Search

Your search keyword '"Smith, Nicholas L."' showing total 91 results
Start Over Author "Smith, Nicholas L." Topic humans
91 results on '"Smith, Nicholas L."'

1. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes

Author

Keener, Rebecca, Chhetri, Surya B, Connelly, Carla J, Taub, Margaret A, Conomos, Matthew P, Weinstock, Joshua, Ni, Bohan, Strober, Benjamin, Aslibekyan, Stella, Auer, Paul L, Barwick, Lucas, Becker, Lewis C, Blangero, John, Bleecker, Eugene R, Brody, Jennifer A, Cade, Brian E, Celedon, Juan C, Chang, Yi-Cheng, Cupples, L Adrienne, Custer, Brian, Freedman, Barry I, Gladwin, Mark T, Heckbert, Susan R, Hou, Lifang, Irvin, Marguerite R, Isasi, Carmen R, Johnsen, Jill M, Kenny, Eimear E, Kooperberg, Charles, Minster, Ryan L, Naseri, Take, Viali, Satupa’itea, Nekhai, Sergei, Pankratz, Nathan, Peyser, Patricia A, Taylor, Kent D, Telen, Marilyn J, Wu, Baojun, Yanek, Lisa R, Yang, Ivana V, Albert, Christine, Arnett, Donna K, Ashley-Koch, Allison E, Barnes, Kathleen C, Bis, Joshua C, Blackwell, Thomas W, Boerwinkle, Eric, Burchard, Esteban G, Carson, April P, Chen, Zhanghua, Chen, Yii-Der Ida, Darbar, Dawood, de Andrade, Mariza, Ellinor, Patrick T, Fornage, Myriam, Gelb, Bruce D, Gilliland, Frank D, He, Jiang, Islam, Talat, Kaab, Stefan, Kardia, Sharon LR, Kelly, Shannon, Konkle, Barbara A, Kumar, Rajesh, Loos, Ruth JF, Martinez, Fernando D, McGarvey, Stephen T, Meyers, Deborah A, Mitchell, Braxton D, Montgomery, Courtney G, North, Kari E, Palmer, Nicholette D, Peralta, Juan M, Raby, Benjamin A, Redline, Susan, Rich, Stephen S, Roden, Dan, Rotter, Jerome I, Ruczinski, Ingo, Schwartz, David, Sciurba, Frank, Shoemaker, M Benjamin, Silverman, Edwin K, Sinner, Moritz F, Smith, Nicholas L, Smith, Albert V, Tiwari, Hemant K, Vasan, Ramachandran S, Weiss, Scott T, Williams, L Keoki, Zhang, Yingze, Ziv, Elad, Raffield, Laura M, Reiner, Alexander P, Arvanitis, Marios, Greider, Carol W, Mathias, Rasika A, and Battle, Alexis

Subjects
Biological Sciences, Genetics, Human Genome, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Humans, Genome-Wide Association Study, Telomere, K562 Cells, Telomere Homeostasis, Polymorphism, Single Nucleotide, Gene Expression Regulation, CRISPR-Cas Systems, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group
Abstract

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Published
2024

2. Investigating Gene-Diet Interactions Impacting the Association Between Macronutrient Intake and Glycemic Traits.

Author

Westerman, Kenneth E, Walker, Maura E, Gaynor, Sheila M, Wessel, Jennifer, DiCorpo, Daniel, Ma, Jiantao, Alonso, Alvaro, Aslibekyan, Stella, Baldridge, Abigail S, Bertoni, Alain G, Biggs, Mary L, Brody, Jennifer A, Chen, Yii-Der Ida, Dupuis, Joseé, Goodarzi, Mark O, Guo, Xiuqing, Hasbani, Natalie R, Heath, Adam, Hidalgo, Bertha, Irvin, Marguerite R, Johnson, W Craig, Kalyani, Rita R, Lange, Leslie, Lemaitre, Rozenn N, Liu, Ching-Ti, Liu, Simin, Moon, Jee-Young, Nassir, Rami, Pankow, James S, Pettinger, Mary, Raffield, Laura M, Rasmussen-Torvik, Laura J, Selvin, Elizabeth, Senn, Mackenzie K, Shadyab, Aladdin H, Smith, Albert V, Smith, Nicholas L, Steffen, Lyn, Talegakwar, Sameera, Taylor, Kent D, de Vries, Paul S, Wilson, James G, Wood, Alexis C, Yanek, Lisa R, Yao, Jie, Zheng, Yinan, Boerwinkle, Eric, Morrison, Alanna C, Fornage, Miriam, Russell, Tracy P, Psaty, Bruce M, Levy, Daniel, Heard-Costa, Nancy L, Ramachandran, Vasan S, Mathias, Rasika A, Arnett, Donna K, Kaplan, Robert, North, Kari E, Correa, Adolfo, Carson, April, Rotter, Jerome I, Rich, Stephen S, Manson, JoAnn E, Reiner, Alexander P, Kooperberg, Charles, Florez, Jose C, Meigs, James B, Merino, Jordi, Tobias, Deirdre K, Chen, Han, and Manning, Alisa K

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Nutrition, Diabetes, Human Genome, Minority Health, Genetics, Cardiovascular, Health Disparities, Prevention, Precision Medicine, Clinical Research, Metabolic and endocrine, Good Health and Well Being, Humans, Glycated Hemoglobin, Diet, Diabetes Mellitus, Eating, Guanine Nucleotide Dissociation Inhibitors, Genome-Wide Association Study, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and its interactions with common and rare variants genome-wide. In main effect meta-analyses, participants consuming more carbohydrate had modestly lower glycemic trait values (e.g., for glycated hemoglobin [HbA1c], -0.013% HbA1c/250 kcal substitution). In GDI meta-analyses, a common African ancestry-enriched variant (rs79762542) reached study-wide significance and replicated in the UK Biobank cohort, indicating a negative carbohydrate-HbA1c association among major allele homozygotes only. Simulations revealed that >150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error. These results generate hypotheses for further exploration of modifiable metabolic disease risk in additional cohorts with African ancestry.Article highlightsWe aimed to identify genetic modifiers of the dietary macronutrient-glycemia relationship using whole-genome sequence data from 10 Trans-Omics for Precision Medicine program cohorts. Substitution models indicated a modest reduction in glycemia associated with an increase in dietary carbohydrate at the expense of fat. Genome-wide interaction analysis identified one African ancestry-enriched variant near the FRAS1 gene that may interact with macronutrient intake to influence hemoglobin A1c. Simulation-based power calculations accounting for measurement error suggested that substantially larger sample sizes may be necessary to discover further gene-macronutrient interactions.

