Showing papers by "Nilesh J. Samani published in 2013"
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Cristen J. Willer1, Ellen M. Schmidt1, Sebanti Sengupta1, Gina M. Peloso2 +316 more•Institutions (87)
TL;DR: It is found that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index.
Abstract: Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
2,585 citations
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Panos Deloukas1, Stavroula Kanoni1, Christina Willenborg2, Martin Farrall3 +201 more•Institutions (64)
TL;DR: An association analysis in CAD cases and controls identifies 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants strongly associated with CAD at a 5% false discovery rate (FDR).
Abstract: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
1,518 citations
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TL;DR: It is suggested that triglyceride-rich lipoproteins causally influence risk for CAD, and the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk.
Abstract: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
817 citations
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University of Leicester1, King's College London2, Leiden University3, Imperial College London4, VU University Amsterdam5, University of Tartu6, University of Helsinki7, QIMR Berghofer Medical Research Institute8, University of Groningen9, Karolinska Institutet10, University College London11, University of Cambridge12, Erasmus University Rotterdam13, University of Leeds14, University of Georgia15, University of Oulu16, University of Oxford17, University of Washington18, National Institutes of Health19, National Institute for Health and Welfare20, Wellcome Trust Centre for Human Genetics21, National Institute for Health Research22, Georgia Regents University23, Prevention Institute24, Ludwig Maximilian University of Munich25, University of North Carolina at Chapel Hill26, University of Texas MD Anderson Cancer Center27, University of Milan28, University of Pennsylvania29, Harvard University30, Broad Institute31, Glenfield Hospital32
TL;DR: In this paper, a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals was carried out to identify seven loci, including five new loci associated with mean leukocyte telomere length (LTL) (P < 5 × 10−8).
Abstract: Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.
703 citations
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TL;DR: New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
Abstract: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
633 citations
01 Jan 2013
TL;DR: In this article, a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals was carried out to identify seven loci, including five new loci associated with mean leukocyte telomere length (LTL).
Abstract: Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10−8). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5–35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.
604 citations
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TL;DR: A genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry finds a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Abstract: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
576 citations
01 Jan 2013
TL;DR: In this article, the authors identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4).
Abstract: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
494 citations
01 Jan 2013
478 citations
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Joshua C. Randall1, Joshua C. Randall2, Thomas W. Winkler3, Zoltán Kutalik4 +305 more•Institutions (89)
TL;DR: The value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits is demonstrated, with no evidence for genetic effects with opposite directions in men versus women.
Abstract: Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
402 citations
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TL;DR: A high and very consistent heritability estimate for TL is found, evidence for a maternal inheritance component and the influence of parental age at birth on TL is investigated, and a positive association with paternal age is found.
Abstract: Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19,713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64-0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother-offspring (r=0.42; P-value=3.60 × 10(-61)) than father-offspring correlation (r=0.33; P-value=7.01 × 10(-5)), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10(-5)). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10(-30)) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10(-23)) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10(-10)). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.
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Marcel den Hoed1, Mark Eijgelsheim2, Tõnu Esko3, Bianca J. J. M. Brundel4 +264 more•Institutions (85)
TL;DR: A 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci, providing fresh insights into the mechanisms regulating heart rate.
Abstract: Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
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University of Lübeck1, University of Regensburg2, French Institute of Health and Medical Research3, Technische Universität München4, Ruhr University Bochum5, University Hospital Regensburg6, University of Bonn7, University Hospital of Basel8, National Institute for Health Research9, University of Leeds10, Max Planck Society11, Charité12, Medical University of Graz13, University of Pennsylvania14, Massachusetts Institute of Technology15, University of Ottawa16, Rockefeller University17
TL;DR: Starting with a severely affected family, this work has identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation, and demonstrated in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1- sGC protein content, and impair soluble guanyly l cyclase activity.
