Paul R Burton

Publications (67)749.97 Total impact

• Article: Identification of seven loci affecting mean telomere length and their association with disease.

  Veryan Codd, Christopher P Nelson, Eva Albrecht, Massimo Mangino, Joris Deelen, Jessica L Buxton, Jouke Jan Hottenga, Krista Fischer, Tõnu Esko, Ida Surakka, [......], Iiris Hovatta, Christian Gieger, Andres Metspalu, Dorret I Boomsma, Marjo-Riitta Jarvelin, P Eline Slagboom, John R Thompson, Tim D Spector, Pim van der Harst, Nilesh J Samani
  [show abstract] [hide abstract]
  ABSTRACT: Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.
  Nature Genetics 03/2013; 45(4):422-427. · 35.53 Impact Factor
• Article: Integration of Genetics into a Systems Model of ECG Traits using HumanCVD BeadChip.

  Tom R Gaunt, Sonia Shah, Christopher P Nelson, Fotios Drenos, Peter S Braund, Ismail Adeniran, Lasse Folkersen, Debbie A Lawlor, Juan-Pablo Casas, Antoinette Amuzu, [......], Maciej Tomaszewski, Paul R Burton, Martin D Tobin, Steve E Humphries, Philippa J Talmud, Peter W Macfarlane, Aroon D Hingorani, Nilesh J Samani, Meena Kumari, Ian N M Day
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  ABSTRACT: BACKGROUND: -Electrocardiographic (ECG) traits are important, substantially heritable, determinants of risk of arrhythmias and sudden cardiac death. METHODS AND RESULTS: -In this study, three population-based cohorts (n=10,526) genotyped with the Illumina HumanCVD Beadchip and four quantitative ECG traits (PR interval, QRS axis, QRS duration and QTc interval) were evaluated for single nucleotide polymorphism (SNP) associations. Six gene regions contained SNPs associated with these traits at p< 10(-6), including SCN5A (PR interval and QRS duration), CAV1-CAV2 locus (PR interval), CDKN1A (QRS duration), NOS1AP, KCNH2 and KCNQ1 (QTc interval). Expression QTL analyses of top associated SNPs were undertaken in human heart and aortic tissues. NOS1AP, SCN5A, IGFBP3, CYP2C9 and CAV1 showed evidence of differential allelic expression. We modelled the effects of ion channel activity on ECG parameters, estimating the change in gene expression that would account for our observed associations, thus relating epidemiological observations and eQTL data to a systems model of the ECG. CONCLUSIONS: -These association results replicate and refine the mapping of previous genome-wide association study (GWAS) findings for ECG traits, whilst the expression analysis and modelling approaches offer supporting evidence for a functional role of some of these loci in cardiac excitation/conduction.
  Circulation Cardiovascular Genetics 11/2012; · 6.11 Impact Factor
• Article: Bayesian refinement of association signals for 14 loci in 3 common diseases.

  Julian B Maller, Gilean McVean, Jake Byrnes, Damjan Vukcevic, Kimmo Palin, Zhan Su, Joanna M M Howson, Adam Auton, Simon Myers, Andrew Morris, [......], Miles Parkes, Nazneen Rahman, Audrey Duncanson, John A Todd, Dominic P Kwiatkowski, Nilesh J Samani, Stephen C L Gough, Mark I McCarthy, Panagiotis Deloukas, Peter Donnelly
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  ABSTRACT: To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies.
  Nature Genetics 10/2012; · 35.53 Impact Factor
• Source

  Available from: Jerome I Rotter

  Article: Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci.

  Folkert W Asselbergs, Yiran Guo, Erik P A van Iperen, Suthesh Sivapalaratnam, Vinicius Tragante, Matthew B Lanktree, Leslie A Lange, Berta Almoguera, Yolande E Appelman, John Barnard, [......], Nilesh J Samani, Alex P Reiner, Robert A Hegele, John J P Kastelein, Aroon D Hingorani, Philippa J Talmud, Hakon Hakonarson, Clara C Elbers, Brendan J Keating, Fotios Drenos
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  ABSTRACT: Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
  The American Journal of Human Genetics 10/2012; · 10.60 Impact Factor
• Article: Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci.