Published
2023

3. The genetic determinants of recurrent somatic mutations in 43,693 blood genomes

Author

Weinstock, Joshua S, Laurie, Cecelia A, Broome, Jai G, Taylor, Kent D, Guo, Xiuqing, Shuldiner, Alan R, O’Connell, Jeffrey R, Lewis, Joshua P, Boerwinkle, Eric, Barnes, Kathleen C, Chami, Nathalie, Kenny, Eimear E, Loos, Ruth JF, Fornage, Myriam, Redline, Susan, Cade, Brian E, Gilliland, Frank D, Chen, Zhanghua, Gauderman, W James, Kumar, Rajesh, Grammer, Leslie, Schleimer, Robert P, Psaty, Bruce M, Bis, Joshua C, Brody, Jennifer A, Silverman, Edwin K, Yun, Jeong H, Qiao, Dandi, Weiss, Scott T, Lasky-Su, Jessica, DeMeo, Dawn L, Palmer, Nicholette D, Freedman, Barry I, Bowden, Donald W, Cho, Michael H, Vasan, Ramachandran S, Johnson, Andrew D, Yanek, Lisa R, Becker, Lewis C, Kardia, Sharon, He, Jiang, Kaplan, Robert, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Arnett, Donna K, Irvin, Marguerite R, Tiwari, Hemant, Correa, Adolfo, Raffield, Laura M, Gao, Yan, de Andrade, Mariza, Rotter, Jerome I, Rich, Stephen S, Manichaikul, Ani W, Konkle, Barbara A, Johnsen, Jill M, Wheeler, Marsha M, Custer, Brian S, Duggirala, Ravindranath, Curran, Joanne E, Blangero, John, Gui, Hongsheng, Xiao, Shujie, Williams, L Keoki, Meyers, Deborah A, Li, Xingnan, Ortega, Victor, McGarvey, Stephen, Gu, C Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M Benjamin, Darbar, Dawood, Roden, Dan, Albert, Christine, Kooperberg, Charles, Desai, Pinkal, Blackwell, Thomas W, Abecasis, Goncalo R, Smith, Albert V, Kang, Hyun M, Mathias, Rasika, Natarajan, Pradeep, Jaiswal, Siddhartha, Reiner, Alexander P, Bick, Alexander G, and Consortium, NHLBI Trans-Omics for Precision Medicine

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Lung, Genetic Testing, Clinical Research, Biotechnology, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Humans, Middle Aged, Hematopoiesis, Mutation, Germ-Line Mutation, Mutation, Missense, Phenotype, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Abstract

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

Published
2023

4. Circulating Androgen Concentrations and Risk of Incident Heart Failure in Older Men: The Cardiovascular Health Study

Author

Njoroge, Joyce N, Tressel, William, Biggs, Mary L, Matsumoto, Alvin M, Smith, Nicholas L, Rosenberg, Emily, Hirsch, Calvin H, Gottdiener, John S, Mukamal, Kenneth J, and Kizer, Jorge R

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Cardiovascular, Heart Disease, Clinical Research, Prevention, Aging, Good Health and Well Being, Male, Humans, Aged, Sex Hormone-Binding Globulin, Dihydrotestosterone, Androgens, Cardiovascular Diseases, Estradiol, Testosterone, Heart Failure, aging, heart failure, men, sex hormones, testosterone, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology
Abstract

Background Circulating androgen concentrations in men decline with age and have been linked to diabetes and atherosclerotic cardiovascular disease (ASCVD). A similar relationship has been reported for low total testosterone and incident heart failure (HF) but remains unstudied for free testosterone or the more potent androgen dihydrotestosterone (DHT). We hypothesized that total/free testosterone are inversely related, sex hormone-binding globulin is positively related, and total/free DHT bear a U-shaped relationship with incident HF. Methods and Results In a sample of men from the CHS (Cardiovascular Health Study) without atherosclerotic cardiovascular disease or HF, serum testosterone and DHT concentrations were measured by liquid chromatography-tandem mass spectrometry, and sex hormone-binding globulin by immunoassay. Free testosterone or DHT was calculated from total testosterone or total DHT, sex hormone-binding globulin, and albumin. We used Cox regression to estimate relative risks of HF after adjustment for potential confounders. In 1061 men (aged 76±5 years) followed for a median of 9.6 years, there were 368 HF events. After adjustment, lower calculated free testosterone was significantly associated with higher risk of HF (hazard ratio [HR], 1.14 [95% CI, 1.01-1.28]). Risk estimates for total testosterone (HR, 1.12 [95% CI, 0.99-1.26]), total DHT (HR, 1.10 [95% CI, 0.97-1.24]), calculated free dihydrotestosterone (HR, 1.09 [95% CI, 0.97-1.23]), and sex hormone-binding globulin (HR, 1.07 [95% CI, 0.95-1.21]) were directionally similar but not statistically significant. Conclusions Calculated free testosterone was inversely associated with incident HF, suggesting a contribution of testosterone deficiency to HF incidence among older men. Additional research is necessary to determine whether testosterone replacement therapy might be an effective strategy to lower HF risk in older men.

Published
2022

5. Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author

Temprano‐Sagrera, Gerard, Sitlani, Colleen M, Bone, William P, Martin‐Bornez, Miguel, Voight, Benjamin F, Morrison, Alanna C, Damrauer, Scott M, de Vries, Paul S, Smith, Nicholas L, Sabater‐Lleal, Maria, Dehghan, Abbas, Heath, Adam S, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward‐Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook‐Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank WG, Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Liu, Melissa, Brown, Michael R, Conomos, Matthew P, Jhun, Min‐A, Chen, Ming‐Huei, de Maat, Moniek PM, Pankratz, Nathan, Peyser, Patricia A, Elliot, Paul, Wei, Peng, Wild, Philipp S, Morange, Pierre E, van der Harst, Pim, Yang, Qiong, Le, Ngoc‐Quynh, Marioni, Riccardo, Li, Ruifang, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J Wouter, Guo, Xiuqing, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Turman, Constance, Germain, Marine, MacDonald, James, and Braekkan, Sigrid K

Subjects
Genetics, Biotechnology, Human Genome, Atherosclerosis, Prevention, Cardiovascular, Hematology, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular Diseases, Factor XI, Genetic Predisposition to Disease, Genome-Wide Association Study, Hemostasis, Hemostatics, Humans, Phenotype, Polymorphism, Single Nucleotide, Tissue Plasminogen Activator, blood coagulation, cardiovascular diseases, genetic pleiotropy, genome-wide association study, hemostasis, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract

