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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.


Papers
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Journal ArticleDOI
TL;DR: Using oligonucleotide arrays, the breakpoints of this microdeletion were refined, defining a 478-kb critical region containing six genes that were deleted in all four individuals, and it was found that these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions.
Abstract: Genomic disorders are characterized by the presence of flanking segmental duplications that predispose these regions to recurrent rearrangement. Based on the duplication architecture of the genome, we investigated 130 regions that we hypothesized as candidates for previously undescribed genomic disorders. We tested 290 individuals with mental retardation by BAC array comparative genomic hybridization and identified 16 pathogenic rearrangements, including de novo microdeletions of 17q21.31 found in four individuals. Using oligonucleotide arrays, we refined the breakpoints of this microdeletion, defining a 478-kb critical region containing six genes that were deleted in all four individuals. We mapped the breakpoints of this deletion and of four other pathogenic rearrangements in 1q21.1, 15q13, 15q24 and 17q12 to flanking segmental duplications, suggesting that these are also sites of recurrent rearrangement. In common with the 17q21.31 deletion, these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions.

600 citations

Journal ArticleDOI
TL;DR: Significantly elevated risks of VTE were found, in all three populations studied, in people with a hospital record of admission for autoimmune haemolytic anaemia, chronic active hepatitis, dermatomyositis/polymyositis, type 1 diabetes mellitus, multiple sclerosis, myasthenia gravis, myxoedema, pemphigus/pemphIGoid, polyarteritis nodosa, psoriasis, rheumatoid arthritis, Sj
Abstract: Venous thromboembolism (VTE) is a common complication during and after a hospital admission. Although it is mainly considered a complication of surgery, it often occurs in people who have not undergone surgery, with recent evidence suggesting that immune-mediated diseases may play a role in VTE risk. We, therefore, decided to study the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in people admitted to hospital with a range of immune-mediated diseases. We analysed databases of linked statistical records of hospital admissions and death certificates for the Oxford Record Linkage Study area (ORLS1:1968 to 1998 and ORLS2:1999 to 2008) and the whole of England (1999 to 2008). Rate ratios for VTE were determined, comparing immune-mediated disease cohorts with comparison cohorts. Significantly elevated risks of VTE were found, in all three populations studied, in people with a hospital record of admission for autoimmune haemolytic anaemia, chronic active hepatitis, dermatomyositis/polymyositis, type 1 diabetes mellitus, multiple sclerosis, myasthenia gravis, myxoedema, pemphigus/pemphigoid, polyarteritis nodosa, psoriasis, rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. Rate ratios were considerably higher for some of these diseases than others: for example, for systemic lupus erythematosus the rate ratios were 3.61 (2.36 to 5.31) in the ORLS1 population, 4.60 (3.19 to 6.43) in ORLS2 and 3.71 (3.43 to 4.02) in the England dataset. People admitted to hospital with immune-mediated diseases may be at an increased risk of subsequent VTE. Our findings need independent confirmation or refutation; but, if confirmed, there may be a role for thromboprophylaxis in some patients with these diseases.

591 citations

Journal ArticleDOI
TL;DR: A dimensionality-reduction method is developed, (Z)ero (I)nflated (F)actor (A)nalysis (ZIFA), which explicitly models the dropout characteristics, and it is shown that it improves modeling accuracy on simulated and biological data sets.
Abstract: Single-cell RNA-seq data allows insight into normal cellular function and various disease states through molecular characterization of gene expression on the single cell level. Dimensionality reduction of such high-dimensional data sets is essential for visualization and analysis, but single-cell RNA-seq data are challenging for classical dimensionality-reduction methods because of the prevalence of dropout events, which lead to zero-inflated data. Here, we develop a dimensionality-reduction method, (Z)ero (I)nflated (F)actor (A)nalysis (ZIFA), which explicitly models the dropout characteristics, and show that it improves modeling accuracy on simulated and biological data sets.

583 citations

Journal ArticleDOI
TL;DR: In this article, a meta-analysis of genome-wide association scans from 14 studies with 28,141 participants of European descent was conducted, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genomewide significance, five of which are novel.
Abstract: Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.

581 citations

Journal ArticleDOI
TL;DR: A genome‐wide association study meta‐analysis of body fat distribution, measured by waist‐to‐hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci found heritability and variant effects were generally stronger in women than men, and one‐third of all signals to be sexually dimorphic.
Abstract: More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

580 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