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Showing papers by "Nilesh J. Samani published in 2012"


Journal ArticleDOI
Benjamin F. Voight1, Benjamin F. Voight2, Benjamin F. Voight3, Gina M. Peloso4, Gina M. Peloso5, Marju Orho-Melander6, Ruth Frikke-Schmidt7, Maja Barbalić8, Majken K. Jensen3, George Hindy6, Hilma Holm9, Eric L. Ding3, Toby Johnson10, Heribert Schunkert11, Nilesh J. Samani12, Nilesh J. Samani13, Robert Clarke14, Jemma C. Hopewell14, John F. Thompson13, Mingyao Li1, Gudmar Thorleifsson9, Christopher Newton-Cheh, Kiran Musunuru3, Kiran Musunuru2, James P. Pirruccello3, James P. Pirruccello2, Danish Saleheen15, Li Chen16, Alexandre F.R. Stewart16, Arne Schillert11, Unnur Thorsteinsdottir17, Unnur Thorsteinsdottir9, Gudmundur Thorgeirsson17, Sonia S. Anand18, James C. Engert19, Thomas M. Morgan20, John A. Spertus21, Monika Stoll22, Klaus Berger22, Nicola Martinelli23, Domenico Girelli23, Pascal P. McKeown24, Christopher Patterson24, Stephen E. Epstein25, Joseph M. Devaney25, Mary Susan Burnett25, Vincent Mooser26, Samuli Ripatti27, Ida Surakka27, Markku S. Nieminen27, Juha Sinisalo27, Marja-Liisa Lokki27, Markus Perola4, Aki S. Havulinna4, Ulf de Faire28, Bruna Gigante28, Erik Ingelsson28, Tanja Zeller29, Philipp S. Wild29, Paul I.W. de Bakker, Olaf H. Klungel30, Anke-Hilse Maitland-van der Zee30, Bas J M Peters30, Anthonius de Boer30, Diederick E. Grobbee30, Pieter Willem Kamphuisen31, Vera H.M. Deneer, Clara C. Elbers30, N. Charlotte Onland-Moret30, Marten H. Hofker31, Cisca Wijmenga31, W. M. Monique Verschuren, Jolanda M. A. Boer, Yvonne T. van der Schouw30, Asif Rasheed, Philippe M. Frossard, Serkalem Demissie5, Serkalem Demissie4, Cristen J. Willer32, Ron Do3, Jose M. Ordovas33, Jose M. Ordovas34, Gonçalo R. Abecasis32, Michael Boehnke32, Karen L. Mohlke35, Mark J. Daly3, Mark J. Daly2, Candace Guiducci2, Noël P. Burtt2, Aarti Surti2, Elena Gonzalez2, Shaun Purcell2, Shaun Purcell3, Stacey Gabriel2, Jaume Marrugat, John F. Peden14, Jeanette Erdmann11, Patrick Diemert11, Christina Willenborg11, Inke R. König11, Marcus Fischer36, Christian Hengstenberg36, Andreas Ziegler11, Ian Buysschaert37, Diether Lambrechts37, Frans Van de Werf37, Keith A.A. Fox38, Nour Eddine El Mokhtari39, Diana Rubin, Jürgen Schrezenmeir, Stefan Schreiber39, Arne Schäfer39, John Danesh15, Stefan Blankenberg29, Robert Roberts16, Ruth McPherson16, Hugh Watkins14, Alistair S. Hall40, Kim Overvad41, Eric B. Rimm3, Eric Boerwinkle8, Anne Tybjærg-Hansen7, L. Adrienne Cupples4, L. Adrienne Cupples5, Muredach P. Reilly1, Olle Melander6, Pier Mannuccio Mannucci42, Diego Ardissino, David S. Siscovick43, Roberto Elosua, Kari Stefansson17, Kari Stefansson9, Christopher J. O'Donnell4, Christopher J. O'Donnell3, Veikko Salomaa4, Daniel J. Rader1, Leena Peltonen44, Leena Peltonen27, Stephen M. Schwartz43, David Altshuler, Sekar Kathiresan 
11 Aug 2012
TL;DR: In this paper, a Mendelian randomisation analysis was performed to compare the effect of HDL cholesterol, LDL cholesterol, and genetic score on risk of myocardial infarction.
Abstract: Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. – ¹³) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10