BackgroundMulti-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.ObjectivesTo discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events.MethodsSummary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10-9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27).ResultsAcross the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes.ConclusionsThe discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Published
2022

6. Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

Author

Stacey, David, Chen, Lingyan, Stanczyk, Paulina J, Howson, Joanna MM, Mason, Amy M, Burgess, Stephen, MacDonald, Stephen, Langdown, Jonathan, McKinney, Harriett, Downes, Kate, Farahi, Neda, Peters, James E, Basu, Saonli, Pankow, James S, Tang, Weihong, Pankratz, Nathan, Sabater-Lleal, Maria, de Vries, Paul S, Smith, Nicholas L, Gelinas, Amy D, Schneider, Daniel J, Janjic, Nebojsa, Samani, Nilesh J, Ye, Shu, Summers, Charlotte, Chilvers, Edwin R, Danesh, John, and Paul, Dirk S

Subjects
Biological Sciences, Genetics, Prevention, Cardiovascular, Atherosclerosis, Hematology, Heart Disease - Coronary Heart Disease, Heart Disease, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Antigens, CD, Crosses, Genetic, Endothelial Cells, Endothelial Protein C Receptor, Humans, Protein C, Receptors, Cell Surface, Thrombosis, Venous Thromboembolism, CHARGE Hemostasis Working Group
Abstract

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte-endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.

Published
2022

7. Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data

Author

Wainschtein, Pierrick, Jain, Deepti, Zheng, Zhili, Cupples, L Adrienne, Shadyab, Aladdin H, McKnight, Barbara, Shoemaker, Benjamin M, Mitchell, Braxton D, Psaty, Bruce M, Kooperberg, Charles, Liu, Ching-Ti, Albert, Christine M, Roden, Dan, Chasman, Daniel I, Darbar, Dawood, Lloyd-Jones, Donald M, Arnett, Donna K, Regan, Elizabeth A, Boerwinkle, Eric, Rotter, Jerome I, O’Connell, Jeffrey R, Yanek, Lisa R, de Andrade, Mariza, Allison, Matthew A, McDonald, Merry-Lynn N, Chung, Mina K, Fornage, Myriam, Chami, Nathalie, Smith, Nicholas L, Ellinor, Patrick T, Vasan, Ramachandran S, Mathias, Rasika A, Loos, Ruth JF, Rich, Stephen S, Lubitz, Steven A, Heckbert, Susan R, Redline, Susan, Guo, Xiuqing, Chen, Y-D Ida, Laurie, Cecelia A, Hernandez, Ryan D, McGarvey, Stephen T, Goddard, Michael E, Laurie, Cathy C, North, Kari E, Lange, Leslie A, Weir, Bruce S, Yengo, Loic, Yang, Jian, and Visscher, Peter M

Subjects
Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Alleles, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Multifactorial Inheritance, Polymorphism, Single Nucleotide, TOPMed Anthropometry Working Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.

Published
2022

8. Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative

Author

Little, Amarise, Hu, Yao, Sun, Quan, Jain, Deepti, Broome, Jai, Chen, Ming-Huei, Thibord, Florian, McHugh, Caitlin, Surendran, Praveen, Blackwell, Thomas W, Brody, Jennifer A, Bhan, Arunoday, Chami, Nathalie, de Vries, Paul S, Ekunwe, Lynette, Heard-Costa, Nancy, Hobbs, Brian D, Manichaikul, Ani, Moon, Jee-Young, Preuss, Michael H, Ryan, Kathleen, Wang, Zhe, Wheeler, Marsha, Yanek, Lisa R, Abecasis, Goncalo R, Almasy, Laura, Beaty, Terri H, Becker, Lewis C, Blangero, John, Boerwinkle, Eric, Butterworth, Adam S, Choquet, Hélène, Correa, Adolfo, Curran, Joanne E, Faraday, Nauder, Fornage, Myriam, Glahn, David C, Hou, Lifang, Jorgenson, Eric, Kooperberg, Charles, Lewis, Joshua P, Lloyd-Jones, Donald M, Loos, Ruth JF, Min, Yuan-I, Mitchell, Braxton D, Morrison, Alanna C, Nickerson, Deborah A, North, Kari E, O'Connell, Jeffrey R, Pankratz, Nathan, Psaty, Bruce M, Vasan, Ramachandran S, Rich, Stephen S, Rotter, Jerome I, Smith, Albert V, Smith, Nicholas L, Tang, Hua, Tracy, Russell P, Conomos, Matthew P, Laurie, Cecelia A, Mathias, Rasika A, Li, Yun, Auer, Paul L, Consortium, NHLBI Trans-Omics for Precision Medicine, Thornton, Timothy, Reiner, Alexander P, Johnson, Andrew D, and Raffield, Laura M

Subjects
Biological Sciences, Genetics, Hematology, Biotechnology, Clinical Research, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Blood Platelets, Genome-Wide Association Study, Humans, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Polymorphism, Single Nucleotide, Precision Medicine, United States, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Medical and Health Sciences, Genetics & Heredity
Abstract

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

Published
2022

9. Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program

Author

Mikhaylova, Anna V, McHugh, Caitlin P, Polfus, Linda M, Raffield, Laura M, Boorgula, Meher Preethi, Blackwell, Thomas W, Brody, Jennifer A, Broome, Jai, Chami, Nathalie, Chen, Ming-Huei, Conomos, Matthew P, Cox, Corey, Curran, Joanne E, Daya, Michelle, Ekunwe, Lynette, Glahn, David C, Heard-Costa, Nancy, Highland, Heather M, Hobbs, Brian D, Ilboudo, Yann, Jain, Deepti, Lange, Leslie A, Miller-Fleming, Tyne W, Min, Nancy, Moon, Jee-Young, Preuss, Michael H, Rosen, Jonathon, Ryan, Kathleen, Smith, Albert V, Sun, Quan, Surendran, Praveen, de Vries, Paul S, Walter, Klaudia, Wang, Zhe, Wheeler, Marsha, Yanek, Lisa R, Zhong, Xue, Abecasis, Goncalo R, Almasy, Laura, Barnes, Kathleen C, Beaty, Terri H, Becker, Lewis C, Blangero, John, Boerwinkle, Eric, Butterworth, Adam S, Chavan, Sameer, Cho, Michael H, Choquet, Hélène, Correa, Adolfo, Cox, Nancy, DeMeo, Dawn L, Faraday, Nauder, Fornage, Myriam, Gerszten, Robert E, Hou, Lifang, Johnson, Andrew D, Jorgenson, Eric, Kaplan, Robert, Kooperberg, Charles, Kundu, Kousik, Laurie, Cecelia A, Lettre, Guillaume, Lewis, Joshua P, Li, Bingshan, Li, Yun, Lloyd-Jones, Donald M, Loos, Ruth JF, Manichaikul, Ani, Meyers, Deborah A, Mitchell, Braxton D, Morrison, Alanna C, Ngo, Debby, Nickerson, Deborah A, Nongmaithem, Suraj, North, Kari E, O’Connell, Jeffrey R, Ortega, Victor E, Pankratz, Nathan, Perry, James A, Psaty, Bruce M, Rich, Stephen S, Soranzo, Nicole, Rotter, Jerome I, Silverman, Edwin K, Smith, Nicholas L, Tang, Hua, Tracy, Russell P, Thornton, Timothy A, Vasan, Ramachandran S, Zein, Joe, Mathias, Rasika A, Consortium, NHLBI Trans-Omics for Precision Medicine, Reiner, Alexander P, and Auer, Paul L

