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Frances M K Williams,
Angela M Carter,
Pirro G Hysi,
Gabriela Surdulescu,
Dylan Hodgkiss,
Nicole Soranzo,
Matthew Traylor,
Steve Bevan,
Martin Dichgans,
Peter M W Rothwell, [......],
Karen L Furie,
Jonathan Rosand,
Mike Nalls,
James Meschia,
Thomas H Mosely,
Alun Evans,
Aarno Palotie,
Hugh S Markus,
Peter J Grant,
Tim D Spector
[show abstract]
[hide abstract]
ABSTRACT: Objective: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype. Methods: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3). Results: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8) ) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186) ), rs10665 with FVII (p = 2.4 × 10(-47) ), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57) ) and factor VIII (p = 1.2 × 10(-36) ). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). Interpretation: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype. Ann Neurol 2013.
Annals of Neurology 01/2013; 73(1):16-31. · 11.09 Impact Factor
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Ida Surakka,
John B Whitfield,
Markus Perola,
Peter M Visscher,
Grant W Montgomery,
Mario Falchi,
Gonneke Willemsen,
Eco J C de Geus,
Patrik K E Magnusson,
Kaare Christensen, [......],
Ann-Christine Syvänen,
Aarno Palotie,
Jaakko Kaprio,
Kirsten O Kyvik,
Nancy L Pedersen,
Dorret I Boomsma,
Tim Spector,
Nicholas G Martin,
Samuli Ripatti,
Leena Peltonen
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association analysis on monozygotic twin-pairs offers a route to discovery of gene-environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin-pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high-density lipoprotein cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (P = 3.98 × 10-8). We followed up the association in further genotyped monozygotic twins (N = 1,261), which showed a moderate association for the variant (P = 0.200, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (P = 4.03 × 10-8).
Twin Research and Human Genetics 10/2012; · 1.70 Impact Factor
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Tanya M Teslovich,
Kiran Musunuru,
Albert V Smith,
Andrew C Edmondson,
Ioannis M Stylianou,
Masahiro Koseki,
James P Pirruccello,
Samuli Ripatti,
Daniel I Chasman,
Cristen J Willer, [......],
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Cornelia M van Duijn,
Leena Peltonen,
Gonçalo R Abecasis,
Michael Boehnke,
Sekar Kathiresan
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Tanya M Teslovich,
Kiran Musunuru,
Albert V Smith,
Andrew C Edmondson,
Ioannis M Stylianou,
Masahiro Koseki,
James P Pirruccello,
Samuli Ripatti,
Daniel I Chasman,
Cristen J Willer, [......],
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Cornelia M van Duijn,
Leena Peltonen,
Gonçalo R Abecasis,
Michael Boehnke,
Sekar Kathiresan
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Moritz F Sinner,
Kimmo Porthan,
Peter A Noseworthy,
Aki S Havulinna,
Jani T Tikkanen,
Martina Müller-Nurasyid,
Gina Peloso,
Sheila Ulivi,
Britt Maria Beckmann,
A Catharina Brockhaus, [......],
Barbara Thorand,
H-Erich Wichmann,
Gianfranco Sinagra,
Jorma Viikari,
Christopher J O'Donnell,
Patrick T Ellinor,
Heikki V Huikuri,
Stefan Kääb,
Christopher Newton-Cheh,
Veikko Salomaa
[show abstract]
[hide abstract]
ABSTRACT: The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases.
To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP.
We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10(-5) in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages.
Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36-0.61; P = 6.9 × 10(-9)). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25-1.69; P = 8.5 × 10(-7)). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance.
In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.
Heart rhythm: the official journal of the Heart Rhythm Society 06/2012; 9(10):1627-34. · 4.56 Impact Factor
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Zari Dastani,
Marie-France Hivert,
Nicholas Timpson,
John R B Perry,
Xin Yuan,
Robert A Scott,
Peter Henneman,
Iris M Heid,
Jorge R Kizer,
Leo-Pekka Lyytikäinen, [......],
Eric E Schadt,
David P Strachan,
Muredach P Reilly,
Nilesh J Samani,
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Sekar Kathiresan
[show abstract]
[hide abstract]
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.