1,878 citations


Benjamin F. Voight, Gina M. Peloso, Marju Orho-Melander, Ruth Frikke-Schmidt, Maja Barbalić, Majken K. Jensen, George Hindy, Hilma Holm, Eric L. Ding, Toby Johnson, Heribert Schunkert, Nilesh J. Samani, Robert Clarke, Jemma C. Hopewell, John F. Thompson, Mingyao Li, Gudmar Thorleifsson, Christopher Newton-Cheh, Kiran Musunuru, James P. Pirruccello, Danish Saleheen, Li Chen, Alexandre F.R. Stewart, Arne Schillert, Unnur Thorsteinsdottir, Gudmundur Thorgeirsson, Sonia S. Anand, James C. Engert, Thomas M. Morgan, John A. Spertus, Monika Stoll, Klaus Berger, Nicola Martinelli, Domenico Girelli, Pascal P. McKeown, Christopher Patterson, Stephen E. Epstein, Joseph M. Devaney, Mary-Susan Burnett, Vincent Mooser, Samuli Ripatti, Ida Surakka, Markku S. Nieminen, Juha Sinisalo, Marja-Liisa Lokki, Markus Perola, Aki S. Havulinna, Ulf de Faire, Bruna Gigante, Erik Ingelsson, Tanja Zeller, Philipp S. Wild, Paul I.W. de Bakker, Olaf H. Klungel, Anke-Hilse Maitland-van der Zee, Bas J M Peters, Anthonius de Boer, Diederick E. Grobbee, Pieter Willem Kamphuisen, Vera H.M. Deneer, Clara C. Elbers, N. Charlotte Onland-Moret, Marten H. Hofker, Cisca Wijmenga, W. M. Monique Verschuren, Jolanda M. A. Boer, Yvonne T. van der Schouw, Asif Rasheed, Philippe M. Frossard, Serkalem Demissie, Cristen J. Willer, Ron Do, Jose M. Ordovas, Gonçalo R. Abecasis, Michael Boehnke, Karen L. Mohlke, Mark J. Daly, Candace Guiducci, Noël P. Burtt, Aarti Surti, Elena Gonzalez, Shaun Purcell, Stacey Gabriel, Jaume Marrugat, John F. Peden, Jeanette Erdmann, Patrick Diemert, Christina Willenborg, Inke R. Koenig, Marcus Fischer, Christian Hengstenberg, Andreas Ziegler, Ian Buysschaert, Diether Lambrechts, Frans Van de Werf, Keith A.A. Fox, Nour Eddine El Mokhtari, Diana Rubin, Juergen Schrezenmeir, Stefan Schreiber, Arne S. Schaefer, John Danesh, Stefan Blankenberg, Robert Roberts, Ruth McPherson, Hugh Watkins, Alistair S. Hall, Kim Overvad, Eric B. Rimm, Eric Boerwinkle, Anne Tybjærg-Hansen, L. Adrienne Cupples, Muredach P. Reilly, Olle Melander, Pier Mannuccio Mannucci, Diego Ardissino, David S. Siscovick, Roberto Elosua, Kari Stefansson, Christopher J. O'Donnell, Veikko Salomaa, Daniel J. Rader, Leena Peltonen, Stephen M. Schwartz, David Altshuler, Sekar Kathiresan 
01 Jan 2012
TL;DR: Mendelian randomisation analyses challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
Abstract: Summary Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. Findings Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10−10). Interpretation Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. Funding US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.

1,550 citations


Journal ArticleDOI
Lam C. Tsoi1, Sarah L. Spain1, Sarah L. Spain2, Jo Knight1  +212 moreInstitutions (52)
TL;DR: A meta-analysis of genome-wide association studies and independent data sets genotyped on the Immunochip identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals, and identified five independent signals within previously known loci.
Abstract: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.