Subjects
Human Genome, Genetics, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, Asthma, Biomarkers, Dermatitis, Atopic, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Leukocytes, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Polymorphism, Single Nucleotide, Prognosis, Proteome, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, United Kingdom, United States, Whole Genome Sequencing, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, blood-cell counts, whole-genome sequencing, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

Published
2021

10. FGL1 as a modulator of plasma D‐dimer levels: Exome‐wide marker analysis of plasma tPA, PAI‐1, and D‐dimer

Author

Thibord, Florian, Song, Ci, Pattee, Jack, Rodriguez, Benjamin AT, Chen, Ming‐Huei, O’Donnell, Christopher J, Kleber, Marcus E, Delgado, Graciela E, Guo, Xiuqing, Yao, Jie, Taylor, Kent D, Ozel, Ayse Bilge, Brody, Jennifer A, McKnight, Barbara, Gyorgy, Beata, Simonsick, Eleanor, Leonard, Hampton L, Carrasquilla, Germán D, Guindo‐Martinez, Marta, Silveira, Angela, Temprano‐Sagrera, Gerard, Yanek, Lisa R, Becker, Diane M, Mathias, Rasika A, Becker, Lewis C, Raffield, Laura M, Kilpeläinen, Tuomas O, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Hamsten, Anders, Watkins, Hugh, Sabater‐Lleal, Maria, Nalls, Mike A, Trégouët, David‐Alexandre, Morange, Pierre‐Emmanuel, Psaty, Bruce M, Tracy, Russel P, Smith, Nicholas L, Desch, Karl C, Cushman, Mary, Rotter, Jerome I, de Vries, Paul S, Pankratz, Nathan D, Folsom, Aaron R, Morrison, Alanna C, März, Winfried, Tang, Weihong, and Johnson, Andrew D

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Clinical Research, Hematology, Genetics, Human Genome, Prevention, Exome, Fibrin Fibrinogen Degradation Products, Fibrinogen, Fibrinolysis, Humans, Plasminogen Activator Inhibitor 1, Tissue Plasminogen Activator, computational biology, exome, fibrinogen, fibrinolysis, genetic association study, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundUse of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.ObjectivesWe sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.MethodsCohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.ResultsFive variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P

Published
2021

11. Robust, flexible, and scalable tests for Hardy-Weinberg Equilibrium across diverse ancestries

Author

Kwong, Alan M, Blackwell, Thomas W, LeFaive, Jonathon, de Andrade, Mariza, Barnard, John, Barnes, Kathleen C, Blangero, John, Boerwinkle, Eric, Burchard, Esteban G, Cade, Brian E, Chasman, Daniel I, Chen, Han, Conomos, Matthew P, Cupples, L Adrienne, Ellinor, Patrick T, Eng, Celeste, Gao, Yan, Guo, Xiuqing, Irvin, Marguerite Ryan, Kelly, Tanika N, Kim, Wonji, Kooperberg, Charles, Lubitz, Steven A, Mak, Angel CY, Manichaikul, Ani W, Mathias, Rasika A, Montasser, May E, Montgomery, Courtney G, Musani, Solomon, Palmer, Nicholette D, Peloso, Gina M, Qiao, Dandi, Reiner, Alexander P, Roden, Dan M, Shoemaker, M Benjamin, Smith, Jennifer A, Smith, Nicholas L, Su, Jessica Lasky, Tiwari, Hemant K, Weeks, Daniel E, Weiss, Scott T, Consortium, TOPMed Analysis Working Group NHLBI Trans-Omics for Precision Medicine, Scott, Laura J, Smith, Albert V, Abecasis, Gonçalo R, Boehnke, Michael, and Kang, Hyun Min

Subjects
Genetics, Alleles, Gene Frequency, Genetics, Population, Genotype, Humans, Linkage Disequilibrium, Models, Genetic, Models, Statistical, Phenotype, Software, population structure, principal components analysis, next-generation sequencing, genotype likelihoods, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Analysis Working Group, Developmental Biology
Abstract

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

Published
2021

12. Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program

Author

Hu, Yao, Stilp, Adrienne M, McHugh, Caitlin P, Rao, Shuquan, Jain, Deepti, Zheng, Xiuwen, Lane, John, de Bellefon, Sébastian Méric, Raffield, Laura M, Chen, Ming-Huei, Yanek, Lisa R, Wheeler, Marsha, Yao, Yao, Ren, Chunyan, Broome, Jai, Moon, Jee-Young, de Vries, Paul S, Hobbs, Brian D, Sun, Quan, Surendran, Praveen, Brody, Jennifer A, Blackwell, Thomas W, Choquet, Hélène, Ryan, Kathleen, Duggirala, Ravindranath, Heard-Costa, Nancy, Wang, Zhe, Chami, Nathalie, Preuss, Michael H, Min, Nancy, Ekunwe, Lynette, Lange, Leslie A, Cushman, Mary, Faraday, Nauder, Curran, Joanne E, Almasy, Laura, Kundu, Kousik, Smith, Albert V, Gabriel, Stacey, Rotter, Jerome I, Fornage, Myriam, Lloyd-Jones, Donald M, Vasan, Ramachandran S, Smith, Nicholas L, North, Kari E, Boerwinkle, Eric, Becker, Lewis C, Lewis, Joshua P, Abecasis, Goncalo R, Hou, Lifang, O’Connell, Jeffrey R, Morrison, Alanna C, Beaty, Terri H, Kaplan, Robert, Correa, Adolfo, Blangero, John, Jorgenson, Eric, Psaty, Bruce M, Kooperberg, Charles, Walton, Russell T, Kleinstiver, Benjamin P, Tang, Hua, Loos, Ruth JF, Soranzo, Nicole, Butterworth, Adam S, Nickerson, Debbie, Rich, Stephen S, Mitchell, Braxton D, Johnson, Andrew D, Auer, Paul L, Li, Yun, Mathias, Rasika A, Lettre, Guillaume, Pankratz, Nathan, Laurie, Cathy C, Laurie, Cecelia A, Bauer, Daniel E, Conomos, Matthew P, Reiner, Alexander P, and Consortium, NHLBI Trans-Omics for Precision Medicine