  Richa Saxena, Clara C Elbers, Yiran Guo, Inga Peter, Tom R Gaunt, Jessica L Mega, Matthew B Lanktree, Archana Tare, Berta Almoguera Castillo, Yun R Li, [......], Paul I W de Bakker, Jeanne McCaffery, Cisca Wijmenga, Marc S Sabatine, James G Wilson, Alex Reiner, Donald W Bowden, Hakon Hakonarson, David S Siscovick, Brendan J Keating
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  ABSTRACT: To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.
  The American Journal of Human Genetics 02/2012; 90(3):410-25. · 10.60 Impact Factor
• Article: Participant identification in genetic association studies: improved methods and practical implications.

  Nicholas Masca, Paul R Burton, Nuala A Sheehan
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  ABSTRACT: In a recent paper by Homer et al. (Resolving individuals contributing trace amounts of DNA to highly complex mixtures using high-density SNP genotyping microarrays. PLoS Genet 2008;4:e1000167), a method for detecting whether a given individual is a contributor to a particular genomic mixture was proposed. This prompted grave concern about the public dissemination of aggregate statistics from genome-wide association studies. It is of clear scientific importance that such data be shared widely, but the confidentiality of study participants must not be compromised. The issue of what summary genomic data can safely be posted on the web is only addressed satisfactorily when the theoretical underpinnings of the proposed method are clarified and its performance evaluated in terms of dependence on underlying assumptions. The original method raised a number of concerns and several alternatives have since been proposed, including a simple linear regression approach. In our proposed generalized estimating equation approach, we maintain the simplicity of the linear regression model but obtain inferences that are more robust to approximation of the variance/covariance structure and can accommodate linkage disequilibrium. We affirm that, in principle, it is possible to determine that a 'candidate' individual has participated in a study, given a subset of aggregate statistics from that study. However, the methods depend critically on a number of key factors including: the ancestry of participants in the study; the absolute and relative numbers of cases and controls; and the number of single nucleotide polymorphisms. Simple guidelines for publication that are based on a single criterion are therefore unlikely to suffice. In particular, 'directed' summary statistics should not be posted openly on the web but could be protected by an internet-based access check as proposed by the P3G_Consortium et al. (Public access to genome-wide data: five views on balancing research with privacy and protection. PLoS Genet 2009;5:e1000665).
  International Journal of Epidemiology 12/2011; 40(6):1629-42. · 6.41 Impact Factor
• Article: Blood pressure loci identified with a gene-centric array.

  Toby Johnson, Tom R Gaunt, Stephen J Newhouse, Sandosh Padmanabhan, Maciej Tomaszewski, Meena Kumari, Richard W Morris, Ioanna Tzoulaki, Eoin T O'Brien, Neil R Poulter, [......], Robert Roberts, Christopher Newton-Cheh, Lude Franke, Alice V Stanton, Anna F Dominiczak, Martin Farrall, Aroon D Hingorani, Nilesh J Samani, Mark J Caulfield, Patricia B Munroe
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  ABSTRACT: Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
  The American Journal of Human Genetics 11/2011; 89(6):688-700. · 10.60 Impact Factor
• Article: Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function.

  María Soler Artigas, Louise V Wain, Emmanouela Repapi, Ma'en Obeidat, Ian Sayers, Paul R Burton, Toby Johnson, Jing Hua Zhao, Eva Albrecht, Anna F Dominiczak, [......], Mika Kähönen, John R Britton, Fredrik Nyberg, John W Holloway, Debbie A Lawlor, Richard W Morris, Alan L James, Cathy M Jackson, Ian P Hall, Martin D Tobin
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  ABSTRACT: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied. To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP. By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV1 (β = -72.21 ml, P = 3.90 × 10(-4)) and FEV1/FVC (β = -1.53%, P = 6.35 × 10(-6)), and with COPD (odds ratio = 1.63, P = 1.46 × 10(-5)). Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.
  American Journal of Respiratory and Critical Care Medicine 10/2011; 184(7):786-95. · 11.08 Impact Factor
• Article: Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy.

