scispace - formally typeset
Search or ask a question

Showing papers by "Wellcome Trust Centre for Human Genetics published in 2010"


Journal ArticleDOI
TL;DR: By combining genome-wide association data from 8,130 individuals with type 2 diabetes and 38,987 controls of European descent and following up previously unidentified meta-analysis signals, 12 new T2D association signals are identified with combined P < 5 × 10−8.
Abstract: By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

1,785 citations


Journal ArticleDOI
TL;DR: A few common alleles are associated with disease risk at all ages and suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation in asthma.
Abstract: A b s t r ac t Background Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. Methods We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. Results We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P =3×10 −9 ); rs9273349 on chromosome 6, implicating HLA-DQ (P = 7×10 −14 ); rs1342326 on chromosome 9, flanking IL33 (P = 9×10 −10 ); rs744910 on chromosome 15 in SMAD3 (P = 4×10 −9 ); and rs2284033 on chromosome 22 in IL2RB (P = 1.1×10 −8 ). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P = 6×10 −23 ). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. Conclusions Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)

1,764 citations


Journal ArticleDOI
TL;DR: Seven leading geneticists offer their opinion about where the 'missing heritability' of complex diseases might be found, what this could tell us about the underlying genetic architecture of common diseases and how this could inform research strategies for uncovering genetic risk factors.
Abstract: Although recent genome-wide studies have provided valuable insights into the genetic basis of human disease, they have explained relatively little of the heritability of most complex traits, and the variants identified through these studies have small effect sizes. This has led to the important and hotly debated issue of where the 'missing heritability' of complex diseases might be found. Here, seven leading geneticists offer their opinion about where this heritability is likely to lie, what this could tell us about the underlying genetic architecture of common diseases and how this could inform research strategies for uncovering genetic risk factors.

1,653 citations


Journal ArticleDOI
Thomas J. Wang1, Feng Zhang2, J. Brent Richards, Bryan Kestenbaum3, Joyce B. J. van Meurs4, Diane J. Berry5, Douglas P. Kiel, Elizabeth A. Streeten6, Claes Ohlsson7, Daniel L. Koller8, Leena Peltonen9, Leena Peltonen10, Jason D. Cooper2, Paul F. O'Reilly11, Denise K. Houston12, Nicole L. Glazer3, Liesbeth Vandenput7, Munro Peacock8, Julia Shi6, Fernando Rivadeneira4, Mark I. McCarthy13, Mark I. McCarthy14, Mark I. McCarthy15, Pouta Anneli, Ian H. de Boer3, Massimo Mangino2, Bernet S. Kato2, Deborah J. Smyth7, Sarah L. Booth16, Paul F. Jacques16, Greg L. Burke12, Mark O. Goodarzi17, Ching-Lung Cheung18, Myles Wolf19, Kenneth Rice3, David Goltzman2, Nick Hidiroglou20, Martin Ladouceur, Nicholas J. Wareham7, Lynne J. Hocking16, Deborah J. Hart2, Nigel K Arden13, Cyrus Cooper13, Suneil Malik21, William D. Fraser22, Anna Liisa Hartikainen2, Guangju Zhai2, Helen M. Macdonald2, Nita G. Forouhi23, Ruth J. F. Loos23, David M. Reid24, Alan Hakim, Elaine M. Dennison25, Yongmei Liu10, Chris Power5, Helen Stevens2, Laitinen Jaana21, Ramachandran S. Vasan26, Nicole Soranzo9, Nicole Soranzo27, Jörg Bojunga28, Bruce M. Psaty3, Mattias Lorentzon7, Tatiana Foroud8, Tamara B. Harris10, Albert Hofman4, John-Olov Jansson11, Jane A. Cauley29, André G. Uitterlinden, Quince Gibson, Marjo-Riitta Järvelin, David Karasik, David S. Siscovick3, Michael J. Econs8, Stephen B. Kritchevsky22, Jose C. Florez, John A. Todd7, Josée Dupuis26, Elina Hyppönen5, Tim D. Spector27 
TL;DR: In this article, a genome-wide association study of 25-hydroxyvitamin D concentrations in 33,996 individuals of European descent from 15 cohorts was conducted to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.