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Biotechnology, Clinical Research, Hematology, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Aged, Chromosomes, Human, Pair 16, Datasets as Topic, Erythrocytes, Female, Gene Editing, Genetic Variation, Genome-Wide Association Study, HEK293 Cells, Humans, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Quality Control, Reproducibility of Results, United States, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, base editing, red blood cell traits, whole-genome sequencing, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

Published
2021

13. Genome-wide analysis identifies novel susceptibility loci for myocardial infarction

Author

Hartiala, Jaana A, Han, Yi, Jia, Qiong, Hilser, James R, Huang, Pin, Gukasyan, Janet, Schwartzman, William S, Cai, Zhiheng, Biswas, Subarna, Trégouët, David-Alexandre, Smith, Nicholas L, Consortium, The INVENT, Group, The CHARGE Consortium Hemostasis Working, Consortium, The GENIUS-CHD, Seldin, Marcus, Pan, Calvin, Mehrabian, Margarete, Lusis, Aldons J, Bazeley, Peter, Sun, Yan V, Liu, Chang, Quyyumi, Arshed A, Scholz, Markus, Thiery, Joachim, Delgado, Graciela E, Kleber, Marcus E, März, Winfried, Howe, Laurence J, Asselbergs, Folkert W, van Vugt, Marion, Vlachojannis, Georgios J, Patel, Riyaz S, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Lehtimäki, Terho, Nieminen, Tuomo VM, Kuukasjärvi, Pekka, Laurikka, Jari O, Chang, Xuling, Heng, Chew-Kiat, Jiang, Rong, Kraus, William E, Hauser, Elizabeth R, Ferguson, Jane F, Reilly, Muredach P, Ito, Kaoru, Koyama, Satoshi, Kamatani, Yoichiro, Komuro, Issei, Japan, Biobank, Stolze, Lindsey K, Romanoski, Casey E, Khan, Mohammad Daud, Turner, Adam W, Miller, Clint L, Aherrahrou, Redouane, Civelek, Mete, Ma, Lijiang, Björkegren, Johan LM, Kumar, S Ram, Tang, WH Wilson, Hazen, Stanley L, and Allayee, Hooman

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Cardiovascular, Heart Disease, Clinical Research, Heart Disease - Coronary Heart Disease, Human Genome, Genetics, Aging, Atherosclerosis, Aetiology, 2.1 Biological and endogenous factors, Coronary Artery Disease, Endothelial Cells, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Japan, Myocardial Infarction, Polymorphism, Single Nucleotide, Risk Factors, Myocardial infarction, Genetic factors, Genome-wide association study, Meta-analysis, SLC44A3, INVENT Consortium, CHARGE Consortium Hemostasis Working Group, GENIUS-CHD Consortium, Biobank Japan, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

AimsWhile most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation.Methods and resultsWe carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro.ConclusionsA large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

Published
2021

14. Inherited causes of clonal haematopoiesis in 97,691 whole genomes

Author

Bick, Alexander G, Weinstock, Joshua S, Nandakumar, Satish K, Fulco, Charles P, Bao, Erik L, Zekavat, Seyedeh M, Szeto, Mindy D, Liao, Xiaotian, Leventhal, Matthew J, Nasser, Joseph, Chang, Kyle, Laurie, Cecelia, Burugula, Bala Bharathi, Gibson, Christopher J, Niroula, Abhishek, Lin, Amy E, Taub, Margaret A, Aguet, Francois, Ardlie, Kristin, Mitchell, Braxton D, Barnes, Kathleen C, Moscati, Arden, Fornage, Myriam, Redline, Susan, Psaty, Bruce M, Silverman, Edwin K, Weiss, Scott T, Palmer, Nicholette D, Vasan, Ramachandran S, Burchard, Esteban G, Kardia, Sharon LR, He, Jiang, Kaplan, Robert C, Smith, Nicholas L, Arnett, Donna K, Schwartz, David A, Correa, Adolfo, de Andrade, Mariza, Guo, Xiuqing, Konkle, Barbara A, Custer, Brian, Peralta, Juan M, Gui, Hongsheng, Meyers, Deborah A, McGarvey, Stephen T, Chen, Ida Yii-Der, Shoemaker, M Benjamin, Peyser, Patricia A, Broome, Jai G, Gogarten, Stephanie M, Wang, Fei Fei, Wong, Quenna, Montasser, May E, Daya, Michelle, Kenny, Eimear E, North, Kari E, Launer, Lenore J, Cade, Brian E, Bis, Joshua C, Cho, Michael H, Lasky-Su, Jessica, Bowden, Donald W, Cupples, L Adrienne, Mak, Angel CY, Becker, Lewis C, Smith, Jennifer A, Kelly, Tanika N, Aslibekyan, Stella, Heckbert, Susan R, Tiwari, Hemant K, Yang, Ivana V, Heit, John A, Lubitz, Steven A, Johnsen, Jill M, Curran, Joanne E, Wenzel, Sally E, Weeks, Daniel E, Rao, Dabeeru C, Darbar, Dawood, Moon, Jee-Young, Tracy, Russell P, Buth, Erin J, Rafaels, Nicholas, Loos, Ruth JF, Durda, Peter, Liu, Yongmei, Hou, Lifang, Lee, Jiwon, Kachroo, Priyadarshini, Freedman, Barry I, Levy, Daniel, Bielak, Lawrence F, Hixson, James E, Floyd, James S, Whitsel, Eric A, Ellinor, Patrick T, Irvin, Marguerite R, Fingerlin, Tasha E, Raffield, Laura M, and Armasu, Sebastian M