PLoS Genetics 03/2012; 8(3):e1002607. · 8.69 Impact Factor
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Nicholette D Palmer,
Caitrin W McDonough,
Pamela J Hicks,
Bong H Roh,
Maria R Wing,
S Sandy An,
Jessica M Hester,
Jessica N Cooke,
Meredith A Bostrom,
Megan E Rudock, [......],
Angelo Scuteri,
David Schlessinger,
Manuela Uda,
Aimo Ruokonen,
Marjo-Riitta Jarvelin,
Dawn M Waterworth,
Peter Vollenweider,
Leena Peltonen,
Vincent Mooser,
Robert Sladek
[show abstract]
[hide abstract]
ABSTRACT: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
PLoS ONE 01/2012; 7(1):e29202. · 4.09 Impact Factor
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Johannes Kettunen,
Taru Tukiainen,
Antti-Pekka Sarin,
Alfredo Ortega-Alonso,
Emmi Tikkanen,
Leo-Pekka Lyytikäinen,
Antti J Kangas,
Pasi Soininen,
Peter Würtz, Kaisa Silander, [......],
Olli T Raitakari,
Veikko Salomaa,
Jaakko Kaprio,
Marjo-Riitta Järvelin,
Leena Peltonen,
Markus Perola,
Nelson B Freimer,
Mika Ala-Korpela,
Aarno Palotie,
Samuli Ripatti
[show abstract]
[hide abstract]
ABSTRACT: Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10(-10)) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.
Nature Genetics 01/2012; 44(3):269-76. · 35.53 Impact Factor
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Maria F Hughes,
Olli Saarela,
Jan Stritzke,
Frank Kee, Kaisa Silander,
Norman Klopp,
Jukka Kontto,
Juha Karvanen,
Christina Willenborg,
Veikko Salomaa, [......],
Patrick Diemert,
David-Alexandre Trégouët,
Christian Hengstenberg,
Annette Peters,
Alun Evans,
Wolfgang Koenig,
Jeanette Erdmann,
Nilesh J Samani,
Kari Kuulasmaa,
Heribert Schunkert
[show abstract]
[hide abstract]
ABSTRACT: 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.
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.
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.
Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men.
PLoS ONE 01/2012; 7(7):e40922. · 4.09 Impact Factor
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Yingleong Chan,
Oddgeir L Holmen,
Andrew Dauber,
Lars Vatten,
Aki S Havulinna,
Frank Skorpen,
Kirsti Kvaløy, Kaisa Silander,
Thutrang T Nguyen,
Cristen Willer,
Michael Boehnke,
Markus Perola,
Aarno Palotie,
Veikko Salomaa,
Kristian Hveem,
Timothy M Frayling,
Joel N Hirschhorn,
Michael N Weedon
[show abstract]
[hide abstract]
ABSTRACT: Common genetic variants have been shown to explain a fraction of the inherited variation for many common diseases and quantitative traits, including height, a classic polygenic trait. The extent to which common variation determines the phenotype of highly heritable traits such as height is uncertain, as is the extent to which common variation is relevant to individuals with more extreme phenotypes. To address these questions, we studied 1,214 individuals from the top and bottom extremes of the height distribution (tallest and shortest ∼1.5%), drawn from ∼78,000 individuals from the HUNT and FINRISK cohorts. We found that common variants still influence height at the extremes of the distribution: common variants (49/141) were nominally associated with height in the expected direction more often than is expected by chance (p<5×10⁻²⁸), and the odds ratios in the extreme samples were consistent with the effects estimated previously in population-based data. To examine more closely whether the common variants have the expected effects, we calculated a weighted allele score (WAS), which is a weighted prediction of height for each individual based on the previously estimated effect sizes of the common variants in the overall population. The average WAS is consistent with expectation in the tall individuals, but was not as extreme as expected in the shortest individuals (p<0.006), indicating that some of the short stature is explained by factors other than common genetic variation. The discrepancy was more pronounced (p<10⁻⁶) in the most extreme individuals (height<0.25 percentile). The results at the extreme short tails are consistent with a large number of models incorporating either rare genetic non-additive or rare non-genetic factors that decrease height. We conclude that common genetic variants are associated with height at the extremes as well as across the population, but that additional factors become more prominent at the shorter extreme.