1,381 citations


Journal ArticleDOI
TL;DR: This protocol details the steps for data quality assessment and control that are typically carried out during case-control association studies, including the identification and removal of DNA samples and markers that introduce bias.
Abstract: This protocol details the steps for data quality assessment and control that are typically carried out during case-control association studies. The steps described involve the identification and removal of DNA samples and markers that introduce bias. These critical steps are paramount to the success of a case-control study and are necessary before statistically testing for association. We describe how to use PLINK, a tool for handling SNP data, to perform assessments of failure rate per individual and per SNP and to assess the degree of relatedness between individuals. We also detail other quality-control procedures, including the use of SMARTPCA software for the identification of ancestral outliers. These platforms were selected because they are user-friendly, widely used and computationally efficient. Steps needed to detect and establish a disease association using case-control data are not discussed here. Issues concerning study design and marker selection in case-control studies have been discussed in our earlier protocols. This protocol, which is routinely used in our labs, should take approximately 8 h to complete.

1,106 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
12 Feb 2010-Science
TL;DR: The involvement of PRDM9, which causes histone H3 lysine 4 trimethylation, implies that there is a common mechanism for recombination hotspots in eukaryotes but raises questions about what forces have driven such rapid change.
Abstract: Although present in both humans and chimpanzees, recombination hotspots, at which meiotic crossover events cluster, differ markedly in their genomic location between the species. We report that a 13-base pair sequence motif previously associated with the activity of 40% of human hotspots does not function in chimpanzees and is being removed by self-destructive drive in the human lineage. Multiple lines of evidence suggest that the rapidly evolving zinc-finger protein PRDM9 binds to this motif and that sequence changes in the protein may be responsible for hotspot differences between species. The involvement of PRDM9, which causes histone H3 lysine 4 trimethylation, implies that there is a common mechanism for recombination hotspots in eukaryotes but raises questions about what forces have driven such rapid change.

636 citations


Journal ArticleDOI
Thorgeir E. Thorgeirsson1, Daniel F. Gudbjartsson2, Ida Surakka3, Ida Surakka4, Jacqueline M. Vink5, Najaf Amin6, Frank Geller2, Patrick Sulem2, Thorunn Rafnar2, Tõnu Esko7, Tõnu Esko8, Stefan Walter6, Christian Gieger, Rajesh Rawal, Massimo Mangino9, Inga Prokopenko10, Reedik Mägi11, Reedik Mägi10, Kaisu Keskitalo3, Iris H Gudjonsdottir2, Solveig Gretarsdottir2, Hreinn Stefansson2, John R. Thompson12, Yurii S. Aulchenko6, Mari Nelis8, Mari Nelis7, Katja K.H. Aben13, Martin den Heijer13, Asger Dirksen, Haseem Ashraf, Nicole Soranzo14, Nicole Soranzo9, Ana M. Valdes9, Claire J. Steves9, André G. Uitterlinden6, Albert Hofman6, Anke Tönjes15, Peter Kovacs15, Jouke-Jan Hottenga5, Gonneke Willemsen5, Nicole Vogelzangs16, Angela Döring, Norbert Dahmen17, Barbara Nitz, Michele L. Pergadia18, Berta Saez, Veronica De Diego, Victoria Lezcano, Maria D. Garcia-Prats, Samuli Ripatti4, Samuli Ripatti3, Markus Perola4, Johannes Kettunen14, Anna-Liisa Hartikainen19, Anneli Pouta, Jaana Laitinen20, Matti Isohanni19, Shen Huei-Yi4, Shen Huei-Yi3, Maxine Allen10, Maria Krestyaninova21, Alistair S. Hall22, Gregory T. Jones23, Andre M. van Rij23, Thomas Mueller, Benjamin Dieplinger, Meinhard Haltmayer, Steinn Jonsson, Stefan E Matthiasson24, Hogni Oskarsson, Thorarinn Tyrfingsson, Lambertus A. Kiemeney13, Jose I. Mayordomo25, Jes S. Lindholt, Jesper Holst Pedersen26, Wilbur A. Franklin27, Holly J. Wolf28, Grant W. Montgomery29, Andrew C. Heath18, Nicholas G. Martin29, Pamela A. F. Madden18, Ina Giegling30, Dan Rujescu30, Marjo-Riitta Järvelin, Veikko Salomaa4, Michael Stumvoll15, Tim D. Spector9, H-Erich Wichmann30, Andres Metspalu7, Andres Metspalu8, Nilesh J. Samani12, Brenda W.J.H. Penninx16, Ben A. Oostra6, Dorret I. Boomsma5, Henning Tiemeier6, Cornelia M. van Duijn6, Jaakko Kaprio3, Jaakko Kaprio4, Jeffrey R. Gulcher2, Mark I. McCarthy11, Mark I. McCarthy10, Leena Peltonen3, Leena Peltonen14, Unnur Thorsteinsdottir24, Unnur Thorsteinsdottir2, Kari Stefansson2, Kari Stefansson24 
TL;DR: The authors conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium.
Abstract: Smoking is a common risk factor for many diseases. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).

