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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TL;DR: A new method of quantitative-trait linkage analysis that combines the simplicity and robustness of regression-based methods and the generality and greater power of variance-components models is presented.
Abstract: We present a new method of quantitative-trait linkage analysis that combines the simplicity and robustness of regression-based methods and the generality and greater power of variance-components models. The new method is based on a regression of estimated identity-by-descent (IBD) sharing between relative pairs on the squared sums and squared differences of trait values of the relative pairs. The method is applicable to pedigrees of arbitrary structure and to pedigrees selected on the basis of trait value, provided that population parameters of the trait distribution can be correctly specified. Ambiguous IBD sharing (due to incomplete marker information) can be accommodated in the method by appropriate specification of the variance-covariance matrix of IBD sharing between relative pairs. We have implemented this regression-based method and have performed simulation studies to assess, under a range of conditions, estimation accuracy, type I error rate, and power. For normally distributed traits and in large samples, the method is found to give the correct type I error rate and an unbiased estimate of the proportion of trait variance accounted for by the additive effects of the locus—although, in cases where asymptotic theory is doubtful, significance levels should be checked by simulations. In large sibships, the new method is slightly more powerful than variance-components models. The proposed method provides a practical and powerful tool for the linkage analysis of quantitative traits.
282 citations
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University of Toronto1, Montreal Neurological Institute and Hospital2, University of British Columbia3, Mount Sinai Hospital, Toronto4, University of Calgary5, Wellcome Trust Centre for Human Genetics6, Boston Children's Hospital7, Alberta Children's Hospital8, Centre Hospitalier Universitaire de Sherbrooke9, McMaster Children's Hospital10, Montreal Children's Hospital11, Children's Hospital of Eastern Ontario12, Queen's University13, Saint John Regional Hospital14, Halifax15, Royal University Hospital16, Janeway Children's Health and Rehabilitation Centre17, Trillium Health Centre18, Dalhousie University19, University of Manitoba20
TL;DR: Risk of multiple sclerosis in children can be stratified by presence of HLA-DRB1*15 alleles, remote Epstein-Barr virus infection, and low serum 25-hydroxyvitamin D concentrations, suggesting established disease.
Abstract: Summary Background HLA-DRB1*15 genotype, previous infection with Epstein-Barr virus, and vitamin D insufficiency are susceptibility factors for multiple sclerosis, but whether they act synergistically to increase risk is unknown. We aimed to assess the contributions of these risk factors and the effect of established precursors of multiple sclerosis, such as brain lesions on MRI and oligoclonal bands in CSF at the time of incident demyelination, on development of multiple sclerosis in children. Methods In our prospective national cohort study, we assessed children who presented with incident CNS demyelination to any of the 16 paediatric health-care facilities or seven regional health-care facilities in Canada. We did univariate and multivariable analyses to assess contributions of HLA-DRB1*15 , Epstein-Barr virus, vitamin D status, MRI evidence of brain lesions, and CSF oligoclonal bands as determinants of multiple sclerosis. We used classification and regression tree analyses to generate a risk stratification algorithm for clinical use. Findings Between Sept 1, 2004, and June 30, 2010, we screened 332 children of whom 302 (91%) were eligible and followed-up for a median of 3·14 years (IQR 1·61–4·51). 63 (21%) children were diagnosed with multiple sclerosis after a median of 127 days (99–222). Although the risk of multiple sclerosis was increased with presence of one or more HLA-DRB1*15 alleles (hazard ratio [HR] 2·32, 95% CI 1·25–4·30), reduced serum 25-hydroxyvitamin D concentration (HR per 10 nmol/L decrease 1·11, 1·00–1·25), and previous Epstein-Barr-virus infection (HR 2·04, 0·99–4·20), no interactions between these variables were detected on multivariate analysis. Multiple sclerosis was strongly associated with baseline MRI evidence of one or more brain lesion (HR 37·9, 5·26–273·85) or CSF oligoclonal bands (6·33, 3·35–11·96), suggesting established disease. One patient diagnosed with multiple sclerosis had a normal MRI scan, and therefore sensitivity of an abnormal MRI scan for multiple sclerosis diagnosis was 98·4%. Interpretation Risk of multiple sclerosis in children can be stratified by presence of HLA-DRB1*15 alleles, remote Epstein-Barr virus infection, and low serum 25-hydroxyvitamin D concentrations. Similar to previous studies in adults, brain lesions detected on MRI and CSF oligoclonal bands in children are probable precursors to the clinical onset of multiple sclerosis. Children with a normal MRI are very likely to have a monophasic illness. Funding Canadian Multiple Sclerosis Scientific Research Foundation.