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Biotechnology, Regenerative Medicine, Stem Cell Research, Human Genome, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Cardiovascular, Generic health relevance, Inflammatory and immune system, Good Health and Well Being, Adult, Africa, Aged, Aged, 80 and over, Black People, Cell Self Renewal, Clonal Hematopoiesis, DNA-Binding Proteins, Dioxygenases, Female, Genetic Predisposition to Disease, Genome, Human, Germ-Line Mutation, Hematopoietic Stem Cells, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Precision Medicine, Proto-Oncogene Proteins, Tripartite Motif Proteins, United States, Whole Genome Sequencing, alpha Karyopherins, NHLBI Trans-Omics for Precision Medicine Consortium, General Science & Technology
Abstract

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Published
2020

15. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Regeneron Genetics Center, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, and Stott, David J

Subjects
Regeneron Genetics Center, Humans, Atrial Fibrillation, Cardiomyopathies, Microfilament Proteins, Adaptor Proteins, Signal Transducing, Carrier Proteins, Muscle Proteins, Risk Factors, Case-Control Studies, Ventricular Function, Left, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Coronary Artery Disease, Heart Failure, Genome-Wide Association Study, Mendelian Randomization Analysis, Adaptor Proteins, Signal Transducing, Ventricular Function, Left
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Published
2020

16. Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.

Author

Kowalski, Madeline H, Qian, Huijun, Hou, Ziyi, Rosen, Jonathan D, Tapia, Amanda L, Shan, Yue, Jain, Deepti, Argos, Maria, Arnett, Donna K, Avery, Christy, Barnes, Kathleen C, Becker, Lewis C, Bien, Stephanie A, Bis, Joshua C, Blangero, John, Boerwinkle, Eric, Bowden, Donald W, Buyske, Steve, Cai, Jianwen, Cho, Michael H, Choi, Seung Hoan, Choquet, Hélène, Cupples, L Adrienne, Cushman, Mary, Daya, Michelle, de Vries, Paul S, Ellinor, Patrick T, Faraday, Nauder, Fornage, Myriam, Gabriel, Stacey, Ganesh, Santhi K, Graff, Misa, Gupta, Namrata, He, Jiang, Heckbert, Susan R, Hidalgo, Bertha, Hodonsky, Chani J, Irvin, Marguerite R, Johnson, Andrew D, Jorgenson, Eric, Kaplan, Robert, Kardia, Sharon LR, Kelly, Tanika N, Kooperberg, Charles, Lasky-Su, Jessica A, Loos, Ruth JF, Lubitz, Steven A, Mathias, Rasika A, McHugh, Caitlin P, Montgomery, Courtney, Moon, Jee-Young, Morrison, Alanna C, Palmer, Nicholette D, Pankratz, Nathan, Papanicolaou, George J, Peralta, Juan M, Peyser, Patricia A, Rich, Stephen S, Rotter, Jerome I, Silverman, Edwin K, Smith, Jennifer A, Smith, Nicholas L, Taylor, Kent D, Thornton, Timothy A, Tiwari, Hemant K, Tracy, Russell P, Wang, Tao, Weiss, Scott T, Weng, Lu-Chen, Wiggins, Kerri L, Wilson, James G, Yanek, Lisa R, Zöllner, Sebastian, North, Kari E, Auer, Paul L, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology & Hemostasis Working Group, Raffield, Laura M, Reiner, Alexander P, and Li, Yun

Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology & Hemostasis Working Group, Humans, Genetic Predisposition to Disease, Computational Biology, Genetics, Population, Gene Frequency, Linkage Disequilibrium, Databases, Genetic, Adult, Aged, Aged, 80 and over, Middle Aged, African Americans, Hispanic Americans, United States, Female, Male, Genome-Wide Association Study, beta-Globins, Genotyping Techniques, Precision Medicine, Whole Genome Sequencing, Genetics, Population, Databases, Genetic, and over, Developmental Biology
Abstract

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.

Published
2019

17. A large‐scale exome array analysis of venous thromboembolism

Author

Lindström, Sara, Brody, Jennifer A, Turman, Constance, Germain, Marine, Bartz, Traci M, Smith, Erin N, Chen, Ming‐Huei, Puurunen, Marja, Chasman, Daniel, Hassler, Jeffrey, Pankratz, Nathan, Basu, Saonli, Guan, Weihua, Gyorgy, Beata, Ibrahim, Manal, Empana, Jean‐Philippe, Olaso, Robert, Jackson, Rebecca, Brækkan, Sigrid K, McKnight, Barbara, Deleuze, Jean‐Francois, O’Donnell, Cristopher J, Jouven, Xavier, Frazer, Kelly A, Psaty, Bruce M, Wiggins, Kerri L, Taylor, Kent, Reiner, Alexander P, Heckbert, Susan R, Kooperberg, Charles, Ridker, Paul, Hansen, John‐Bjarne, Tang, Weihong, Johnson, Andrew D, Morange, Pierre‐Emmanuel, Trégouët, David A, Kraft, Peter, Smith, Nicholas L, Kabrhel, Christopher, and Consortium, on behalf of the INVENT

Subjects
Prevention, Clinical Research, Biotechnology, Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Black or African American, Alleles, Case-Control Studies, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, High-Throughput Nucleotide Sequencing, Humans, Male, Microarray Analysis, Odds Ratio, Polymorphism, Single Nucleotide, Sample Size, Venous Thromboembolism, exome, genetic association, venous thromboembolism, INVENT Consortium, Public Health and Health Services, Epidemiology
Abstract

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.

Published
2019

18. Efficient Variant Set Mixed Model Association Tests for Continuous and Binary Traits in Large-Scale Whole-Genome Sequencing Studies

Author

Chen, Han, Huffman, Jennifer E, Brody, Jennifer A, Wang, Chaolong, Lee, Seunggeun, Li, Zilin, Gogarten, Stephanie M, Sofer, Tamar, Bielak, Lawrence F, Bis, Joshua C, Blangero, John, Bowler, Russell P, Cade, Brian E, Cho, Michael H, Correa, Adolfo, Curran, Joanne E, de Vries, Paul S, Glahn, David C, Guo, Xiuqing, Johnson, Andrew D, Kardia, Sharon, Kooperberg, Charles, Lewis, Joshua P, Liu, Xiaoming, Mathias, Rasika A, Mitchell, Braxton D, O’Connell, Jeffrey R, Peyser, Patricia A, Post, Wendy S, Reiner, Alex P, Rich, Stephen S, Rotter, Jerome I, Silverman, Edwin K, Smith, Jennifer A, Vasan, Ramachandran S, Wilson, James G, Yanek, Lisa R, Consortium, NHLBI Trans-Omics for Precision Medicine, Group, TOPMed Hematology and Hemostasis Working, Redline, Susan, Smith, Nicholas L, Boerwinkle, Eric, Borecki, Ingrid B, Cupples, L Adrienne, Laurie, Cathy C, Morrison, Alanna C, Rice, Kenneth M, and Lin, Xihong

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Biotechnology, Aetiology, 2.5 Research design and methodologies (aetiology), Generic health relevance, Good Health and Well Being, Chromosomes, Human, Pair 4, Cloud Computing, Female, Fibrinogen, Genetic Association Studies, Genetics, Population, Humans, Male, Models, Genetic, National Heart, Lung, and Blood Institute (U.S.), Precision Medicine, Research Design, Time Factors, United States, Whole Genome Sequencing, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed, generalized linear mixed model, population structure, rare variants, relatedness, variant set association test, whole-genome sequencing, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.