626 citations


Journal ArticleDOI
26 Mar 2010-Immunity
TL;DR: The combinatorial assembly of tissue- and signal-specific transcription factors determines the activity of a distinct group of enhancers and it is suggested that this may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation.

608 citations


Journal ArticleDOI
TL;DR: The results demonstrate that methods based on accumulations of rare variants discovered through re‐sequencing offer substantially greater power than conventional analysis of GWA data, and thus provide an exciting opportunity for future discovery of genetic determinants of complex traits.
Abstract: Genome-wide association (GWA) studies have proved to be extremely successful in identifying novel common polymorphisms contributing effects to the genetic component underlying complex traits. Nevertheless, one source of, as yet, undiscovered genetic determinants of complex traits are those mediated through the effects of rare variants. With the increasing availability of large-scale re-sequencing data for rare variant discovery, we have developed a novel statistical method for the detection of complex trait associations with these loci, based on searching for accumulations of minor alleles within the same functional unit. We have undertaken simulations to evaluate strategies for the identification of rare variant associations in population-based genetic studies when data are available from re-sequencing discovery efforts or from commercially available GWA chips. Our results demonstrate that methods based on accumulations of rare variants discovered through re-sequencing offer substantially greater power than conventional analysis of GWA data, and thus provide an exciting opportunity for future discovery of genetic determinants of complex traits. Genet. Epidemiol. 34: 188–193, 2010. © 2009 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: The GWAMA (Genome-Wide Association Meta-Analysis) software has been developed to perform meta-analysis of summary statistics generated from genome-wide association studies of dichotomous phenotypes or quantitative traits.
Abstract: Despite the recent success of genome-wide association studies in identifying novel loci contributing effects to complex human traits, such as type 2 diabetes and obesity, much of the genetic component of variation in these phenotypes remains unexplained. One way to improving power to detect further novel loci is through meta-analysis of studies from the same population, increasing the sample size over any individual study. Although statistical software analysis packages incorporate routines for meta-analysis, they are ill equipped to meet the challenges of the scale and complexity of data generated in genome-wide association studies. We have developed flexible, open-source software for the meta-analysis of genome-wide association studies. The software incorporates a variety of error trapping facilities, and provides a range of meta-analysis summary statistics. The software is distributed with scripts that allow simple formatting of files containing the results of each association study and generate graphical summaries of genome-wide meta-analysis results. The GWAMA (Genome-Wide Association Meta-Analysis) software has been developed to perform meta-analysis of summary statistics generated from genome-wide association studies of dichotomous phenotypes or quantitative traits. Software with source files, documentation and example data files are freely available online at http://www.well.ox.ac.uk/GWAMA .