  Sonia Shah, Christopher P Nelson, Tom R Gaunt, Pim van der Harst, Timothy Barnes, Peter S Braund, Debbie A Lawlor, Juan-Pablo Casas, Sandosh Padmanabhan, Fotios Drenos, [......], Rudolf A de Boer, Gerjan Navis, Wiek H van Gilst, Bongani M Mayosi, John R Thompson, Meena Kumari, Peter W MacFarlane, Ian N M Day, Aroon D Hingorani, Nilesh J Samani
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  ABSTRACT: Presence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of 4 commonly measured indices of ECG-LVH. We calculated the Sokolow-Lyon index, Cornell product, 12-lead QRS voltage sum, and 12-lead QRS voltage product in 10 256 individuals from 3 population-based cohorts and typed their DNA using a customized gene array (the Illumina HumanCVD BeadChip 50K array), containing 49 094 genetic variants in ≈2100 genes of cardiovascular relevance. We followed-up promising associations in 11 777 additional individuals. We identified and replicated 4 loci associated with ECG-LVH indices: 3p22.2 (SCN5A, rs6797133, P=1.22 × 10(-7)) with Cornell product and 12q13.3 (PTGES3, rs2290893, P=3.74 × 10(-8)), 15q25.2 (NMB, rs2292462, P=3.23 × 10(-9)), and 15q26.3 (IGF1R, rs4966014, P=1.26 × 10(-7)) with the 12-lead QRS voltage sum. The odds ratio of being in the top decile for the 12-lead QRS voltage sum for those carrying 6 trait-raising alleles at the 12q13.3, 15q25.2, and 15q26.3 loci versus those carrying 0 to 1 alleles was 1.60 (95% CI: 1.20 to 2.29). Lead single-nucleotide polymorphisms at the 12q13.3 and 15q25.2 loci showed significant expression quantitative trait loci effects in monocytes. These findings provide novel insights into the genetic determination of ECG-LVH. The findings could help to improve our understanding of the mechanisms determining this prognostically important trait.
  Circulation Cardiovascular Genetics 09/2011; 4(6):626-35. · 6.11 Impact Factor
• Source

  Available from: Andrew A. Hicks

  Article: Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

  Georg B Ehret, Patricia B Munroe, Kenneth M Rice, Murielle Bochud, Andrew D Johnson, Daniel I Chasman, Albert V Smith, Martin D Tobin, Germaine C Verwoert, Shih-Jen Hwang, [......], Marjo-Riitta Järvelin, Bruce M Psaty, Gonçalo R Abecasis, Aravinda Chakravarti, Paul Elliott, Cornelia M van Duijn, Christopher Newton-Cheh, Daniel Levy, Mark J Caulfield, Toby Johnson
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  ABSTRACT: Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
  Nature 09/2011; 478(7367):103-9. · 36.28 Impact Factor
• Article: Is rigorous retrospective harmonization possible? Application of the DataSHaPER approach across 53 large studies.

  Isabel Fortier, Dany Doiron, Julian Little, Vincent Ferretti, François L'Heureux, Ronald P Stolk, Bartha M Knoppers, Thomas J Hudson, Paul R Burton
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  ABSTRACT: Proper understanding of the roles of, and interactions between genetic, lifestyle, environmental and psycho-social factors in determining the risk of development and/or progression of chronic diseases requires access to very large high-quality databases. Because of the financial, technical and time burdens related to developing and maintaining very large studies, the scientific community is increasingly synthesizing data from multiple studies to construct large databases. However, the data items collected by individual studies must be inferentially equivalent to be meaningfully synthesized. The DataSchema and Harmonization Platform for Epidemiological Research (DataSHaPER; http://www.datashaper.org) was developed to enable the rigorous assessment of the inferential equivalence, i.e. the potential for harmonization, of selected information from individual studies. This article examines the value of using the DataSHaPER for retrospective harmonization of established studies. Using the DataSHaPER approach, the potential to generate 148 harmonized variables from the questionnaires and physical measures collected in 53 large population-based studies (6.9 million participants) was assessed. Variable and study characteristics that might influence the potential for data synthesis were also explored. Out of all assessment items evaluated (148 variables for each of the 53 studies), 38% could be harmonized. Certain characteristics of variables (i.e. relative importance, individual targeted, reference period) and of studies (i.e. observational units, data collection start date and mode of questionnaire administration) were associated with the potential for harmonization. For example, for variables deemed to be essential, 62% of assessment items paired could be harmonized. The current article shows that the DataSHaPER provides an effective and flexible approach for the retrospective harmonization of information across studies. To implement data synthesis, some additional scientific, ethico-legal and technical considerations must be addressed. The success of the DataSHaPER as a harmonization approach will depend on its continuing development and on the rigour and extent of its use. The DataSHaPER has the potential to take us closer to a truly collaborative epidemiology and offers the promise of enhanced research potential generated through synthesized databases.
  International Journal of Epidemiology 07/2011; 40(5):1314-28. · 6.41 Impact Factor
• Source

  Available from: PubMed Central

  Article: Realizing the promise of population biobanks: a new model for translation.