PLoS Genetics 12/2011; 7(12):e1002439. · 8.69 Impact Factor
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Ron Do,
Changchun Xie,
Xiaohe Zhang,
Satu Männistö,
Kennet Harald,
Shofiqul Islam,
Swneke D Bailey,
Sumathy Rangarajan,
Matthew J McQueen,
Rafael Diaz,
Liu Lisheng,
Xingyu Wang, Kaisa Silander,
Leena Peltonen,
Salim Yusuf,
Veikko Salomaa,
James C Engert,
Sonia S Anand
[show abstract]
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ABSTRACT: One of the most robust genetic associations for cardiovascular disease (CVD) is the Chromosome 9p21 region. However, the interaction of this locus with environmental factors has not been extensively explored. We investigated the association of 9p21 with myocardial infarction (MI) in individuals of different ethnicities, and tested for an interaction with environmental factors.
We genotyped four 9p21 SNPs in 8,114 individuals from the global INTERHEART study. All four variants were associated with MI, with odds ratios (ORs) of 1.18 to 1.20 (1.85×10(-8)≤p≤5.21×10(-7)). A significant interaction (p = 4.0×10(-4)) was observed between rs2383206 and a factor-analysis-derived "prudent" diet pattern score, for which a major component was raw vegetables. An effect of 9p21 on MI was observed in the group with a low prudent diet score (OR = 1.32, p = 6.82×10(-7)), but the effect was diminished in a step-wise fashion in the medium (OR = 1.17, p = 4.9×10(-3)) and high prudent diet scoring groups (OR = 1.02, p = 0.68) (p = 0.014 for difference). We also analyzed data from 19,129 individuals (including 1,014 incident cases of CVD) from the prospective FINRISK study, which used a closely related dietary variable. In this analysis, the 9p21 risk allele demonstrated a larger effect on CVD risk in the groups with diets low or average for fresh vegetables, fruits, and berries (hazard ratio [HR] = 1.22, p = 3.0×10(-4), and HR = 1.35, p = 4.1×10(-3), respectively) compared to the group with high consumption of these foods (HR = 0.96, p = 0.73) (p = 0.0011 for difference). The combination of the least prudent diet and two copies of the risk allele was associated with a 2-fold increase in risk for MI (OR = 1.98, p = 2.11×10(-9)) in the INTERHEART study and a 1.66-fold increase in risk for CVD in the FINRISK study (HR = 1.66, p = 0.0026).
The risk of MI and CVD conferred by Chromosome 9p21 SNPs appears to be modified by a prudent diet high in raw vegetables and fruits. Please see later in the article for the Editors' Summary.
PLoS Medicine 10/2011; 8(10):e1001106. · 16.27 Impact Factor
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Juliane Winkelmann,
Darina Czamara,
Barbara Schormair,
Franziska Knauf,
Eva C Schulte,
Claudia Trenkwalder,
Yves Dauvilliers,
Olli Polo,
Birgit Högl,
Klaus Berger, [......],
Holger Prokisch,
Peter Lichtner,
Paul Peppard,
Juliette Faraco,
Emmanuel Mignot,
Christian Gieger,
Thomas Illig,
H-Erich Wichmann,
Bertram Müller-Myhsok,
Thomas Meitinger
PLoS Genetics 08/2011; 7(8). · 8.69 Impact Factor
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Juliane Winkelmann,
Darina Czamara,
Barbara Schormair,
Franziska Knauf,
Eva C Schulte,
Claudia Trenkwalder,
Yves Dauvilliers,
Olli Polo,
Birgit Högl,
Klaus Berger, [......],
Holger Prokisch,
Peter Lichtner,
Paul Peppard,
Juliette Faraco,
Emmanuel Mignot,
Christian Gieger,
Thomas Illig,
H-Erich Wichmann,
Bertram Müller-Myhsok,
Thomas Meitinger
[show abstract]
[hide abstract]
ABSTRACT: Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10(-11), OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10(-19), OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767.