Journal ArticleDOI
Robin G. Walters1, Sébastien Jacquemont2, Armand Valsesia3, Armand Valsesia4, Armand Valsesia5, A J de Smith1, Danielle Martinet2, Johanna C. Andersson1, Mario Falchi1, Fei Chen6, Joris Andrieux, Stéphane Lobbens7, Bruno Delobel, Fanny Stutzmann7, J. S. El-Sayed Moustafa1, Jean-Claude Chèvre7, C. Lecoeur7, Vincent Vatin7, Sonia Bouquillon, Jessica L. Buxton1, Odile Boute, Muriel Holder-Espinasse, Jean-Marie Cuisset, Marie-Pierre Lemaitre, Anne-Emmanuelle Ambresin2, A. Brioschi2, Muriel Gaillard2, Vittorio Giusti2, Florence Fellmann2, Alessandra Ferrarini2, Nouchine Hadjikhani8, Nouchine Hadjikhani6, Dominique Campion9, Audrey Guilmatre9, Alice Goldenberg, Nadège Calmels, Jean-Louis Mandel, C Le Caignec9, Albert David, Bertrand Isidor, Marie-Pierre Cordier, Sophie Dupuis-Girod, Audrey Labalme, Damien Sanlaville, M. Béri-Dexheimer10, Philippe Jonveaux10, B. Leheup10, Katrin Õunap11, Elena G. Bochukova12, Elana Henning12, Julia M. Keogh12, Richard J. Ellis, Kay D. MacDermot, M. M. van Haelst13, Catherine Vincent-Delorme, Ghislaine Plessis, R. Touraine, Anne Philippe14, Valérie Malan14, Michèle Mathieu-Dramard, Jean Chiesa, Bettina Blaumeiser15, R. F. Kooy15, Robert Caiazzo16, Robert Caiazzo9, Marie Pigeyre16, B. Balkau9, Robert Sladek17, Sven Bergmann4, Sven Bergmann3, Vincent Mooser18, Dawn M. Waterworth18, Alexandre Reymond4, Peter Vollenweider2, Gérard Waeber2, Ants Kurg19, Priit Palta19, Tõnu Esko19, Tõnu Esko20, Andres Metspalu19, Andres Metspalu20, Mari Nelis20, Mari Nelis19, Paul Elliott1, A.-L. Hartikainen21, Mark I. McCarthy22, Mark I. McCarthy23, Leena Peltonen24, Leena Peltonen25, Lena M. S. Carlsson, Peter Jacobson, Lars Sjöström, Ni Huang25, Matthew E. Hurles25, Stephen O'Rahilly12, I. S. Farooqi12, Katrin Männik19, Marjo-Riitta Järvelin21, Marjo-Riitta Järvelin1, François Pattou9, François Pattou16, David Meyre7, Andrew Walley1, Lachlan J. M. Coin1, Alexandra I. F. Blakemore1, Philippe Froguel1, Philippe Froguel7, Jacques S. Beckmann2, Jacques S. Beckmann4 
04 Feb 2010-Nature
TL;DR: A highly penetrant form of obesity is reported, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits, which highlights a promising strategy for identifying missing heritability in obesity and other complex traits.
Abstract: Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.


Journal ArticleDOI
TL;DR: A meta-analysis of three GWAS from the UK provides evidence that additional CRC-associated variants of similar effect size remain to be discovered and identifies four new CRC risk loci.
Abstract: Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10−10 and rs6687758, OR = 1.09, P = 2.27 × 10−9), 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10−8), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10−10 and rs7136702, OR = 1.06, P = 4.02 × 10−8) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10−10). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.