  Madeleine J Murtagh, Ipek Demir, Jennifer R Harris, Paul R Burton
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  ABSTRACT: The promise of science lies in expectations of its benefits to societies and is matched by expectations of the realisation of the significant public investment in that science. In this paper, we undertake a methodological analysis of the science of biobanking and a sociological analysis of translational research in relation to biobanking. Part of global and local endeavours to translate raw biomedical evidence into practice, biobanks aim to provide a platform for generating new scientific knowledge to inform development of new policies, systems and interventions to enhance the public's health. Effectively translating scientific knowledge into routine practice, however, involves more than good science. Although biobanks undoubtedly provide a fundamental resource for both clinical and public health practice, their potentiating ontology--that their outputs are perpetually a promise of scientific knowledge generation--renders translation rather less straightforward than drug discovery and treatment implementation. Biobanking science, therefore, provides a perfect counterpoint against which to test the bounds of translational research. We argue that translational research is a contextual and cumulative process: one that is necessarily dynamic and interactive and involves multiple actors. We propose a new multidimensional model of translational research which enables us to imagine a new paradigm: one that takes us from bench to bedside to backyard and beyond, that is, attentive to the social and political context of translational science, and is cognisant of all the players in that process be they researchers, health professionals, policy makers, industry representatives, members of the public or research participants, amongst others.
  Human Genetics 06/2011; 130(3):333-45. · 5.07 Impact Factor
• Source

  Available from: Maria Soler Artigas

  Article: Effect of 5 Genetic Variants Associated with Lung Function on the Risk of COPD, and their Joint Effects on Lung Function.

  María Soler Artigas, Louise V Wain, Emmanouela Repapi, Ma'en Obeidat, Ian Sayers, Paul R Burton, Toby Johnson, Jing Hua Zhao, Eva Albrecht, Anna F Dominiczak, [......], Mika Kähönen, John R Britton, Fredrik Nyberg, John W Holloway, Debbie A Lawlor, Richard W Morris, Alan L James, Cathy M Jackson, Ian P Hall, Martin D Tobin
  [show abstract] [hide abstract]
  ABSTRACT: RATIONALE: Genomic loci are associated with forced expiratory volume in one second (FEV1) or the ratio of FEV1 to forced vital capacity (FVC) in population samples, but their association with COPD has not yet been proven, nor have their combined effects on lung function and COPD been studied. OBJECTIVES: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER and THSD4) and evaluate joint effects on lung function and COPD of these SNPs, and variants at the previously reported locus near HHIP. METHODS: Sampling from 12 population-based studies (n=31,422), we obtained genotype data on 3,284 COPD cases and 17,538 controls for sentinel SNPs in TNS1, GSTCD, HTR4, AGER and THSD4. In 24,648 individuals (including 2,890 COPD cases and 13,862 controls), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. RESULTS: Association with COPD was significant for three loci (TNS1, GSTCD, HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV1 (β=-72.21 ml, P=3.90x10-4) and FEV1/FVC (β=-1.53%, P=6.35x10-6), and with COPD (OR=1.63, P=1.46x10-5). CONCLUSIONS: Variants in TNS1, GSTCD and HTR4 are associated with COPD. Our highest risk score category was associated with 1.6-fold higher COPD risk than the population average score.
  American Journal of Respiratory and Critical Care Medicine 06/2011; · 11.08 Impact Factor
• Article: From genomic databases to translation: a call to action.