Abstract: Myocardial infarction, a leading cause of death intheWesternworld(1), usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery(2). The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history(3). Nextgeneration sequencing in families with several affected individuals has revolutionized mutation identification(4). Here we report the segregation of two private, heterozygous mutations in two functionally relatedgenes, GUCY1A3 (p.Leu163Phefs*24) andCCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the alpha 1 subunit of soluble guanylyl cyclase (alpha 1-sGC)(5), and CCT7 encodes CCT eta, a member of the tailless complex polypeptide 1 ring complex(6), which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation(7). Wedemonstratein vitro that mutations inbothGUCY1A3 and CCT7 severely reduce alpha 1-sGC as well as beta 1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxideinduced cGMP formation. Mice deficient in alpha 1-sGC protein displayed accelerated thrombus formation in themicrocirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.
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TL;DR: In this study, Prokopenko and colleagues provide novel evidence for causal relationship between adiposity and heart failure and increased liver enzymes using a Mendelian randomization study design.
Abstract: Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it ...
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Erasmus University Rotterdam1, McMaster University2, University of Washington3, Harvard University4, National Institutes of Health5, Radboud University Nijmegen6, King's College London7, University of Lausanne8, Karolinska Institutet9, VU University Amsterdam10, University of Cambridge11, Cedars-Sinai Medical Center12, University of Oxford13, University of Lübeck14, Wageningen University and Research Centre15, Glenfield Hospital16, University of Münster17, Tufts University18, University of Bergen19, Imperial College London20, University of Pennsylvania21, University of Leicester22, University of Surrey23
TL;DR: Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tH Cy concentrations and tHCy-related pathways for CAD.
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TL;DR: A network-driven integrative analysis not only identified CHD-related genes, but also defined network structure that sheds light on the molecular interactions of genes associated with CHD risk.
Abstract: Objective— Genetic approaches have identified numerous loci associated with coronary heart disease (CHD). The molecular mechanisms underlying CHD gene–disease associations, however, remain unclear. We hypothesized that genetic variants with both strong and subtle effects drive gene subnetworks that in turn affect CHD. Approach and Results— We surveyed CHD-associated molecular interactions by constructing coexpression networks using whole blood gene expression profiles from 188 CHD cases and 188 age- and sex-matched controls. Twenty-four coexpression modules were identified, including 1 case-specific and 1 control-specific differential module (DM). The DMs were enriched for genes involved in B-cell activation, immune response, and ion transport. By integrating the DMs with gene expression–associated single-nucleotide polymorphisms and with results of genome-wide association studies of CHD and its risk factors, the control-specific DM was implicated as CHD causal based on its significant enrichment for both CHD and lipid expression–associated single-nucleotide polymorphisms. This causal DM was further integrated with tissue-specific Bayesian networks and protein–protein interaction networks to identify regulatory key driver genes. Multitissue key drivers ( SPIB and TNFRSF13C ) and tissue-specific key drivers (eg, EBF1 ) were identified. Conclusions— Our network-driven integrative analysis not only identified CHD-related genes, but also defined network structure that sheds light on the molecular interactions of genes associated with CHD risk.
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University of Michigan1, Utrecht University2, Case Western Reserve University3, University of Pennsylvania4, University of Western Ontario5, University of California, San Diego6, Queen Mary University of London7, Cleveland Clinic8, University of Maryland, Baltimore9, University of Oxford10, University of Wisconsin-Madison11, University of North Carolina at Chapel Hill12, University of Bristol13, University of Florida14, Erasmus University Rotterdam15, Heidelberg University16, University of Groningen17, Lund University18, University of Glasgow19, Medical Research Council20, University of Washington21, Columbia University22, University College London23, NHS Blood and Transplant24, Tulane University25, Harvard University26, University of Texas Health Science Center at Houston27, Merck & Co.28, University of Mississippi29, Translational Genomics Research Institute30, National Institutes of Health31, Dalhousie University32, Georgia Regents University33, Fred Hutchinson Cancer Research Center34, Boston University35, Northwestern University36, University of Amsterdam37, Ludwig Maximilian University of Munich38, Broad Institute39, VU University Amsterdam40, Medical University of Graz41, Scripps Research Institute42, Veterans Health Administration43, Johns Hopkins University44, University of Ulm45, Hannover Medical School46, Synlab Group47, Scripps Health48, Icahn School of Medicine at Mount Sinai49, Cleveland Clinic Lerner Research Institute50, Royal College of Surgeons in Ireland51, University of Leicester52, Glenfield Hospital53
TL;DR: Two novel loci associated with BP are identified and multiple previously reported associations are confirmed, extending the understanding of genes involved in BP regulation and some of which may eventually provide new targets for therapeutic intervention.