Published
2019

19. Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels

Author

Sabater-Lleal, Maria, Huffman, Jennifer E, de Vries, Paul S, Marten, Jonathan, Mastrangelo, Michael A, Song, Ci, Pankratz, Nathan, Ward-Caviness, Cavin K, Yanek, Lisa R, Trompet, Stella, Delgado, Graciela E, Guo, Xiuqing, Bartz, Traci M, Martinez-Perez, Angel, Germain, Marine, de Haan, Hugoline G, Ozel, Ayse B, Polasek, Ozren, Smith, Albert V, Eicher, John D, Reiner, Alex P, Tang, Weihong, Davies, Neil M, Stott, David J, Rotter, Jerome I, Tofler, Geoffrey H, Boerwinkle, Eric, de Maat, Moniek PM, Kleber, Marcus E, Welsh, Paul, Brody, Jennifer A, Chen, Ming-Huei, Vaidya, Dhananjay, Soria, José Manuel, Suchon, Pierre, van Hylckama Vlieg, Astrid, Desch, Karl C, Kolcic, Ivana, Joshi, Peter K, Launer, Lenore J, Harris, Tamara B, Campbell, Harry, Rudan, Igor, Becker, Diane M, Li, Jun Z, Rivadeneira, Fernando, Uitterlinden, André G, Hofman, Albert, Franco, Oscar H, Cushman, Mary, Psaty, Bruce M, Morange, Pierre-Emmanuel, McKnight, Barbara, Chong, Michael R, Fernandez-Cadenas, Israel, Rosand, Jonathan, Lindgren, Arne, Consortium, INVENT Consortium MEGASTROKE Consortium of the International Stroke Genetics, Gudnason, Vilmundur, Wilson, James F, Hayward, Caroline, Ginsburg, David, Fornage, Myriam, Rosendaal, Frits R, Souto, Juan Carlos, Becker, Lewis C, Jenny, Nancy S, März, Winfried, Jukema, J Wouter, Dehghan, Abbas, Trégouët, David-Alexandre, Morrison, Alanna C, Johnson, Andrew D, O’Donnell, Christopher J, Strachan, David P, Lowenstein, Charles J, and Smith, Nicholas L

Subjects
Epidemiology, Health Sciences, Hematology, Biotechnology, Rare Diseases, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Blood, Cardiovascular, Arterial Occlusive Diseases, Biomarkers, Blood Coagulation, Blood Coagulation Disorders, Inherited, Factor VIII, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Phenotype, Ribosomal Protein L3, Risk Factors, Venous Thrombosis, von Willebrand Factor, cardiovascular diseases, factor VIII, genome-wide association studies, genetics, risk factors, von Willebrand factor, INVENT Consortium, MEGASTROKE Consortium of the International Stroke Genetics Consortium, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences, Sports science and exercise
Abstract

BackgroundFactor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.MethodsWe meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.ResultsWe identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.ConclusionsThe meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

Published
2019

20. Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease

Author

Ward-Caviness, Cavin K, de Vries, Paul S, Wiggins, Kerri L, Huffman, Jennifer E, Yanek, Lisa R, Bielak, Lawrence F, Giulianini, Franco, Guo, Xiuqing, Kleber, Marcus E, Kacprowski, Tim, Groß, Stefan, Petersman, Astrid, Smith, George Davey, Hartwig, Fernando P, Bowden, Jack, Hemani, Gibran, Müller-Nuraysid, Martina, Strauch, Konstantin, Koenig, Wolfgang, Waldenberger, Melanie, Meitinger, Thomas, Pankratz, Nathan, Boerwinkle, Eric, Tang, Weihong, Fu, Yi-Ping, Johnson, Andrew D, Song, Ci, de Maat, Moniek PM, Uitterlinden, André G, Franco, Oscar H, Brody, Jennifer A, McKnight, Barbara, Chen, Yii-Der Ida, Psaty, Bruce M, Mathias, Rasika A, Becker, Diane M, Peyser, Patricia A, Smith, Jennifer A, Bielinski, Suzette J, Ridker, Paul M, Taylor, Kent D, Yao, Jie, Tracy, Russell, Delgado, Graciela, Trompet, Stella, Sattar, Naveed, Jukema, J Wouter, Becker, Lewis C, Kardia, Sharon LR, Rotter, Jerome I, März, Winfried, Dörr, Marcus, Chasman, Daniel I, Dehghan, Abbas, O’Donnell, Christopher J, Smith, Nicholas L, Peters, Annette, and Morrison, Alanna C

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Heart Disease, Cardiovascular, Prevention, Human Genome, Heart Disease - Coronary Heart Disease, Alleles, Coronary Disease, Fibrinogen, Genetic Pleiotropy, Genetic Variation, Genome-Wide Association Study, Humans, Incidence, Mendelian Randomization Analysis, Models, Genetic, Multivariate Analysis, Myocardial Infarction, Odds Ratio, General Science & Technology
Abstract

BackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.Methods and findingsWe evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.ConclusionsA small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

Published
2019

21. Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.

