T2D) predisposition and glucose homeostasis. However, the specific genes through which these regulatory variants act remain poorly characterized. We generated expression quantitative trait locus (eQTL) data in 118 human islet samples using RNA-sequencing and high-density genotyping. We identified fourteen loci at which cis-exon-eQTL signals overlapped active islet chromatin signatures and were coincident with established T2D and/or glycemic trait associations. At some, these data provide an experimental link between GWAS signals and biological candidates, such as DGKB and ADCY5. At others, the cis-signals implicate genes with no prior connection to islet biology, including WARS and ZMIZ1. At the ZMIZ1 locus, we show that perturbation of ZMIZ1 expression in human islets and beta-cells influences exocytosis and insulin secretion, highlighting a novel role for ZMIZ1 in the maintenance of glucose homeostasis. Together, these findings provide a significant advance in the mechanistic insights of T2D and glycemic trait association loci.
178 citations
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TL;DR: Although tumor Pik3CA mutation does not predict benefit from rofecoxib treatment, it merits further evaluation as a predictive biomarker for aspirin therapy, and support the prospective investigation of adjuvant aspirin in PIK3CA-mutant CRC.
Abstract: Purpose Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) and are associated with reduced disease recurrence and improved outcome after primary treatment. However, toxicities of NSAIDs have limited their use as antineoplastic therapy. Recent data have suggested that the benefit of aspirin after CRC diagnosis is limited to patients with PIK3CA-mutant cancers. We sought to determine the predictive utility of PIK3CA mutation for benefit from both cyclooxygenase-2 inhibition and aspirin. Methods We performed molecular analysis of tumors from 896 participants in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial, a large randomized trial comparing rofecoxib with placebo after primary CRC resection. We compared relapse-free survival and overall survival between rofecoxib therapy and placebo and between the use and nonuse of low-dose aspirin, according to tumor PIK3CA mutation status. Results We found no evidence of a greater ...
177 citations
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VU University Medical Center1, VU University Amsterdam2, Leiden University Medical Center3, King's College London4, University of Tartu5, Erasmus University Rotterdam6, QIMR Berghofer Medical Research Institute7, Technische Universität München8, University Medical Center Groningen9, Queensland University of Technology10, Ludwig Maximilian University of Munich11, Hannover Medical School12, Cornell University13, University of Oxford14, National Institute for Health Research15, Wellcome Trust Centre for Human Genetics16
TL;DR: In a discovery sample of 7,478 individuals of European descent, 4,068 genome- and metabolome-wide significant associations between single-nucleotide polymorphisms (SNPs) and metabolites are found, involving 59 independent SNPs and 85 metabolites.
Abstract: Metabolites are small molecules involved in cellular metabolism, which can be detected in biological samples using metabolomic techniques. Here we present the results of genome-wide association and meta-analyses for variation in the blood serum levels of 129 metabolites as measured by the Biocrates metabolomic platform. In a discovery sample of 7,478 individuals of European descent, we find 4,068 genome- and metabolome-wide significant (Z-test, P < 1.09 × 10(-9)) associations between single-nucleotide polymorphisms (SNPs) and metabolites, involving 59 independent SNPs and 85 metabolites. Five of the fifty-nine independent SNPs are new for serum metabolite levels, and were followed-up for replication in an independent sample (N = 1,182). The novel SNPs are located in or near genes encoding metabolite transporter proteins or enzymes (SLC22A16, ARG1, AGPS and ACSL1) that have demonstrated biomedical or pharmaceutical importance. The further characterization of genetic influences on metabolic phenotypes is important for progress in biological and medical research.
177 citations
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TL;DR: The findings argue the need for much larger samples than anticipated in genetic association studies and that the biological basis of emotional disorders is extremely complex.
Abstract: We describe a multistage approach to identify single nucleotide polymorphisms (SNPs) associated with neuroticism, a personality trait that shares genetic determinants with major depression and anxiety disorders Whole genome association with 452 574 SNPs was performed on DNA pools from B2000 individuals selected on extremes of neuroticism scores from a cohort of 88 142 people from southwest England The most significant SNPs were then genotyped on independent samples to replicate findings We were able to replicate association of one SNP within the PDE4D gene in a second sample collected by our laboratory and in a family-based test in an independent sample; however, the SNP was not significantly associated with neuroticism in two other independent samples We also observed an enrichment of low P-values in known regions of copy number variations Simulation indicates that our study had B80% power to identify neuroticism loci in the genome with odds ratio (OR) > 2, and B50% power to identify small effects (OR = 15) Since we failed to find any loci accounting for more than 1% of the variance, the heritability of neuroticism probably arises from many loci each explaining much less than 1% Our findings argue the need for much larger samples than anticipated in genetic association studies and that the biological basis of emotional disorders is extremely complex Molecular Psychiatry (2008) 13, 302–312; doi:101038/sjmp4002048; published online 31 July 2007
177 citations
Authors
Showing all 2127 results
Name | H-index | Papers | Citations |
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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 |