Abstract: Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
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Karolinska University Hospital1, Brigham and Women's Hospital2, Erasmus University Rotterdam3, Greifswald University Hospital4, Fred Hutchinson Cancer Research Center5, University of Minnesota6, St George's, University of London7, Leiden University Medical Center8, University of Washington9, Cedars-Sinai Medical Center10, VU University Amsterdam11, University of Bristol12, University of Edinburgh13, University of Helsinki14, National Institutes of Health15, Johns Hopkins University School of Medicine16, French Institute of Health and Medical Research17, Western General Hospital18, University of Split19, Beth Israel Deaconess Medical Center20, Josip Juraj Strossmayer University of Osijek21, University of Hawaii22, University of Iowa23, University of California, Los Angeles24, Brown University25, University of Texas Health Science Center at Houston26, Northwestern University27, King's College London28, University of Leeds29, University of Vermont30, Hannover Medical School31, Wellcome Trust Centre for Human Genetics32, Mario Negri Institute for Pharmacological Research33, University of Münster34, University of Oxford35, University of Glasgow36, University College Cork37, Boston University38, University of Sydney39, Karolinska Institutet40, University of Mississippi Medical Center41, Ludwig Maximilian University of Munich42, Imperial College London43, University of Pennsylvania44, University of Cambridge45, University of Leicester46, University of Lübeck47, Harvard University48, Aix-Marseille University49, Helsinki University Central Hospital50, Wellcome Trust51, University of Ulm52, Pierre-and-Marie-Curie University53
TL;DR: Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
Abstract: Background—Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-...
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University College London1, French Institute of Health and Medical Research2, Pierre-and-Marie-Curie University3, Karolinska Institutet4, Utrecht University5, University of Edinburgh6, Utah System of Higher Education7, Brigham and Women's Hospital8, University of Amsterdam9, University of Pennsylvania10, Leiden University11, Erasmus University Rotterdam12, University of Leicester13, German Cancer Research Center14, University of Ulm15, Leipzig University16, University of Copenhagen17, University of Cambridge18, University of London19, University of Oxford20, Cyprus University of Technology21, University of Milan22, Ludwig Maximilian University of Munich23, University Medical Center Groningen24, Swansea University25, University of Leeds26, Linköping University27, Imperial College London28, University of Bristol29, University of Glasgow30, University of California, San Diego31, University of Colorado Denver32, Children's Hospital of Philadelphia33, McMaster University34, University of Warwick35
TL;DR: In this paper, the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease was investigated by using a Mendelian randomization meta-analysis of 19 general population studies and 10 acute coronary syndrome (ACS) cohorts.
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TL;DR: Data suggest that regular engagement in ultra-endurance aerobic exercise attenuates cellular aging and is associated with shorter mean leukocyte telomere length.
Abstract: Telomere length is recognized as a marker of biological age, and shorter mean leukocyte telomere length is associated with increased risk of cardiovascular disease. It is unclear whether repeated exposure to ultra-endurance aerobic exercise is beneficial or detrimental in the long-term and whether it attenuates biological aging. We quantified 67 ultra-marathon runners' and 56 apparently healthy males' leukocyte telomere length (T/S ratio) using real-time quantitative PCR. The ultra-marathon runners had 11% longer telomeres (T/S ratio) than controls (ultra-marathon runners: T/S ratio = 3.5 +/- 0.68, controls: T/S ratio = 3.1 +/- 0.41; beta = 0.40, SE = 0.10, P = 1.4x10(-4)) in age-adjusted analysis. The difference remained statistically significant after adjustment for cardiovascular risk factors (P = 2.2x10(-4)). The magnitude of this association translates into 16.2 +/- 0.26 years difference in biological age and approximately 324-648bp difference in leukocyte telomere length between ultra-marathon runners and healthy controls. Neither traditional cardiovascular risk factors nor markers of inflammation/adhesion molecules explained the difference in leukocyte telomere length between ultra-marathon runners and controls. Taken together these data suggest that regular engagement in ultra-endurance aerobic exercise attenuates cellular aging.