PLoS Genetics 07/2011; 7(7):e1002171. · 8.69 Impact Factor
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Philipp S Wild,
Tanja Zeller,
Arne Schillert,
Silke Szymczak,
Christoph R Sinning,
Arne Deiseroth,
Renate B Schnabel,
Edith Lubos,
Till Keller,
Medea S Eleftheriadis, [......],
Christopher J O'Donnell,
Nilesh J Samani,
Heribert Schunkert,
Francois Cambien,
Karl J Lackner,
Laurence Tiret,
Veikko Salomaa,
Thomas Munzel,
Andreas Ziegler,
Stefan Blankenberg
[show abstract]
[hide abstract]
ABSTRACT: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD).
In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-3)).
The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.
Circulation Cardiovascular Genetics 05/2011; 4(4):403-12. · 6.11 Impact Factor
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[show abstract]
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ABSTRACT: Evidence from prospective observational studies suggests that elevated circulating C-reactive protein (CRP) concentrations are associated with cancer risk, but it is unclear whether this association is causal. In order to examine this, we investigated whether genetic variants that are associated with circulating CRP concentrations are associated with cancer risk.
We pooled data from three population-based prospective Finnish studies: FINRISK 1992 (n = 5289), FINRISK 1997 (n = 7160) and Health 2000 (n = 6299). Cancer cases were identified from cancer registrations. Thirteen CRP-associated SNPs, identified from genome-wide association studies, were genotyped. We examined the associations of the SNPs and cancer risk using Cox, probit and instrumented probit regression models.
Compared to common allele homozygotes, individuals carrying one or two variant T alleles at rs1892534 had 1.05-fold (95% confidence interval (CI): 0.90, 1.23) and 1.2-fold (95% CI: 1.01, 1.42) increased overall cancer risk, respectively. Individuals with one or two variant A alleles at rs1169300 or rs2464196 had approximately 1.5- and 2-fold increased risk of lung cancer, respectively (p trend for both: 0.007). CRP SNPs were not associated with colorectal, prostate or breast cancer risk nor was CRP-associated with the probability of developing cancer in the instrumented probit analyses.
We found some evidence for an association of a small number of CRP-associated SNPs with the overall cancer risk and lung cancer risk. Our instrumental variable analyses provided no clear evidence for a causal association of CRP and cancer. These findings suggest that circulating CRP concentrations are unlikely to have a causal role in cancer.
European journal of cancer (Oxford, England: 1990) 02/2011; 47(3):404-12. · 4.12 Impact Factor
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Iris M Heid,
Anne U Jackson,
Joshua C Randall,
Thomas W Winkler,
Lu Qi,
Valgerdur Steinthorsdottir,
Gudmar Thorleifsson,
M Carola Zillikens,
Elizabeth K Speliotes,
Reedik Mägi, [......],
Unnur Thorsteinsdottir,
Cornelia M van Duijn,
Kari Stefansson,
L Adrienne Cupples,
Ruth J F Loos,
Inês Barroso,
Mark I McCarthy,
Caroline S Fox,
Karen L Mohlke,
Cecilia M Lindgren
Nature Genetics 01/2011; 43(11):1164. · 35.53 Impact Factor
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Michael Inouye,
Johannes Kettunen,
Pasi Soininen, Kaisa Silander,
Samuli Ripatti,
Linda S Kumpula,
Eija H|[auml]|m|[auml]|l|[auml]|inen,
Pekka Jousilahti,
Antti J Kangas,
Satu M|[auml]|nnist|[ouml,
Markku J Savolainen,
Antti Jula,
Jaana Leivisk|[auml,
Aarno Palotie,
Veikko Salomaa,
Markus Perola,
Mika Ala-Korpela,
Leena Peltonen
[show abstract]
[hide abstract]
ABSTRACT: Comprehensive characterization of human tissues promises novel insights into the biological architecture of human diseases and traits. We assessed metabonomic, transcriptomic, and genomic variation for a large population-based cohort from the capital region of Finland. Network analyses identified a set of highly correlated genes, the lipid–leukocyte (LL) module, as having a prominent role in over 80 serum metabolites (of 134 measures quantified), including lipoprotein subclasses, lipids, and amino acids. Concurrent association with immune response markers suggested the LL module as a possible link between inflammation, metabolism, and adiposity. Further, genomic variation was used to generate a directed network and infer LL module's largely reactive nature to metabolites. Finally, gene co-expression in circulating leukocytes was shown to be dependent on serum metabolite concentrations, providing evidence for the hypothesis that the coherence of molecular networks themselves is conditional on environmental factors. These findings show the importance and opportunity of systematic molecular investigation of human population samples. To facilitate and encourage this investigation, the metabonomic, transcriptomic, and genomic data used in this study have been made available as a resource for the research community.
