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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: A spectrum of ATP2A2 mutations in 19 families and six sporadic cases with Darier's disease supports the proposal that haploin-sufficiency is a common molecular mechanism for DD and suggests that additional factors are important contributors to the clinical phenotype.
Abstract: Darier's disease (DD) is an autosomal dominantly inherited skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently, we identified ATP2A2 encoding the sarco/endoplasmic reticulum Ca(2+)ATPase isoform 2 as the defective gene in DD. Now we report a spectrum of ATP2A2 mutations in 19 families and six sporadic cases with DD and investigate genotype-phenotype correlations. All 21 exons and flanking intron boundaries were amplified and screened for mutations by conformation-sensitive gel electrophoresis and direct sequencing. We identified 24 novel mutations that are scattered throughout the ATP2A2 gene. Two families shared an identical mutation on a common disease-associated haplotype, suggesting inheritance from a common ancestor. The majority of the mutations (54%; 13/24) led to a premature termination codon which further supports the proposal that haploin-sufficiency is a common molecular mechanism for DD. Thirty-eight per cent of mutations (9/24) result in non-conservative amino acid substitutions at highly conserved positions. Two mutations predict mutated polypeptides lacking or carrying additional amino acids. Marked inter- and intrafamilial phenotypic variability of the disease was observed. These results illustrate the considerable diversity of ATP2A2 mutations causing DD and suggest that additional factors are important contributors to the clinical phenotype.

151 citations

Journal ArticleDOI
04 Nov 2004-Nature
TL;DR: It is shown that the electron density also reveals the icosahedral lipid bilayer, beneath the protein capsid, enveloping the viral DNA, which is likely to be important during membrane-mediated DNA translocation into the host cell.
Abstract: Membranes are essential for selectively controlling the passage of molecules in and out of cells and mediating the response of cells to their environment. Biological membranes and their associated proteins present considerable difficulties for structural analysis. Although enveloped viruses have been imaged at about 9 A resolution by cryo-electron microscopy and image reconstruction1,2, no detailed crystallographic structure of a membrane system has been described. The structure of the bacteriophage PRD1 particle, determined by X-ray crystallography at about 4 A resolution, allows the first detailed analysis of a membrane-containing virus3. The architecture of the viral capsid and its implications for virus assembly are presented in the accompanying paper3. Here we show that the electron density also reveals the icosahedral lipid bilayer, beneath the protein capsid, enveloping the viral DNA. The viral membrane contains about 26,000 lipid molecules asymmetrically distributed between the membrane leaflets. The inner leaflet is composed predominantly of zwitterionic phosphatidylethanolamine molecules, facilitating a very close interaction with the viral DNA, which we estimate to be packaged to a pressure of about 45 atm, factors that are likely to be important during membrane-mediated DNA translocation into the host cell. In contrast, the outer leaflet is enriched in phosphatidylglycerol and cardiolipin, which show a marked lateral segregation within the icosahedral asymmetric unit. In addition, the lipid headgroups show a surprising degree of order.

151 citations

Journal ArticleDOI
TL;DR: Common variants in the FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification.

151 citations

Journal ArticleDOI
TL;DR: The results suggest that women are more aware of family medical histories than men, which emphasises the potential for ascertainment bias in unstratified data for a sex-limited disease.
Abstract: Summary Background Evidence of an association between multiple sclerosis (MS) and other autoimmune diseases would substantiate the hypothesis that MS is an autoimmune disease, and implicate a common mechanism. We aimed to investigate and compare the rate of autoimmune disease in MS patients, in their first-degree relatives, and in their unrelated spouses. Methods We used data from a national, multicentre, population-based sample to investigate the rate of autoimmune disease in 5031 MS patients, 30 259 of their first-degree relatives, and 2707 spousal controls. We asked patients and controls whether they had any of ten autoimmune diseases: Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, psoriasis, pernicious anaemia, systemic lupus erythematosus, autoimmune thyroid disease, vitiligo, and myasthenia gravis. MS probands were also asked whether their first-degree relatives had Crohn's disease, ulcerative colitis, rheumatoid arthritis, or type 1 diabetes. Findings After correction for age and sex, we did not identify any increased risk of autoimmune diseases in MS patients compared with their spousal controls (odds ratio [OR]=1·07, 95% CI 0·86–1·23, χ 2 =0·47, p=0·49), or in the first-degree relatives of MS probands compared with controls (OR=0·89, 0·63–1·17, χ 2 =1·11, p=0·29). However, the reported frequency of autoimmune diseases did differ according to the sex of the interviewee (female vs male patients χ 2 =92·2, p vs male spousal controls χ 2 =87·1, p Interpretation When data were adjusted for sex, no excess of common autoimmune diseases could be identified in MS patients or their families, including multicase pedigrees. Our results suggest that women are more aware of family medical histories than men, which emphasises the potential for ascertainment bias in unstratified data for a sex-limited disease. Family histories should thus be taken from male patients in the presence of a spouse.

150 citations

Journal ArticleDOI
TL;DR: The Metformin Genetics Consortium reported a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries as discussed by the authors, showing that the C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10−14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry.
Abstract: Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

150 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