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Washington University in St. Louis1, Broad Institute2, Harvard University3, University of Wisconsin–Milwaukee4, Fred Hutchinson Cancer Research Center5, University of Oxford6, Wellcome Trust Centre for Human Genetics7, Karolinska Institutet8, University of Leicester9, Lund University10, University of Ottawa11, University of Verona12, Ohio State University13, University of North Carolina at Chapel Hill14, University of Parma15, University of Pennsylvania16, Technische Universität München17, University of Lübeck18, University of Amsterdam19
TL;DR: This study diagnosed clinically unapparent cholesterol ester storage disease in the affected individuals from this kindred and addressed an outstanding question about risk of cardiovascular disease in LIPA E8SJM heterozygous carriers.
Abstract: Objective— Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1 . We identified a family with autosomal recessive hypercholesterolemia not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular pathogenesis of autosomal recessive hypercholesterolemia in this family. Approach and Results— We used exome sequencing to assess all protein-coding regions of the genome in 3 family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Because homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease, we performed directed follow-up phenotyping by noninvasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of cholesterol ester storage disease. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27 000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance. Conclusions— By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent cholesterol ester storage disease in the affected individuals from this kindred and addressed an outstanding question about risk of cardiovascular disease in LIPA E8SJM heterozygous carriers.
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Glenfield Hospital1, University of Leicester2, University of Iceland3, University of Leeds4, University of Western Australia5, Utrecht University6, Mayo Clinic7, University of Otago8, Waikato Hospital9, Christchurch Hospital10, Auckland City Hospital11, Imperial College London12, Wellcome Trust Sanger Institute13, James Cook University14
TL;DR: A genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA, given the potential genetic overlap between risk factor and disease phenotypes.
Abstract: Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7); however, only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (CAD) (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate whether the loci for these two phenotypes are also associated with AAA. Validated CAD and dyslipidaemia loci underwent screening using the Otago AAA genome-wide association data set. Putative associations underwent staged secondary validation in 10 additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidaemia and CAD, reached genome-wide significance in 11 combined independent cohorts (meta-analysis with 7048 AAA cases and 75 976 controls: G allele OR 0.81, 95% CI 0.76–0.85, P = 7.2 × 10⁻¹⁴). Modelling for confounding interactions of concurrent dyslipidaemia, heart disease and other risk factors suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well-characterized case–control cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.
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Queen's University Belfast1, University of Otago2, University College London3, University of Leicester4, Wellcome Trust Sanger Institute5, Utrecht University6, University of Iceland7, Guy's and St Thomas' NHS Foundation Trust8, University of London9, University of Leeds10, University of Western Australia11, VU University Amsterdam12, Radboud University Nijmegen Medical Centre13, Aarhus University14, James Cook University15, Imperial College London16, Karolinska Institutet17
TL;DR: Low-density lipoprotein receptor (LDLR) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies, consistent with established effects of this variant on coronary artery disease.
Abstract: Background— Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance.
Methods and Results— A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter ≥30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P <1×10−4 were carried through to in silico replication in 1292 AAA cases and 30 503 controls. One single-nucleotide polymorphism associated with P <0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor ( LDLR ) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio, 0.76; 95% confidence interval, 0.70–0.83; P =2.08×10−10).
Conclusions— LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.
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University of Kiel1, University of Lübeck2, Boston University3, University Hospitals of Leicester NHS Trust4, University of Leicester5, Broad Institute6, Harvard University7, University of Pennsylvania8, Stanford University9, University of Leeds10, University of Ottawa11, deCODE genetics12, University of Iceland13
TL;DR: Most blood pressure–associated polymorphisms also confer an increased risk for coronary artery disease, consistent with a causal relationship of increasing blood pressure to coronary artery Disease.