Journal ArticleDOI
Sandosh Padmanabhan1, Olle Melander2, Toby Johnson3, Anna Maria Di Blasio, Wai K. Lee1, Davide Gentilini, Claire E. Hastie1, Cristina Menni1, Cristina Menni4, Maria Cristina Monti5, Christian Delles1, Stewart Laing1, Barbara Corso5, Gerjan Navis6, Arjan J. Kwakernaak6, Pim van der Harst6, Murielle Bochud7, Marc Maillard7, Michel Burnier7, Thomas Hedner8, Sverre E. Kjeldsen9, Björn Wahlstrand8, Marketa Sjögren2, Cristiano Fava2, Cristiano Fava10, Martina Montagnana10, Martina Montagnana2, Elisa Danese10, Elisa Danese2, Ole Torffvit, Bo Hedblad2, Harold Snieder6, John M. C. Connell11, Morris Brown12, Nilesh J. Samani13, Martin Farrall14, Giancarlo Cesana4, Giuseppe Mancia4, Stefano Signorini, Guido Grassi4, Susana Eyheramendy15, H.-Erich Wichmann16, Maris Laan17, David P. Strachan18, Peter S. Sever19, Denis C. Shields20, Alice Stanton21, Peter Vollenweider7, Alexander Teumer22, Henry Völzke22, Rainer Rettig22, Christopher Newton-Cheh23, Christopher Newton-Cheh24, Pankaj Arora24, Pankaj Arora23, Feng Zhang25, Nicole Soranzo25, Nicole Soranzo26, Tim D. Spector25, Gavin Lucas, Sekar Kathiresan24, Sekar Kathiresan23, David S. Siscovick27, Jian'an Luan, Ruth J. F. Loos, Nicholas J. Wareham, Brenda W.J.H. Penninx28, Brenda W.J.H. Penninx6, Brenda W.J.H. Penninx29, Ilja M. Nolte6, Martin W. McBride1, William H. Miller1, Stuart A. Nicklin1, Andrew H. Baker1, Delyth Graham1, Robert A. McDonald1, Jill P. Pell1, Naveed Sattar1, Paul Welsh1, Patricia B. Munroe3, Mark J. Caulfield3, Alberto Zanchetti30, Anna F. Dominiczak1 
TL;DR: The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.
Abstract: Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Journal ArticleDOI
TL;DR: This study demonstrates that genome-wide association studies can identify new susceptibility loci for infectious diseases, even in African populations, in which levels of linkage disequilibrium are particularly low.
Abstract: We combined two tuberculosis genome-wide association studies from Ghana and The Gambia with subsequent replication in a combined 11,425 individuals. rs4331426, located in a gene-poor region on chromosome 18q11.2, was associated with disease (combined P = 6.8 x 10(-9), odds ratio = 1.19, 95% CI = 1.13-1.27). Our study demonstrates that genome-wide association studies can identify new susceptibility loci for infectious diseases, even in African populations, in which levels of linkage disequilibrium are particularly low.

Journal ArticleDOI
05 Aug 2010-Oncogene
TL;DR: It is demonstrated that severe hypoxia leads to ER stress and induces ATF4-dependent autophagy through LC3 as a survival mechanism, and small interfering RNA and microarray analysis is used to provide the first whole-genome analysis of genes regulated by ATF4 in cancer cells in response to severe and prolonged hypoxic stress.
Abstract: Activating transcription factor 4 (ATF4) is a transcription factor induced under severe hypoxia and a component of the PERK pathway involved in the unfolded protein response (UPR), a process that protects cells from the negative consequences of endoplasmic reticulum (ER) stress. In this study, we have used small interfering RNA (siRNA) and microarray analysis to provide the first whole-genome analysis of genes regulated by ATF4 in cancer cells in response to severe and prolonged hypoxic stress. We show that ATF4 is required for ER stress and hypoxia-induced expansion of autophagy. MAP1LC3B (LC3B) is a key component of the autophagosomal membrane, and in this study we demonstrate that ATF4 facilitates autophagy through direct binding to a cyclic AMP response element binding site in the LC3B promoter, resulting in LC3B upregulation. Previously, we have shown that Bortezomib-induced ATF4 stabilization, which then upregulated LC3B expression and had a critical role in activating autophagy, protecting cells from Bortezomib-induced cell death. We also showed that severe hypoxia stabilizes ATF4. In this study, we demonstrate that severe hypoxia leads to ER stress and induces ATF4-dependent autophagy through LC3 as a survival mechanism. In summary, we show that ATF4 has a key role in the regulation of autophagy in response to ER stress and provide a direct mechanistic link between the UPR and the autophagic machinery.