  Bartha Maria Knoppers, Jennifer R Harris, Paul R Burton, Madeleine Murtagh, David Cox, Mylène Deschênes, Isabel Fortier, Thomas J Hudson, Jane Kaye, Klaus Lindpaintner
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  ABSTRACT: The rapid rise of international collaborative science has enabled access to genomic data. In this article, it is argued that to move beyond mapping genomic variation to understanding its role in complex disease aetiology and treatment will require extending data sharing for the purposes of clinical research translation and implementation.
  Journal of medical ethics 05/2011; 37(8):515-6. · 1.21 Impact Factor
• Source

  Available from: Robert A Hegele

  Article: Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

  Matthew B Lanktree, Yiran Guo, Muhammed Murtaza, Joseph T Glessner, Swneke D Bailey, N Charlotte Onland-Moret, Guillaume Lettre, Halit Ongen, Ramakrishnan Rajagopalan, Toby Johnson, [......], Wolfgang Koenig, Tom R Gaunt, Sonia S Anand, Yvonne T van der Schouw, Nicole Soranzo, Garret A Fitzgerald, Alex Reiner, Robert A Hegele, Hakon Hakonarson, Brendan J Keating
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  ABSTRACT: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
  The American Journal of Human Genetics 01/2011; 88(1):6-18. · 10.60 Impact Factor
• Article: Comprehensive catalog of European biobanks.

  H-Erich Wichmann, Klaus A Kuhn, Melanie Waldenberger, Dominik Schmelcher, Simone Schuffenhauer, Thomas Meitinger, Sebastian H R Wurst, Gregor Lamla, Isabel Fortier, Paul R Burton, [......], Jan-Eric Litton, Martin N Fransson, Johann Eder, Anne Cambon-Thomsen, Jasper Bovenberg, Georges Dagher, Gert-Jan van Ommen, Michael Griffith, Martin Yuille, Kurt Zatloukal
  Nature Biotechnology 01/2011; 29(9):795-7. · 29.50 Impact Factor
• Source

  Available from: Hans Robert Kalbitzer

  Article: Large-scale candidate gene analysis of HDL particle features.

  Bernhard M Kaess, Maciej Tomaszewski, Peter S Braund, Klaus Stark, Suzanne Rafelt, Marcus Fischer, Robert Hardwick, Christopher P Nelson, Radoslaw Debiec, Fritz Huber, Werner Kremer, Hans Robert Kalbitzer, Lynda M Rose, Daniel I Chasman, Jemma Hopewell, Robert Clarke, Paul R Burton, Martin D Tobin, Christian Hengstenberg, Nilesh J Samani
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  ABSTRACT: HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis. We measured plasma HDL-C and determined mean HDL particle size and particle number by NMR spectroscopy in 2024 individuals from 512 British Caucasian families. Genotypes were 49,094 SNPs in >2,100 cardiometabolic candidate genes/loci as represented on the HumanCVD BeadChip version 2. False discovery rates (FDR) were calculated to account for multiple testing. Analyses on classical HDL-C revealed significant associations (FDR<0.05) only for CETP (cholesteryl ester transfer protein; lead SNP rs3764261: p = 5.6*10(-15)) and SGCD (sarcoglycan delta; rs6877118: p = 8.6*10(-6)). In contrast, analysis with HDL mean particle size yielded additional associations in LIPC (hepatic lipase; rs261332: p = 6.1*10(-9)), PLTP (phospholipid transfer protein, rs4810479: p = 1.7*10(-8)) and FBLN5 (fibulin-5; rs2246416: p = 6.2*10(-6)). The associations of SGCD and Fibulin-5 with HDL particle size could not be replicated in PROCARDIS (n = 3,078) and/or the Women's Genome Health Study (n = 23,170). We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C.
  PLoS ONE 01/2011; 6(1):e14529. · 4.09 Impact Factor
• Source

  Available from: Jennifer E Huffman

  Article: A comprehensive evaluation of potential lung function associated genes in the SpiroMeta general population sample.