786 citations


Journal ArticleDOI
Nadeem Sarwar1, Adam S. Butterworth1, Daniel F. Freitag1, John Gregson1, Peter Willeit1, Donal Gorman1, Pei Gao1, Danish Saleheen1, Augusto Rendon1, Christopher P. Nelson1, Peter S. Braund1, Alistair S. Hall1, Daniel I. Chasman1, Anne Tybjærg-Hansen1, John C. Chambers1, Emelia J. Benjamin1, Paul W. Franks, Robert Clarke1, Arthur A. M. Wilde1, Mieke D. Trip1, Maristella Steri1, Jacqueline C. M. Witteman1, Lu Qi1, C. Ellen van der Schoot1, Ulf de Faire1, Jeanette Erdmann1, Heather M. Stringham1, Wolfgang Koenig1, Daniel J. Rader1, David Melzer1, David Reich1, Bruce M. Psaty1, Marcus E. Kleber1, Demosthenes B. Panagiotakos1, Johann Willeit1, Patrik Wennberg1, Mark Woodward1, Svetlana Adamovic1, Eric B. Rimm1, Tom W. Meade1, Richard F. Gillum1, Jonathan A. Shaffer1, Albert Hofman1, Altan Onat1, Johan Sundström1, S. Wassertheil-Smoller1, Dan Mellström1, John Gallacher1, Mary Cushman1, Russell P. Tracy2, Jussi Kauhanen3, Magnus Karlsson, Jukka T. Salonen4, Lars Wilhelmsen5, Philippe Amouyel6, Bernard Cantin7, Lyle G. Best, Yoav Ben-Shlomo, JoAnn E. Manson8, George Davey-Smith2, Paul I.W. de Bakker8, Christopher J. O'Donnell8, James F. Wilson9, Anthony G. Wilson10, Themistocles L. Assimes11, John-Olov Jansson5, Claes Ohlsson5, Åsa Tivesten5, Östen Ljunggren12, Muredach P. Reilly13, Anders Hamsten14, Erik Ingelsson14, François Cambien15, Joseph Hung, G. Neil Thomas16, Michael Boehnke17, Heribert Schunkert18, Folkert W. Asselbergs19, John J.P. Kastelein20, Vilmundur Gudnason21, Veikko Salomaa22, Tamara B. Harris23, Jaspal S. Kooner24, Kristine H. Allin25, Kristine H. Allin26, Børge G. Nordestgaard25, Jemma C. Hopewell27, Alison H. Goodall28, Paul M. Ridker8, Hilma Holm29, Hugh Watkins30, Willem H. Ouwehand1, Nilesh J. Samani28, Stephen Kaptoge1, Emanuele Di Angelantonio1, Olivier Harari, John Danesh1 
31 Mar 2012
TL;DR: In this article, a functional genetic variant known to affect IL6R signalling was studied to assess whether this pathway is causally relevant to coronary heart disease, and Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking.
Abstract: Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele >= 0.04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4-38.2) and of interleukin 6 by 14.6% (10.7-18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9-9.1) and of fibrinogen by 1.0% (0.7-1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8-5.0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.

628 citations


Journal ArticleDOI
TL;DR: The Metabochip and its component SNP sets are described and evaluated, its performance in capturing variation across the allele-frequency spectrum is evaluated, solutions to methodological challenges commonly encountered in its analysis are described, and its performance as a platform for genotype imputation is evaluated.
Abstract: Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the ‘‘Metabochip,’’ a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits.

516 citations


Journal ArticleDOI
TL;DR: In this paper, the authors defined credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs, and showed the value of more detailed mapping to target sequences for functional studies.
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.

468 citations


01 Jan 2012
TL;DR: A meta-analysis of genome-wide association studies and independent data sets genotyped on the Immunochip identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals, and identified five independent signals within previously known loci.
Abstract: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense. © 2012 Nature America, Inc. All rights reserved.

464 citations


Journal ArticleDOI
Zari Dastani1, Hivert M-F.2, Hivert M-F.3, N J Timpson4  +615 moreInstitutions (128)
TL;DR: A meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease identifies novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

456 citations


Journal ArticleDOI
01 Aug 2012
TL;DR: A meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases and 5,019 controls followed by replication studies in 15,460 cases and 11,472 controls provides new insights into pathways contributing to the susceptibility for coronary arteries disease in the Chinese Han population.
Abstract: We performed a meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases and 5,019 controls followed by replication studies in 15,460 cases and 11,472 controls, all of Chinese Han ancestry. We identify four new loci for coronary artery disease that reached the threshold of genome-wide significance (P < 5 × 10(-8)). These loci mapped in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2 and ATP2B1. We also replicated four loci previously identified in European populations (in or near PHACTR1, TCF21, CDKN2A-CDKN2B and C12orf51). These findings provide new insights into pathways contributing to the susceptibility for coronary artery disease in the Chinese Han population.

290 citations


Journal ArticleDOI
Richa Saxena1, Richa Saxena2, Clara C. Elbers3, Clara C. Elbers4  +160 moreInstitutions (54)
09 Mar 2012
TL;DR: Large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to type 2 diabetes risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.
Abstract: To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 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 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 x 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 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 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 x 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.

275 citations


Journal ArticleDOI
Yukinori Okada, Xueling Sim1, Xueling Sim2, Min Jin Go  +411 moreInstitutions (19)
TL;DR: A meta-analysis of genome-wide association studies for kidney function–related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN), identified 17 loci newly associated with kidney function-related traits.
Abstract: Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

Journal ArticleDOI
Folkert W. Asselbergs1, Yiran Guo2, Yiran Guo3, Erik P A Van Iperen4  +181 moreInstitutions (65)
TL;DR: 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, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
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.