Journal ArticleDOI
TL;DR: It is observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity and major common variants related to obesity overlap to a substantial degree between children and adults.
Abstract: Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85x10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84x10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at approximately 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.

Journal ArticleDOI
TL;DR: A frameshift mutation, F139WfsX24, is reported, which segregates perfectly with typical migraine with aura in a large pedigree and demonstrates that it causes a complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominant-negative effect, thus explaining the dominant penetrance of this allele.
Abstract: Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. A role has been suggested for the two-pore domain (K2P) potassium channel, TWIK-related spinal cord potassium channel (TRESK, encoded by KCNK18), in pain pathways and general anaesthesia. We therefore examined whether TRESK is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine. Here we report a frameshift mutation, F139WfsX24, which segregates perfectly with typical migraine with aura in a large pedigree. We also identified prominent TRESK expression in migraine-salient areas such as the trigeminal ganglion. Functional characterization of this mutation demonstrates that it causes a complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominant-negative effect, thus explaining the dominant penetrance of this allele. These results therefore support a role for TRESK in the pathogenesis of typical migraine with aura and further support the role of this channel as a potential therapeutic target.


Journal ArticleDOI
01 Sep 2010-PLOS ONE
TL;DR: The results establish firmly that a history of infectious mononucleosis significantly increases the risk of multiple sclerosis.
Abstract: Background: Multiple sclerosis (MS) appears to develop in genetically susceptible individuals as a result of environmental exposures. Epstein-Barr virus (EBV) infection is an almost universal finding among individuals with MS. Symptomatic EBV infection as manifested by infectious mononucleosis (IM) has been shown in a previous meta-analysis to be associated with the risk of MS, however a number of much larger studies have since been published.Methods/Principal Findings: We performed a Medline search to identify articles published since the original meta-analysis investigating MS risk following IM. A total of 18 articles were included in this study, including 19390 MS patients and 16007 controls. We calculated the relative risk of MS following IM using a generic inverse variance with random effects model. This showed that the risk of MS was strongly associated with IM (relative risk (RR) 2.17; 95% confidence interval 1.97-2.39; p<10(-54)).Discussion: Our results establish firmly that a history of infectious mononucleosis significantly increases the risk of multiple sclerosis. Future work should focus on the mechanism of this association and interaction with other risk factors.

Journal ArticleDOI
26 Apr 2010-PLOS ONE
TL;DR: Induction of these major hallmarks of cancer show that a single microRNA, miR-210, mediates a new mechanism of adaptation to hypoxia, by regulating mitochondrial function via iron-sulfur cluster metabolism and free radical generation.
Abstract: Background Hypoxia in cancers results in the upregulation of hypoxia inducible factor 1 (HIF-1) and a microRNA, hsa-miR-210 (miR-210) which is associated with a poor prognosis.

Journal ArticleDOI
TL;DR: Unconditional unscaled VIMs are a computationally tractable choice for large datasets and are unbiased under the null hypothesis, and examples where this increased importance of correlated predictors may result in spurious signals are shown.
Abstract: Background Random forests (RF) have been increasingly used in applications such as genome-wide association and microarray studies where predictor correlation is frequently observed. Recent works on permutation-based variable importance measures (VIMs) used in RF have come to apparently contradictory conclusions. We present an extended simulation study to synthesize results.

Journal ArticleDOI
TL;DR: Predicted target genes of these differentially expressed microRNAs are involved in pathways relevant to type 2 diabetes, as modelled by the Gyoto–Kakizaki rat.
Abstract: Aims/hypothesis MicroRNAs regulate a broad range of biological mechanisms. To investigate the relationship between microRNA expression and type 2 diabetes, we compared global microRNA expression in insulin target tissues from three inbred rat strains that differ in diabetes susceptibility.