282 citations
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TL;DR: It is shown that intracellular recognition of specific bacterial products affects the presence of childhood asthma, and the deletion allele (ND(1)+32656*) was found to be associated with inflammatory bowel disease.
Abstract: Asthma is a familial inflammatory disease of the airways of the lung. Microbial exposures in childhood protect against asthma through unknown mechanisms. The innate immune system is able to identify microbial components through a variety of pattern-recognition receptors (PRRs). NOD1 is an intracellular PRR that initiates inflammationinresponsetobacterialdiaminopimelicacid(iE-DAP).TheNOD1geneisonchromosome7p14,in aregionthathasbeengeneticallylinkedto asthma. Wecarriedoutasystematic search forpolymorphismin the gene. We found an insertion‐deletion polymorphism (ND1 1 32656) near the beginning of intron IX that accounted for 7% of the variation in IgE in two panels of families (P < 0.0005 in each). Allele*2 (the insertion) was associated with high IgE levels. The same allele was strongly associated with asthma in an independent study of 600 asthmatic children and 1194 super-normal controls [odds ratio (OR) 6.3; 95% confidence interval (CI) 1.4‐28.3, dominant model]. Differential binding of the two ND1 1 32656 alleles was observed to a protein from nuclei of the Calu 3 epithelial cell line. In an accompanying study, the deletion allele (ND1 1 32656*1) was found to be associated with inflammatory bowel disease. The results indicate that intracellular recognition of specific bacterial products affects the presence of childhood asthma.
281 citations
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University of Minnesota1, University of Texas at Austin2, National Institutes of Health3, North Carolina State University4, Wellcome Trust Centre for Human Genetics5, Wellcome Trust Sanger Institute6, Baylor College of Medicine7, University of Alabama at Birmingham8, Queen Mary University of London9, Boston University10, King's College London11, University of North Carolina at Chapel Hill12
TL;DR: DNA methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders was tested in the Atherosclerosis Risk in Communities study.
Abstract: Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC (P < 1 × 10(-7); Bonferroni), including probes in the recently reported HIF3A, CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP, KDM2B, PBX1 and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches.
280 citations
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University of Helsinki1, National Institutes of Health2, Wellcome Trust Centre for Human Genetics3, University of Tartu4, University of Ferrara5, University Medical Center Groningen6, Amgen7, Uppsala University8, Karolinska Institutet9, VU University Amsterdam10, Erasmus University Rotterdam11, Lund University12, Leiden University Medical Center13, National Institute for Health Research14, University of Lübeck15, Medical Research Council16, Technische Universität München17, University of Tampere18, Steno Diabetes Center19, Ludwig Maximilian University of Munich20, Massachusetts Institute of Technology21, Harvard University22, European Bioinformatics Institute23, University of Leicester24, Turku University Hospital25, Uppsala University Hospital26, Erasmus University Medical Center27, University College London28, University of Turku29, University of Oxford30, University of Iceland31, Minerva Foundation Institute for Medical Research32, University of Liverpool33, Imperial College London34, Wellcome Trust Sanger Institute35
TL;DR: Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, association to lipid traits in 93 loci is identified, including 79 previously identified loci with new lead SNPs and 10 new loci, including 15 locu with a low-frequency lead SNP and 10 loco with a missense lead SNP.
Abstract: Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.
279 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 |