Journal ArticleDOI
TL;DR: Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis.

Journal ArticleDOI
TL;DR: A meta-analysis of unpublished datasets suggests that an increase in homocysteine levels is not likely to result in a increase in risk of coronary heart disease.
Abstract: Background: Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so ‘‘Mendelian randomization’’ studies using this variant as an instrumental variable could help test causality Methods and Findings: Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 102 (098–107; p=028) overall, and 101 (095–107) in unsupplemented low-folate populations By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 115 (109–121), significantly discrepant (p=0001) with the OR in the unpublished datasets Within the meta-analysis of published studies, the OR was 112 (104–121) in the 14 larger studies (those with variance of log OR,005; total 13,119 cases) and 118 (109–128) in the 72 smaller ones (total 15,498 cases) Conclusions: The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD The discrepant overall result from previously published studies reflects publication bias or methodological problems Please see later in the article for the Editors’ Summary

Journal ArticleDOI
TL;DR: Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation, and the hypothesis that there may be a causal genetic variation at this locus is supported.
Abstract: Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.

Journal ArticleDOI
Anna Helgadottir1, Solveig Gretarsdottir1, Gudmar Thorleifsson1, Hilma Holm1, Riyaz S. Patel2, Riyaz S. Patel3, Thorarinn Gudnason4, Gregory T. Jones5, Andre M. van Rij5, Danny J. Eapen3, Annette F. Baas6, David-Alexandre Trégouët7, Pierre-Emmanuel Morange8, Joseph Emmerich9, Bengt Lindblad10, Anders Gottsäter10, Lambertus A Kiemeny11, Jes S. Lindholt, Natzi Sakalihasan, Robert E. Ferrell12, David J. Carey, James R. Elmore, Philip S. Tsao13, Niels Grarup14, Torben Jørgensen14, Torben Jørgensen15, Daniel R. Witte16, Torben Hansen14, Torben Hansen17, Oluf Pedersen, Roberto Pola18, Roberto Pola19, Eleonora Gaetani18, Hulda B Magnadottir, Cisca Wijmenga20, Gerard Tromp, Antti Ronkainen, Ynte M. Ruigrok6, Jan D. Blankensteijn21, Thomas Mueller, Philip S. Wells22, Javier Corral23, José Manuel Soria, Juan Carlos Souto, John F. Peden24, Shapour Jalilzadeh24, Bongani M. Mayosi25, Bernard Keavney26, Rona J. Strawbridge27, Maria Sabater-Lleal27, Karl Gertow27, Damiano Baldassarre28, Kristiina Nyyssönen29, Rainer Rauramaa, Andries J. Smit20, Elmo Mannarino30, Philippe Giral, Elena Tremoli28, Ulf de Faire27, Steve E. Humphries31, Anders Hamsten27, Vilhelmina Haraldsdottir, Isleifur Olafsson, Magnus K. Magnusson4, Nilesh J. Samani32, Allan I. Levey3, Hugh S. Markus33, Konstantinos Kostulas34, Martin Dichgans35, Klaus Berger36, Gregor Kuhlenbäumer37, E. Bernd Ringelstein36, Monika Stoll36, Udo Seedorf36, Peter M. Rothwell38, Janet T. Powell39, Helena Kuivaniemi, Pall T. Onundarson4, Einar M. Valdimarsson, Stefan E Matthiasson, Daniel F. Gudbjartsson1, G Thorgeirsson4, Arshed A. Quyyumi3, Hugh Watkins24, Martin Farrall24, Unnur Thorsteinsdottir1, Unnur Thorsteinsdottir4, Kari Stefansson4, Kari Stefansson1 
TL;DR: LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes, and CAD cases carrying LPA risk variants had increased susceptibility to atherosclerosis manifestations outside of the coronary tree.

Journal ArticleDOI
TL;DR: A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome-wide significance in the combined analysis, suggesting the observed signal is partly confounded due to population stratification.
Abstract: Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.We performed a discovery meta-analysis of 5 GWAS involving 13 949 subjects (7123 cases, 6826 control subjects) imputed at approximately 5 million single nucleotide polymorphisms, using pilot 1000 Genomes-based haplotypes. Promising loci were followed up in an additional 5 studies with 11 032 subjects (5211 cases, 5821 control subjects). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome-wide significance in the combined analysis (rs3869109; p(discovery)=3.3×10(-7), p(replication)=5.3×10(-4)p(combined)=1.12×10(-9)). A subanalysis combining discovery GWAS showed an attenuation of significance when stringent corrections for European population structure were used (P=4.1×10(-10) versus 3.2×10(-7)), suggesting that the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity, and self-cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association.We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T-cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).