01 Jan 2010
TL;DR: In this article, a frameshift mutation, F139WfsX24, was found to cause complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominant negative effect, thus explaining the dominant penetrance of this allele.
Abstract: Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. A role has been suggested for the two-pore domain (K2P) potassium channel, TWIK-related spinal cord potassium channel (TRESK, encoded by KCNK18), in pain pathways and general anaesthesia. We therefore examined whether TRESK is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine. Here we report a frameshift mutation, F139WfsX24, which segregates perfectly with typical migraine with aura in a large pedigree. We also identified prominent TRESK expression in migraine-salient areas such as the trigeminal ganglion. Functional characterization of this mutation demonstrates that it causes a complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominant-negative effect, thus explaining the dominant penetrance of this allele. These results therefore support a role for TRESK in the pathogenesis of typical migraine with aura and further support the role of this channel as a potential therapeutic target.

Journal ArticleDOI
18 Nov 2010-PLOS ONE
TL;DR: This study demonstrates that integration of Genome-Wide Association SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases.
Abstract: Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p = 9.40 x 10(-4), permutation p = 1.0 x 10(-3)). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p = 1.13 x 10(-7)). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases.

Journal ArticleDOI
01 May 2010-Cancer
TL;DR: The authors have investigated the role of 3 microRNAs, including the hypoxia‐induced hsa‐miR‐210, as potential markers of Hypoxia or prognosis.
Abstract: BACKGROUND: Hypoxia is an important mechanism of treatment resistance in head and neck squamous cell carcinoma (HNSCC). MicroRNAs are short noncoding RNAs that regulate multiple mRNAs and are frequently dysregulated in cancer. The authors have investigated the role of 3 microRNAs, including the hypoxia-induced hsa-miR-210, as potential markers of hypoxia or prognosis. METHODS: Three hypoxia-related microRNAs, hsa-miR-210, hsa-miR-21, and hsa-miR-10b, were measured in 46 samples from patients with HNSCC. Expression levels were correlated with clinicopathological variables and other markers of hypoxia: a published 99-gene hypoxia metagene, individual hypoxia-related genes such as TWIST1, and immunohistochemical expression of hypoxia-inducible factor 1 and its target gene carbonic anhydrase 9. We then performed survival analyses to investigate the prognostic significance of these microRNAs. RESULTS: Only the level of hsa-miR-210 was significantly correlated with other markers of hypoxia, including the 99-gene hypoxia metagene (rho = 0.67, P < .001). We found no association between hsa-miR-210, hsa-miR-21, or hsa-miR-10b and clinicopathological variables such as tumor size, differentiation, and stage. However, high levels of hsa-miR-210 were associated with locoregional disease recurrence (P = .001) and short overall survival (P = .008). hsa-miR-21 and hsa-miR-10b had no prognostic significance. CONCLUSIONS: Expression of hsa-miR-210 in head and neck cancer correlates with other approaches for assessing hypoxia and is associated with prognosis. This warrants further study as a classification marker of patients for therapies involving modulation of hypoxia. Cancer 2010. © 2010 American Cancer Society.