Molecular Systems Biology. 12/2010; 6(1).
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Michael Inouye,
Johannes Kettunen,
Pasi Soininen, Kaisa Silander,
Samuli Ripatti,
Linda S Kumpula,
Eija Hämäläinen,
Pekka Jousilahti,
Antti J Kangas,
Satu Männistö,
Markku J Savolainen,
Antti Jula,
Jaana Leiviskä,
Aarno Palotie,
Veikko Salomaa,
Markus Perola,
Mika Ala-Korpela,
Leena Peltonen
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ABSTRACT: Comprehensive characterization of human tissues promises novel insights into the biological architecture of human diseases and traits. We assessed metabonomic, transcriptomic, and genomic variation for a large population-based cohort from the capital region of Finland. Network analyses identified a set of highly correlated genes, the lipid-leukocyte (LL) module, as having a prominent role in over 80 serum metabolites (of 134 measures quantified), including lipoprotein subclasses, lipids, and amino acids. Concurrent association with immune response markers suggested the LL module as a possible link between inflammation, metabolism, and adiposity. Further, genomic variation was used to generate a directed network and infer LL module's largely reactive nature to metabolites. Finally, gene co-expression in circulating leukocytes was shown to be dependent on serum metabolite concentrations, providing evidence for the hypothesis that the coherence of molecular networks themselves is conditional on environmental factors. These findings show the importance and opportunity of systematic molecular investigation of human population samples. To facilitate and encourage this investigation, the metabonomic, transcriptomic, and genomic data used in this study have been made available as a resource for the research community.
Molecular Systems Biology 12/2010; 6:441. · 8.63 Impact Factor
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Iris M Heid,
Anne U Jackson,
Joshua C Randall,
Thomas W Winkler,
Lu Qi,
Valgerdur Steinthorsdottir,
Gudmar Thorleifsson,
M Carola Zillikens,
Elizabeth K Speliotes,
Reedik Mägi, [......],
Unnur Thorsteinsdottir,
Cornelia M van Duijn,
Kari Stefansson,
L Adrienne Cupples,
Ruth J F Loos,
Inês Barroso,
Mark I McCarthy,
Caroline S Fox,
Karen L Mohlke,
Cecilia M Lindgren
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ABSTRACT: Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
Nature Genetics 10/2010; 42(11):949-60. · 35.53 Impact Factor
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Elizabeth K Speliotes,
Cristen J Willer,
Sonja I Berndt,
Keri L Monda,
Gudmar Thorleifsson,
Anne U Jackson,
Hana Lango Allen,
Cecilia M Lindgren,
Jian'an Luan,
Reedik Mägi, [......],
Unnur Thorsteinsdottir,
Gonçalo R Abecasis,
Inês Barroso,
Michael Boehnke,
Kari Stefansson,
Kari E North,
Mark I McCarthy,
Joel N Hirschhorn,
Erik Ingelsson,
Ruth J F Loos
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ABSTRACT: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
Nature Genetics 10/2010; 42(11):937-48. · 35.53 Impact Factor