Journal ArticleDOI
25 Jul 2012-PLOS ONE
TL;DR: Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men.
Abstract: Background: More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design. Methods: Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5–18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived. Results: Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50–59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events. Conclusions: Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men.

01 Jan 2012
TL;DR: In this paper, a multilocus genetic risk score was proposed to refine coronary heart disease (CHD) prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design.
Abstract: Background: More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design. Methods: Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5–18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived. Results: Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50–59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events. Conclusions: Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men.

Journal ArticleDOI
TL;DR: In this paper, the associations of genome-wide association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genomewide-association study derived lipid-associated SNPs with other risk factors and CHD events were evaluated.
Abstract: To evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events.

Journal ArticleDOI
TL;DR: A genome-wide association study (GWAS) and meta-analysis to identify genetic loci for activated partial thromboplastin time (aPTT) and prothrombin time (PT) detected and supported by functional data and identified eight genetic locus that account for ∼29% of the variance in aPTT and two loci that accounts for ∼14% ofThe variance in PT.
Abstract: Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulation-factor deficiencies. One genome-wide association study (GWAS) has been reported previously for aPTT, but no GWAS has been reported for PT. We conducted a GWAS and meta-analysis to identify genetic loci for aPTT and PT. The GWAS for aPTT was conducted in 9,240 individuals of European ancestry from the Atherosclerosis Risk in Communities (ARIC) study, and the GWAS for PT was conducted in 2,583 participants from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS) and the Lothian Birth Cohorts (LBC) of 1921 and 1936. Replication was assessed in 1,041 to 3,467 individuals. For aPTT, previously reported associations with KNG1, HRG, F11, F12, and ABO were confirmed. A second independent association in ABO was identified and replicated (rs8176704, p = 4.26 × 10−24). Pooling the ARIC and replication data yielded two additional loci in F5 (rs6028, p = 3.22 × 10−9) and AGBL1 (rs2469184, p = 3.61 × 10−8). For PT, significant associations were identified and confirmed in F7 (rs561241, p = 3.71 × 10−56) and PROCR/EDEM2 (rs2295888, p = 5.25 × 10−13). Assessment of existing gene expression and coronary artery disease (CAD) databases identified associations of five of the GWAS loci with altered gene expression and two with CAD. In summary, eight genetic loci that account for ∼29% of the variance in aPTT and two loci that account for ∼14% of the variance in PT were detected and supported by functional data.

Journal ArticleDOI
TL;DR: LV remodeling appears to be a more important determinant of impaired MPR than stenosis severity per se, and CMR-quantified MPR is independently associated with aerobic exercise capacity in severe AS.
Abstract: Objectives The purpose of this study was to assess the functional significance of cardiac magnetic resonance (CMR) measures of left ventricular (LV) remodeling and myocardial perfusion reserve (MPR) in patients with severe aortic stenosis (AS), without obstructive coronary artery disease. Background Measures of stenosis severity do not correlate well with exercise intolerance in AS. LV remodeling in AS is associated with myocardial fibrosis and impaired MPR. The functional significance and determinants of MPR in AS are unclear. Methods Forty-six patients with isolated severe AS were prospectively studied before aortic valve replacement. The following investigations were undertaken: cardiopulmonary exercise testing to measure aerobic exercise capacity (peak VO2); CMR to assess left ventricular mass index (LVMI), myocardial fibrosis with late gadolinium enhancement (LGE), myocardial blood flow (MBF), and MPR; and transthoracic echocardiography to assess stenosis severity and diastolic function. Results Peak VO2 was associated with sex (β = −0.41), age (β = −0.32), MPR (β = 0.45), resting MBF (β = −0.53), and septal transmitral flow velocity to annular velocity ratio (E/E′) (β = −0.34), but not with LVMI, LGE, or echocardiographic measures of AS severity. On stepwise regression analysis, only MPR was independently associated with age- and sex-corrected peak VO2 (β = 0.46, p = 0.001). MPR was also inversely related to New York Heart Association functional class (p = 0.001). Univariate associations with MPR were sex (β = 0.38, p = 0.02), septal E/E′ (β = −0.30, p = 0.03), peak aortic valve velocity (β = −0.34, p = 0.02), LVMI (β = −0.51, p Conclusions CMR-quantified MPR is independently associated with aerobic exercise capacity in severe AS. LV remodeling appears to be a more important determinant of impaired MPR than stenosis severity per se. Further work is required to determine how CMR assessment of MPR can aid clinical management of patients with AS.