Abstract: Hypertension is a risk factor for coronary artery disease. Recent genome-wide association studies have identified 30 genetic variants associated with higher blood pressure at genome-wide significance (P 1 for coronary artery disease, a proportion much higher than expected by chance (P=4 × 10(-5)). The average relative coronary artery disease risk increase per each of the multiple blood pressure-raising alleles observed in the consortium was 3.0% for systolic blood pressure-associated polymorphisms (95% confidence interval, 1.8%-4.3%) and 2.9% for diastolic blood pressure-associated polymorphisms (95% confidence interval, 1.7%-4.1%). In substudies, individuals carrying most systolic blood pressure- and diastolic blood pressure-related risk alleles (top quintile of a genetic risk score distribution) had 70% (95% confidence interval, 50%-94%) and 59% (95% confidence interval, 40%-81%) higher odds of having coronary artery disease, respectively, as compared with individuals in the bottom quintile. In conclusion, most blood pressure-associated polymorphisms also confer an increased risk for coronary artery disease. These findings are consistent with a causal relationship of increasing blood pressure to coronary artery disease. Genetic variants primarily affecting blood pressure contribute to the genetic basis of coronary artery disease.
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Queen Mary University of London1, Emory University2, Cardiff University3, National Institute for Health Research4, University of Pennsylvania5, MedStar Washington Hospital Center6, Duke University7, Intermountain Medical Center8, Tokyo Medical and Dental University9, Samsung Medical Center10, University of Otago11, Wellcome Trust Centre for Human Genetics12, University of Kiel13, Stanford University14, Kaiser Permanente15, Cleveland Clinic16, University of Florida Health Science Center17, University of London18, University of Southern California19, University of Oxford20, Shanghai Jiao Tong University21, University of Southampton22
TL;DR: The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD, adding further weight to the hypothesis that 9p 21 locus primarily mediates an atherosclerotic phenotype.
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Thorgeir E. Thorgeirsson1, Daniel F. Gudbjartsson1, Patrick Sulem1, Søren Besenbacher2 +313 more•Institutions (90)
TL;DR: The results strongly point to a common biological basis of the regulation of theregulation of the authors' appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity, and the effect of single-nucleotide polymorphisms affecting body mass index (BMI).
Abstract: Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34 216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10−7). These findings replicate in a second large data set (N=127 274, thereof 76 242 smokers) for both SI (P=1.2 × 10−5) and CPD (P=9.3 × 10−5). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.
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TL;DR: In-depth analysis of these 105 cis eQTL revealed that at 76 loci genetic associations were compatible with additive effects of several SNPs, while for the 29 remaining regions data could be compatible with a more complex haplotypic pattern.
Abstract: In order to assess whether gene expression variability could be influenced by several SNPs acting in cis, either throughadditive or more complex haplotype effects, a systematic genome-wide search for cis haplotype expression quantitativetrait loci (eQTL) was conducted in a sample of 758 individuals, part of the Cardiogenics Transcriptomic Study, for whichgenome-wide monocyte expression and GWAS data were available. 19,805 RNA probes were assessed for cis haplotypicregulation through investigation of ,2,1610 9 haplotypic combinations. 2,650 probes demonstrated haplotypic p-values .10 4 -fold smaller than the best single SNP p-value. Replication of significant haplotype effects were tested for 412probes for which SNPs (or proxies) that defined the detected haplotypes were available in the Gutenberg Health Studycomposed of 1,374 individuals. At the Bonferroni correction level of 1.2610 24 (,0.05/412), 193 haplotypic signalsreplicated. 1000G imputation was then conducted, and 105 haplotypic signals still remained more informative than imputedSNPs. In-depth analysis of these 105 cis eQTL revealed that at 76 loci genetic associations were compatible with additiveeffects of several SNPs, while for the 29 remaining regions data could be compatible with a more complex haplotypicpattern. As 24 of the 105 cis eQTL have previously been reported to be disease-associated loci, this work highlights the needfor conducting haplotype-based and 1000G imputed cis eQTL analysis before commencing functional studies at disease-associated loci.
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TL;DR: Coronary artery disease predisposing haplogroup I of the Y chromosome is associated with downregulation of UTY and PRKY genes in macrophages but not with conventional cardiovascular risk factors.