Journal ArticleDOI
TL;DR: The first cohort-based analysis of the impact of genetic disorders in craniosynostosis is described and genetic testing of nonsyndromic cases should be targeted to patients with coronal or multisuture synostoses.
Abstract: OBJECTIVES: We describe the first cohort-based analysis of the impact of genetic disorders in craniosynostosis. We aimed to refine the understanding of prognoses and pathogenesis and to provide rational criteria for clinical genetic testing. METHODS: We undertook targeted molecular genetic and cytogenetic testing for 326 children who required surgery because of craniosynostosis, were born in 1993–2002, presented to a single craniofacial unit, and were monitored until the end of 2007. RESULTS: Eighty-four children (and 64 relatives) had pathologic genetic alterations (86% single-gene mutations and 14% chromosomal abnormalities). The FGFR3 P250R mutation was the single largest contributor (24%) to the genetic group. Genetic diagnoses accounted for 21% of all craniosynostosis cases and were associated with increased rates of many complications. Children with an initial clinical diagnosis of nonsyndromic craniosynostosis were more likely to have a causative mutation if the synostoses were unicoronal or bicoronal (10 of 48 cases) than if they were sagittal or metopic (0 of 55 cases; P = .0003). Repeat craniofacial surgery was required for 58% of children with single-gene mutations but only 17% of those with chromosomal abnormalities (P = .01). CONCLUSIONS: Clinical genetic assessment is critical for the treatment of children with craniosynostosis. Genetic testing of nonsyndromic cases (at least for FGFR3 P250R and FGFR2 exons IIIa/c) should be targeted to patients with coronal or multisuture synostoses. Single-gene disorders that disrupt physiologic signaling in the cranial sutures often require reoperation, whereas chromosomal abnormalities follow a more-indolent course, which suggests a different, secondary origin of the associated craniosynostosis.

Journal ArticleDOI
28 Oct 2010-Nature
TL;DR: These structures, together with biophysical and cellular assays of wild-type and mutant proteins, reveal that semaphorin dimers independently bind two plexin molecules and that signalling is critically dependent on the avidity of the resulting bivalent 2:2 complex.
Abstract: The semaphorin–plexin signalling system is an important cell-guidance cue. It has a central role in the development and homeostasis of a broad range of tissues, and is widely studied for its role in neural connectivity, cancer, cell migration and immune responses. In this issue of Nature, two groups report crystal structures of key components of the semaphorin–plexin system, and propose a mechanism for plexin signalling based on their findings. Janssen et al. determined the crystal structures of complexes of the semaphorin-binding regions of plexins B1 and A2 with their cognate semaphorin ectodomains. Nogi et al. present crystal structures of complexes of semaphorin 6A and plexin A2 ectodomains. Semaphorin proteins mediate signal transduction by interacting with plexin receptors; they have key roles in neuronal development and many other biological processes. Here, crystal structures are presented of the semaphorin-binding regions of plexin B1 and plexin A2 with their cognate semaphorin ectodomains. On the basis of these structures, a signalling mechanism is proposed. Cell-cell signalling of semaphorin ligands through interaction with plexin receptors is important for the homeostasis and morphogenesis of many tissues and is widely studied for its role in neural connectivity, cancer, cell migration and immune responses1. SEMA4D and Sema6A exemplify two diverse vertebrate, membrane-spanning semaphorin classes (4 and 6) that are capable of direct signalling through members of the two largest plexin classes, B and A, respectively2,3. In the absence of any structural information on the plexin ectodomain or its interaction with semaphorins the extracellular specificity and mechanism controlling plexin signalling has remained unresolved. Here we present crystal structures of cognate complexes of the semaphorin-binding regions of plexins B1 and A2 with semaphorin ectodomains (human PLXNB11–2–SEMA4Decto and murine PlxnA21–4–Sema6Aecto), plus unliganded structures of PlxnA21–4 and Sema6Aecto. These structures, together with biophysical and cellular assays of wild-type and mutant proteins, reveal that semaphorin dimers independently bind two plexin molecules and that signalling is critically dependent on the avidity of the resulting bivalent 2:2 complex (monomeric semaphorin binds plexin but fails to trigger signalling). In combination, our data favour a cell-cell signalling mechanism involving semaphorin-stabilized plexin dimerization, possibly followed by clustering, which is consistent with previous functional data. Furthermore, the shared generic architecture of the complexes, formed through conserved contacts of the amino-terminal seven-bladed β-propeller (sema) domains of both semaphorin and plexin, suggests that a common mode of interaction triggers all semaphorin–plexin based signalling, while distinct insertions within or between blades of the sema domains determine binding specificity.