Journal ArticleDOI
Sarah M. Hartz1, Susan E. Short2, Nancy L. Saccone1, Robert Culverhouse1  +153 moreInstitutions (53)
TL;DR: In this article, the association between rs16969968 and smoking is modified by age at onset of regular smoking, which highlights an increased genetic vulnerability to smoking in early-onset smokers.
Abstract: Context Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. Objective To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. Data Sources Primary data. Study Selection Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. Data Extraction Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. Data Synthesis Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19 505) (P = .01). Conclusion These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

Journal ArticleDOI
TL;DR: This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.
Abstract: Background-Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results-To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMTmean, IMTmax, and IMTmean-max), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75x10(-7) for IMTmax; replication P=7.24x10(-6) for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77-0.90], P=6.53x10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83x10(-4), n= 82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126-138). Conclusions-This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent. (Circ Cardiovasc Genet. 2012;5:656-665.)

Journal ArticleDOI
26 Dec 2012-PLOS ONE
TL;DR: This study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers and compares the power to identify cis-acting regulatory SNPs by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping.
Abstract: A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL) analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE) analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs) by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.

Journal ArticleDOI
TL;DR: NMR-based fine mapping of lipoprotein subfractions provides novel information on their biological nature and strengthens the associations with genetic loci and future clinical studies are now needed to investigate their biomedical relevance.
Abstract: Adverse levels of lipoproteins are highly heritable and constitute risk factors for cardiovascular outcomes. Hitherto, genome-wide association studies revealed 95 lipid-associated loci. However, due to the small effect sizes of these associations large sample numbers (>100 000 samples) were needed. Here we show that analyzing more refined lipid phenotypes, namely lipoprotein subfractions, can increase the number of significantly associated loci compared with bulk high-density lipoprotein and low-density lipoprotein analysis in a study with identical sample numbers. Moreover, lipoprotein subfractions provide novel insight into the human lipid metabolism. We measured 15 lipoprotein subfractions (L1-L15) in 1791 samples using (1)H-NMR (nuclear magnetic resonance) spectroscopy. Using cluster analyses, we quantified inter-relationships among lipoprotein subfractions. Additionally, we analyzed associations with subfractions at known lipid loci. We identified five distinct groups of subfractions: one (L1) was only marginally captured by serum lipids and therefore extends our knowledge of lipoprotein biochemistry. During a lipid-tolerance test, L1 lost its special position. In the association analysis, we found that eight loci (LIPC, CETP, PLTP, FADS1-2-3, SORT1, GCKR, APOB, APOA1) were associated with the subfractions, whereas only four loci (CETP, SORT1, GCKR, APOA1) were associated with serum lipids. For LIPC, we observed a 10-fold increase in the variance explained by our regression models. In conclusion, NMR-based fine mapping of lipoprotein subfractions provides novel information on their biological nature and strengthens the associations with genetic loci. Future clinical studies are now needed to investigate their biomedical relevance.

Journal ArticleDOI
TL;DR: A novel VA risk marker, R2I2, is developed and test and shown that it correlated with a structural measure of arrhythmic risk and predicted risk of VA or death in patients with ICM, and may improve risk stratification and merits further evaluation.
Abstract: Background—-Better sudden cardiac death risk markers are needed in ischemic cardiomyopathy (ICM). Increased heterogeneity of electrical restitution is an important mechanism underlying the risk of ventricular arrhythmia (VA). Our aim was to develop and test a novel quantitative surface electrocardiogram‐based measure of VA risk in patients with ICM: the Regional Restitution Instability Index (R2I2). Methods and Results—-R2I2, the mean of the standard deviation of residuals from the mean gradient for each ECG lead at a range of diastolic intervals, was measured retrospectively from high-resolution 12-lead ECGs recorded during an electrophysiology study. Patient groups were as follows: Study group, 26 patients with ICM being assessed for implantable defibrillator; Control group, 29 patients with supraventricular tachycardia undergoing electrophysiology study; and Replication group, 40 further patients with ICM. R2I2 was significantly higher in the Study patients than in Controls (mean ± standard error of the mean: 1.09±0.06 versus 0.63±0.04, P<0.001). Over a median follow-up period of 23 months, 6 of 26 Study group patients had VA or death. R2I2 predicted VA or death independently of demographic factors, electrophysiology study result, left ventricular ejection fraction, or QRS duration (Cox model, P=0.029). R2I2 correlated with peri-infarct zone as assessed by cardiac magnetic resonance imaging (r=0.51, P=0.024). The findings were replicated in the Replication group: R2I2 was significantly higher in 11 of 40 Replication patients experiencing VA (1.18±0.10 versus 0.92±0.05, P=0.019). In combined analysis of ICM cohorts, R2I2 ≥1.03 identified subjects with significantly higher risk of VA or death (43%) compared with R2I2 <1.03 (11%) (P=0.004). Conclusions—-In this pilot study, we have developed a novel VA risk marker, R2I2, and have shown that it correlated with a structural measure of arrhythmic risk and predicted risk of VA or death in patients with ICM. R2I2 may improve risk stratification and merits further evaluation. (J Am Heart Assoc. 2012;1:e001552 doi: 10.1161/JAHA.112.001552.)