Abstract: Objective— Haplogroup I of male-specific region of the human Y chromosome is associated with 50% increased risk of coronary artery disease. It is not clear to what extent conventional cardiovascular risk factors and genes of the male-specific region may explain this association. Approach and Results— A total of 1988 biologically unrelated men from 4 white European populations were genotyped using 11 Y chromosome single nucleotide polymorphisms and classified into 13 most common European haplogroups. Approximately 75% to 93% of the haplotypic variation of the Y chromosome in all cohorts was attributable to I, R1a, and R1b1b2 lineages. None of traditional cardiovascular risk factors, including body mass index, blood pressures, lipids, glucose, C-reactive protein, creatinine, and insulin resistance, was associated with haplogroup I of the Y chromosome in the joint inverse variance meta-analysis. Fourteen of 15 ubiquitous single-copy genes of the male-specific region were expressed in human macrophages. When compared with men with other haplogroups, carriers of haplogroup I had ≈0.61- and 0.64-fold lower expression of ubiquitously transcribed tetratricopeptide repeat, Y-linked gene ( UTY ) and protein kinase, Y-linked, pseudogene ( PRKY ) in macrophages ( P =0.0001 and P =0.002, respectively). Conclusions— Coronary artery disease predisposing haplogroup I of the Y chromosome is associated with downregulation of UTY and PRKY genes in macrophages but not with conventional cardiovascular risk factors.
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TL;DR: The dose-dependent variation in TL of subjects with partial and full PTSD exceeded the chronological age effect, and was equivalent to an estimated 5 years in partial and 10 years in full PTSD of premature aging.
Abstract: Background: A link between severe mental stress and shorter telomere length (TL) has been suggested. We analysed the impact of Posttraumatic Stress Disorder (PTSD) on TL in the general population and postulated a dose-dependent TL association in subjects suffering from partial PTSD compared to full PTSD. Methods: Data are derived from the population-based KORA F4 study (2006–2008), located in southern Germany including 3,000 individuals (1,449 men and 1,551 women) with valid and complete TL data. Leukocyte TL was measured using a quantitative PCR-based technique. PTSD was assessed in a structured interview and by applying the Posttraumatic Diagnostic Scale (PDS) and the Impact of Event Scale (IES). A total of 262 (8.7%) subjects qualified for having partial PTSD and 51 (1.7%) for full PTSD. To assess the association of PTSD with the average TL, linear regression analyses with adjustments for potential confounding factors were performed. Results: The multiple model revealed a significant association between partial PTSD and TL (beta= 20.051, p=0.009) as well as between full PTSD and shorter TL (beta= 20.103, p=0.014) indicating shorter TL on average for partial and full PTSD. An additional adjustment for depression and depressed mood/exhaustion gave comparable beta estimations. Conclusions: Participants with partial and full PTSD had significantly shorter leukocyte TL than participants without PTSD. The dose-dependent variation in TL of subjects with partial and full PTSD exceeded the chronological age effect, and was equivalent to an estimated 5 years in partial and 10 years in full PTSD of premature aging.
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University of Maryland, Baltimore1, Washington University in St. Louis2, University of Colorado Boulder3, Michigan State University4, University of Utah5, Virginia Commonwealth University6, King's College London7, University of Pisa8, University of North Carolina at Chapel Hill9, Heidelberg University10, University of Texas MD Anderson Cancer Center11, Johns Hopkins University12, Yale University13, University of Helsinki14, QIMR Berghofer Medical Research Institute15, University of Oxford16, SRI International17, University of Pittsburgh18, Brown University19, General Electric20, University of Greifswald21, University of Leicester22, VU University Amsterdam23, Wayne State University24, National Institutes of Health25, University of Leeds26, Cornell University27, New York University28, University of Bonn29, Indiana University30, Memorial Sloan Kettering Cancer Center31, Ludwig Maximilian University of Munich32, University of Sydney33, National Institute for Health and Welfare34, University of Oulu35, Erasmus University Rotterdam36, University of Iowa37, West Virginia University38, University of British Columbia39, University of Turku40, University of Texas Health Science Center at Houston41, Max Planck Society42, Oregon Research Institute43, Health Protection Agency44, Stockholm School of Economics45, Karolinska Institutet46, University of Minnesota47, RTI International48, Harvard University49
TL;DR: The results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
Abstract: Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.