  Ma'en Obeidat, Louise V Wain, Nick Shrine, Noor Kalsheker, Maria Soler Artigas, Emmanouela Repapi, Paul R Burton, Toby Johnson, Adaikalavan Ramasamy, Jing Hua Zhao, [......], Marjo-Riitta Jarvelin, Caroline Hayward, David M Evans, Beate Koch, Arthur William Musk, Paul Elliott, David P Strachan, Martin D Tobin, Ian Sayers, Ian P Hall
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  ABSTRACT: Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium). To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample. We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/-10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations. The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV(1) or FEV(1)/FVC traits using a carefully defined significance threshold of 1.3×10(-5). The most significant loci associated with FEV(1) include SNPs tagging MACROD2 (P = 6.81×10(-5)), CNTN5 (P = 4.37×10(-4)), and TRPV4 (P = 1.58×10(-3)). Among ever-smokers, SERPINA1 showed the most significant association with FEV(1) (P = 8.41×10(-5)), followed by PDE4D (P = 1.22×10(-4)). The strongest association with FEV(1)/FVC ratio was observed with ABCC1 (P = 4.38×10(-4)), and ESR1 (P = 5.42×10(-4)) among ever-smokers. Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV(1) among smokers in the general population.
  PLoS ONE 01/2011; 6(5):e19382. · 4.09 Impact Factor
• Article: Genetic architecture of ambulatory blood pressure in the general population: insights from cardiovascular gene-centric array.

  Maciej Tomaszewski, Radoslaw Debiec, Peter S Braund, Christopher P Nelson, Robert Hardwick, Paraskevi Christofidou, Matthew Denniff, Veryan Codd, Suzanne Rafelt, Pim van der Harst, [......], Kijoung Song, Peter Vollenweider, Gerard Waeber, Ewa Zukowska-Szczechowska, Paul R Burton, Vincent Mooser, Fadi J Charchar, John R Thompson, Martin D Tobin, Nilesh J Samani
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  ABSTRACT: Genetic determinants of blood pressure are poorly defined. We undertook a large-scale, gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains ≈ 50 000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure; each minor allele copy of rs13306560 was associated with 2.6 mm Hg lower mean 24-hour diastolic blood pressure (P = 1.2 × 10⁻⁸). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the Genetic Regulation of Arterial Pressure of Humans in the Community Study, the CoLaus Study, and the Silesian Cardiovascular Study (P=5.4 × 10⁻⁶). Additional analysis of associations between variants in gene ontology-defined pathways and mean 24-hour blood pressure in the Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: < 0.05) among polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles. Through a large-scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure.
  Hypertension 11/2010; 56(6):1069-76. · 6.21 Impact Factor
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  Available from: Rex L Chisholm

  Article: Quality, quantity and harmony: the DataSHaPER approach to integrating data across bioclinical studies.

  Isabel Fortier, Paul R Burton, Paula J Robson, Vincent Ferretti, Julian Little, Francois L'Heureux, Mylène Deschênes, Bartha M Knoppers, Dany Doiron, Joost C Keers, [......], Mark Tremblay, Rex L Chisholm, Andrés Garcia-Montero, Hans Hillege, Jan-Eric Litton, Lyle J Palmer, Markus Perola, Bruce H R Wolffenbuttel, Leena Peltonen, Thomas J Hudson
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  ABSTRACT: Vast sample sizes are often essential in the quest to disentangle the complex interplay of the genetic, lifestyle, environmental and social factors that determine the aetiology and progression of chronic diseases. The pooling of information between studies is therefore of central importance to contemporary bioscience. However, there are many technical, ethico-legal and scientific challenges to be overcome if an effective, valid, pooled analysis is to be achieved. Perhaps most critically, any data that are to be analysed in this way must be adequately 'harmonized'. This implies that the collection and recording of information and data must be done in a manner that is sufficiently similar in the different studies to allow valid synthesis to take place. This conceptual article describes the origins, purpose and scientific foundations of the DataSHaPER (DataSchema and Harmonization Platform for Epidemiological Research; http://www.datashaper.org), which has been created by a multidisciplinary consortium of experts that was pulled together and coordinated by three international organizations: P³G (Public Population Project in Genomics), PHOEBE (Promoting Harmonization of Epidemiological Biobanks in Europe) and CPT (Canadian Partnership for Tomorrow Project). The DataSHaPER provides a flexible, structured approach to the harmonization and pooling of information between studies. Its two primary components, the 'DataSchema' and 'Harmonization Platforms', together support the preparation of effective data-collection protocols and provide a central reference to facilitate harmonization. The DataSHaPER supports both 'prospective' and 'retrospective' harmonization. It is hoped that this article will encourage readers to investigate the project further: the more the research groups and studies are actively involved, the more effective the DataSHaPER programme will ultimately be.
  International Journal of Epidemiology 10/2010; 39(5):1383-93. · 6.41 Impact Factor