Journal ArticleDOI
Vesna Boraska1, Ana Jerončić1, Vincenza Colonna2, Vincenza Colonna3, Lorraine Southam2, Dale R. Nyholt4, Nigel W. Rayner5, John R. B. Perry6, Daniela Toniolo7, Eva Albrecht, Wei Ang8, Stefania Bandinelli, Maja Barbalić9, Inês Barroso10, Jacques S. Beckmann11, Reiner Biffar12, Dorret I. Boomsma13, Harry Campbell14, Tanguy Corre7, Jeanette Erdmann15, Tõnu Esko16, Krista Fischer17, Nora Franceschini18, Timothy M. Frayling19, Giorgia Girotto20, Juan R. González, Tamara B. Harris21, Andrew C. Heath22, Iris M. Heid23, Wolfgang Hoffmann12, Albert Hofman, Momoko Horikoshi5, Jing Hua Zhao, Anne U. Jackson24, Jouke-Jan Hottenga13, Antti Jula25, Mika Kähönen, Kay-Tee Khaw10, Lambertus A. Kiemeney26, Norman Klopp, Zoltán Kutalik27, Vasiliki Lagou5, Lenore J. Launer21, Terho Lehtimäki28, Mathieu Lemire29, Marja-Liisa Lokki30, Christina Loley15, Jian'an Luan, Massimo Mangino6, Irene Mateo Leach31, Sarah E. Medland4, Evelin Mihailov17, Grant W. Montgomery4, Gerjan Navis31, John P. Newnham8, Markku S. Nieminen30, Aarno Palotie32, Kalliope Panoutsopoulou2, Annette Peters, Nicola Pirastu20, Ozren Polasek1, Karola Rehnström30, Samuli Ripatti30, Graham R. S. Ritchie2, Graham R. S. Ritchie33, Fernando Rivadeneira34, Antonietta Robino20, Nilesh J. Samani35, So-Youn Shin2, Juha Sinisalo30, Johannes H. Smit13, Nicole Soranzo6, Lisette Stolk34, Dorine W. Swinkels26, Toshiko Tanaka21, Alexander Teumer36, Anke Tönjes37, Michela Traglia7, Jaakko Tuomilehto, Armand Valsesia38, Wiek H. van Gilst31, Joyce B. J. van Meurs34, Albert V. Smith39, Jorma Viikari40, Jacqueline M. Vink13, Gérard Waeber11, Nicole M. Warrington8, Elisabeth Widen30, Gonneke Willemsen13, Alan F. Wright14, Brent W. Zanke41, Lina Zgaga42, Michael Boehnke24, Adamo Pio D'Adamo20, Eco J. C. de Geus13, Ellen W. Demerath43, Martin den Heijer26, Johan G. Eriksson, Luigi Ferrucci21, Christian Gieger, Vilmundur Gudnason39, Caroline Hayward14, Christian Hengstenberg, Thomas J. Hudson44, Marjo-Riitta Järvelin, Manolis Kogevinas, Ruth J. F. Loos, Nicholas G. Martin4, Andres Metspalu16, Craig E. Pennell8, Brenda W.J.H. Penninx45, Markus Perola21, Markus Perola30, Olli T. Raitakari40, Veikko Salomaa25, Stefan Schreiber46, Heribert Schunkert15, Tim D. Spector6, Michael Stumvoll37, André G. Uitterlinden34, Sheila Ulivi, Pim van der Harst31, Peter Vollenweider11, Henry Völzke12, Nicholas J. Wareham, H.-Erich Wichmann47, James F. Wilson14, Igor Rudan14, Yali Xue2, Eleftheria Zeggini2 
TL;DR: This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio, and does not detect any genome-wide significant common SNP differences between men and women in this well-powered meta-analysis.
Abstract: The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10(-8)) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.

