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Institution

Wellcome Trust Centre for Human Genetics

FacilityOxford, 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.


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Journal ArticleDOI
TL;DR: This work identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease and identified 3 associated variants that are correlated with expression changes in response to immune stimulus at two of these genes.
Abstract: Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

813 citations

Journal ArticleDOI
TL;DR: A substantial fraction of extragenic Pol II transcription sites coincides with transcriptional enhancers, which may be relevant for functional annotation of mammalian genomes.
Abstract: Mammalian genomes are pervasively transcribed outside mapped protein-coding genes. One class of extragenic transcription products is represented by long non-coding RNAs (lncRNAs), some of which result from Pol_II transcription of bona-fide RNA genes. Whether all lncRNAs described insofar are products of RNA genes, however, is still unclear. Here we have characterized transcription sites located outside protein-coding genes in a highly regulated response, macrophage activation by endotoxin. Using chromatin signatures, we could unambiguously classify extragenic Pol_II binding sites as belonging to either canonical RNA genes or transcribed enhancers. Unexpectedly, 70% of extragenic Pol_II peaks were associated with genomic regions with a canonical chromatin signature of enhancers. Enhancer-associated extragenic transcription was frequently adjacent to inducible inflammatory genes, was regulated in response to endotoxin stimulation, and generated very low abundance transcripts. Moreover, transcribed enhancers were under purifying selection and contained binding sites for inflammatory transcription factors, thus suggesting their functionality. These data demonstrate that a large fraction of extragenic Pol_II transcription sites can be ascribed to cis-regulatory genomic regions. Discrimination between lncRNAs generated by canonical RNA genes and products of transcribed enhancers will provide a framework for experimental approaches to lncRNAs and help complete the annotation of mammalian genomes.

811 citations

Journal ArticleDOI
TL;DR: ChIP-seq determination of transcription factor binding, in combination with GWA data, provides a powerful approach to further understanding the molecular bases of complex diseases.
Abstract: Initially thought to play a restricted role in calcium homeostasis, the pleiotropic actions of vitamin D in biology and their clinical significance are only now becoming apparent. However, the mode of action of vitamin D, through its cognate nuclear vitamin D receptor (VDR), and its contribution to diverse disorders, remain poorly understood. We determined VDR binding throughout the human genome using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). After calcitriol stimulation, we identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D. VDR binding sites were significantly enriched near autoimmune and cancer associated genes identified from genome-wide association (GWA) studies. Notable genes with VDR binding included IRF8, associated with MS, and PTPN2 associated with Crohn's disease and T1D. Furthermore, a number of single nucleotide polymorphism associations from GWA were located directly within VDR binding intervals, for example, rs13385731 associated with SLE and rs947474 associated with T1D. We also observed significant enrichment of VDR intervals within regions of positive selection among individuals of Asian and European descent. ChIP-seq determination of transcription factor binding, in combination with GWA data, provides a powerful approach to further understanding the molecular bases of complex diseases.

802 citations

Journal ArticleDOI
TL;DR: A critical role of SPINK5 in epidermal barrier function and immunity is disclosed, and a new pathway for high serum IgE levels and atopic manifestations is suggested.
Abstract: We describe here eleven different mutations in SPINK5, encoding the serine protease inhibitor LEKTI, in 13 families with Netherton syndrome (NS, MIM256500). Most of these mutations predict premature termination codons. These results disclose a critical role of SPINK5 in epidermal barrier function and immunity, and suggest a new pathway for high serum IgE levels and atopic manifestations.

800 citations

Journal ArticleDOI
David M. Evans1, Spencer Cca.2, J J Pointon3, Zhan Su2, D Harvey3, Grazyna Kochan2, Udo Oppermann4, Alexander T. Dilthey5, Matti Pirinen5, Millicent A. Stone6, L H Appleton3, Loukas Moutsianas2, Stephen Leslie2, T. W. H. Wordsworth3, Tony J. Kenna7, Tugce Karaderi3, Gethin P. Thomas7, Minghong Ward8, Michael H. Weisman9, C. Farrar3, Linda A. Bradbury7, Patrick Danoy7, Robert D. Inman10, Walter P. Maksymowych11, Dafna D. Gladman10, Proton Rahman12, Ann W. Morgan13, Helena Marzo-Ortega13, Paul Bowness3, Karl Gaffney14, Gaston Jsh.15, Malcolm D. Smith15, Jácome Bruges-Armas16, Couto A-R.17, Rosa Sorrentino17, Fabiana Paladini17, Manuel A. R. Ferreira18, Huji Xu19, Yu Liu19, L. Jiang19, Carlos López-Larrea, Roberto Díaz-Peña, Antonio López-Vázquez, Tetyana Zayats5, Céline Bellenguez2, Hannah Blackburn, Jenefer M. Blackwell20, Elvira Bramon21, Suzannah Bumpstead21, Juan P. Casas22, Aiden Corvin23, N. Craddock24, Panagiotis Deloukas21, Serge Dronov21, Audrey Duncanson25, Sarah Edkins21, Colin Freeman26, Matthew W. Gillman21, Emma Gray21, R. Gwilliam21, Naomi Hammond21, Sarah E. Hunt21, Janusz Jankowski, Alagurevathi Jayakumar21, Cordelia Langford21, Jennifer Liddle21, Hugh S. Markus27, Christopher G. Mathew28, O. T. McCann21, Mark I. McCarthy29, Palmer Cna.21, Leena Peltonen21, Robert Plomin28, Simon C. Potter21, Anna Rautanen21, Radhi Ravindrarajah21, Michelle Ricketts21, Nilesh J. Samani30, Stephen Sawcer31, A. Strange26, Richard C. Trembath28, Ananth C. Viswanathan32, Ananth C. Viswanathan33, Matthew Waller21, Paul A. Weston21, Pamela Whittaker21, Sara Widaa21, Nicholas W. Wood, Gil McVean26, John D. Reveille34, B P Wordsworth35, Matthew A. Brown35, Peter Donnelly26 
TL;DR: In this paper, the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all their datasets (p < 5x 10(-6) overall, with support in each of the three datasets studied).
Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 x 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

798 citations


Authors

Showing all 2127 results

NameH-indexPapersCitations
Mark I. McCarthy2001028187898
John P. A. Ioannidis1851311193612
Gonçalo R. Abecasis179595230323
Simon I. Hay165557153307
Robert Plomin151110488588
Ashok Kumar1515654164086
Julian Parkhill149759104736
James F. Wilson146677101883
Jeremy K. Nicholson14177380275
Hugh Watkins12852491317
Erik Ingelsson12453885407
Claudia Langenberg12445267326
Adrian V. S. Hill12258964613
John A. Todd12151567413
Elaine Holmes11956058975
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
202221
202183
202074
2019134
2018182
2017323