Journal ArticleDOI
02 Aug 2012-PLOS ONE
TL;DR: The results do not support the existence of strong interaction effects as a common risk factor for MI, and a modest upper limit on the magnitude that epistatic risk effects are likely to have at the population level is placed.
Abstract: The genetic loci that have been found by genome-wide association studies to modulate risk of coronary heart disease explain only a fraction of its total variance, and gene-gene interactions have been proposed as a potential source of the remaining heritability. Given the potentially large testing burden, we sought to enrich our search space with real interactions by analyzing variants that may be more likely to interact on the basis of two distinct hypotheses: a biological hypothesis, under which MI risk is modulated by interactions between variants that are known to be relevant for its risk factors; and a statistical hypothesis, under which interacting variants individually show weak marginal association with MI. In a discovery sample of 2,967 cases of early-onset myocardial infarction (MI) and 3,075 controls from the MIGen study, we performed pair-wise SNP interaction testing using a logistic regression framework. Despite having reasonable power to detect interaction effects of plausible magnitudes, we observed no statistically significant evidence of interaction under these hypotheses, and no clear consistency between the top results in our discovery sample and those in a large validation sample of 1,766 cases of coronary heart disease and 2,938 controls from the Wellcome Trust Case-Control Consortium. Our results do not support the existence of strong interaction effects as a common risk factor for MI. Within the scope of the hypotheses we have explored, this study places a modest upper limit on the magnitude that epistatic risk effects are likely to have at the population level (odds ratio for MI risk 1.3-2.0, depending on allele frequency and interaction model).

Vesna Boraska, Ana Jerončić, Vincenza Colonna, Lorraine Southam, Dale R. Nyholt, N W Rayner, John R. B. Perry, Daniela Toniolo, Eva Albrecht, Wei Ang, Stefania Bandinelli, Maja Barbalić, Inês Barroso, Jacques S. Beckmann, Reiner Biffar, Dorret I. Boomsma, Harry Campbell, Tanguy Corre, Jeanette Erdmann, Tõnu Esko, Krista Fischer, Nora Franceschini, Timothy M. Frayling, Giorgia Girotto, Juan R. González, Tamara B. Harris, A. C. Heath, I. M. Heid, W. Hoffmann, Albert Hofman, Momoko Horikoshi, Jing Hua Zhao, Anne U. Jackson, Jouke-Jan Hottenga, A. Jula, Mika Kähönen, Kay-Tee Khaw, Lambertus A. Kiemeney, N Klopp, Zoltán Kutalik, Vasiliki Lagou, Lenore J. Launer, Terho Lehtimäki, Mathieu Lemire, M. L. Lokki, Christina Loley, Jian'an Luan, Massimo Mangino, I. Mateo Leach, S. E. Medland, Evelin Mihailov, Grant W. Montgomery, Gerjan Navis, John P. Newnham, Nieminen, Aarno Palotie, Kalliope Panoutsopoulou, Annette Peters, Nicola Pirastu, Ozren Polasek, Karola Rehnström, Samuli Ripatti, Graham R S Ritchie, Fernando Rivadeneira, Antonietta Robino, Nilesh J. Samani, So-Youn Shin, Juha Sinisalo, J.H. Smit, Nicole Soranzo, Lisette Stolk, Dorine W. Swinkels, Toshiko Tanaka, Alexander Teumer, A Tönjes, Michela Traglia, Jaakko Tuomilehto, Armand Valsesia, W. H. Van Gilst, J.B. van Meurs, Albert V. Smith, Jorma Viikari, J.M. Vink, G. Waeber, Nicole M. Warrington, E. Widen, Gonneke Willemsen, A. F. Wright, Brent W. Zanke, Lina Zgaga, Michael Boehnke, Adamo Pio d'Adamo, E.J.C. de Geus, W. Demerath, M. den Heijer, Johan G. Eriksson, Luigi Ferrucci, Christian Gieger, Vilmundur Gudnason, Caroline Hayward, Christian Hengstenberg, Thomas J. Hudson, Marjo-Riitta Järvelin, Manolis Kogevinas, Ruth J. F. Loos, Nicholas G. Martin, Andres Metspalu, Craig E. Pennell, B.W.J.H. Penninx, Marcus Perola, Olli T. Raitakari, Veikko Salomaa, Stefan Schreiber, Heribert Schunkert, Tim D. Spector, Michael Stumvoll, André G. Uitterlinden, S. Ulivi, P. van der Harst, Peter Vollenweider, Henry Völzke, Nicholas J. Wareham, H. E. Wichmann, James F. Wilson, Igor Rudan, Yali Xue, Eleftheria Zeggini 
01 Jan 2012
TL;DR: This paper conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency > 0.05) single-nucleotide polymorphisms (SNPs).
Abstract: The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 x 10(-8)) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.