Author

Suri, Pradeep, Palmer, Melody R, Tsepilov, Yakov A, Freidin, Maxim B, Boer, Cindy G, Yau, Michelle S, Evans, Daniel S, Gelemanovic, Andrea, Bartz, Traci M, Nethander, Maria, Arbeeva, Liubov, Karssen, Lennart, Neogi, Tuhina, Campbell, Archie, Mellstrom, Dan, Ohlsson, Claes, Marshall, Lynn M, Orwoll, Eric, Uitterlinden, Andre, Rotter, Jerome I, Lauc, Gordan, Psaty, Bruce M, Karlsson, Magnus K, Lane, Nancy E, Jarvik, Gail P, Polasek, Ozren, Hochberg, Marc, Jordan, Joanne M, Van Meurs, Joyce BJ, Jackson, Rebecca, Nielson, Carrie M, Mitchell, Braxton D, Smith, Blair H, Hayward, Caroline, Smith, Nicholas L, Aulchenko, Yurii S, and Williams, Frances MK

Subjects
Humans, Back Pain, Intracellular Signaling Peptides and Proteins, DNA-Binding Proteins, Polymorphism, Single Nucleotide, Introns, European Continental Ancestry Group, Genome-Wide Association Study, SOXD Transcription Factors, Genetic Loci, Chronic Pain, Biomarkers, Tumor, DCC Receptor, Polymorphism, Single Nucleotide, Biomarkers, Tumor, Human Genome, Genetics, Aging, Pain Research, 2.1 Biological and endogenous factors, Developmental Biology
Abstract

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p

Published
2018

22. Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

Author

Song, Ci, Burgess, Stephen, Eicher, John D, O'Donnell, Christopher J, Johnson, Andrew D, Huang, Jie, Sabater‐Lleal, Maria, Asselbergs, Folkert W, Tregouet, David, Shin, So‐Youn, Ding, Jingzhong, Baumert, Jens, Oudot‐Mellakh, Tiphaine, Folkersen, Lasse, Smith, Nicholas L, Williams, Scott M, Ikram, Mohammad A, Kleber, Marcus E, Becker, Diane M, Truong, Vinh, Mychaleckyj, Josyf C, Tang, Weihong, Yang, Qiong, Sennblad, Bengt, Moore, Jason H, Williams, Frances MK, Dehghan, Abbas, Silbernagel, Günther, Schrijvers, Elisabeth MC, Smith, Shelly, Karakas, Mahir, Tofler, Geoffrey H, Silveira, Angela, Navis, Gerjan J, Lohman, Kurt, Chen, Ming‐Huei, Peters, Annette, Goel, Anuj, Hopewell, Jemma C, Chambers, John C, Saleheen, Danish, Lundmark, Per, Psaty, Bruce M, Strawbridge, Rona J, Boehm, Bernhard O, Carter, Angela M, Meisinger, Christa, Peden, John F, Bis, Joshua C, McKnight, Barbara, Öhrvik, John, Taylor, Kent, Franzosi, Maria Grazia, Seedorf, Udo, Collins, Rory, Franco‐Cereceda, Anders, Syvänen, Ann‐Christine, Goodall, Alison H, Yanek, Lisa R, Cushman, Mary, Müller‐Nurasyid, Martina, Folsom, Aaron R, Basu, Saonli, Matijevic, Nena, van Gilst, Wiek H, Kooner, Jaspal S, Hofman, Albert, Danesh, John, Clarke, Robert, Meigs, James B, Kathiresan, Sekar, Reilly, Muredach P, Klopp, Norman, Harris, Tamara B, Winkelmann, Bernhard R, Grant, Peter J, Hillege, Hans L, Watkins, Hugh, Spector, Timothy D, Becker, Lewis C, Tracy, Russell P, März, Winfried, Uitterlinden, Andre G, Eriksson, Per, Cambien, Francois, Morange, Pierre‐Emmanuel, Koenig, Wolfgang, Soranzo, Nicole, van der Harst, Pim, Liu, Yongmei, Hamsten, Anders, Ehret, Georg B, Munroe, Patricia B, Rice, Kenneth M, Bochud, Murielle, Chasman, Daniel I, Smith, Albert V, Tobin, Martin D, and Verwoert, Germaine C

Subjects
Clinical Research, Heart Disease - Coronary Heart Disease, Cardiovascular, Heart Disease, Aging, Biomarkers, Blood Glucose, Coronary Disease, Fibrinolysis, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Incidence, Lipoproteins, HDL, Mendelian Randomization Analysis, Multivariate Analysis, Observational Studies as Topic, Odds Ratio, Plasminogen Activator Inhibitor 1, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, coronary heart disease, genome-wide association study, Mendelian randomization, plasminogen activator inhibitor type 1, single nucleotide polymorphism, genome‐wide association study, Cardiorespiratory Medicine and Haematology
Abstract

Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.

Published
2017

23. Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology

Author

Brody, Jennifer A, Morrison, Alanna C, Bis, Joshua C, O'Connell, Jeffrey R, Brown, Michael R, Huffman, Jennifer E, Ames, Darren C, Carroll, Andrew, Conomos, Matthew P, Gabriel, Stacey, Gibbs, Richard A, Gogarten, Stephanie M, Gupta, Namrata, Jaquish, Cashell E, Johnson, Andrew D, Lewis, Joshua P, Liu, Xiaoming, Manning, Alisa K, Papanicolaou, George J, Pitsillides, Achilleas N, Rice, Kenneth M, Salerno, William, Sitlani, Colleen M, Smith, Nicholas L, Heckbert, Susan R, Laurie, Cathy C, Mitchell, Braxton D, Vasan, Ramachandran S, Rich, Stephen S, Rotter, Jerome I, Wilson, James G, Boerwinkle, Eric, Psaty, Bruce M, and Cupples, L Adrienne

Subjects
Biological Sciences, Genetics, Biotechnology, Networking and Information Technology R&D (NITRD), Lung, Human Genome, 2.5 Research design and methodologies (aetiology), Aetiology, Generic health relevance, Good Health and Well Being, Big Data, Fibrinogen, Genetics, Population, Genome, Humans, Information Dissemination, Mobile Applications, Molecular Epidemiology, Regression Analysis, Software, Workflow, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, TOPMed Hematology and Hemostasis Working Group, CHARGE Analysis and Bioinformatics Working Group, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The exploding volume of whole-genome sequence (WGS) and multi-omics data requires new approaches for analysis. As one solution, we have created a cloud-based Analysis Commons, which brings together genotype and phenotype data from multiple studies in a setting that is accessible by multiple investigators. This framework addresses many of the challenges of multi-center WGS analyses, including data sharing mechanisms, phenotype harmonization, integrated multi-omics analyses, annotation, and computational flexibility. In this setting, the computational pipeline facilitates a sequence-to-discovery analysis workflow illustrated here by an analysis of plasma fibrinogen levels in 3996 individuals from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) WGS program. The Analysis Commons represents a novel model for transforming WGS resources from a massive quantity of phenotypic and genomic data into knowledge of the determinants of health and disease risk in diverse human populations.

Published
2017

24. Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

Author

Wild, Philipp S, Felix, Janine F, Schillert, Arne, Teumer, Alexander, Chen, Ming-Huei, Leening, Maarten JG, Völker, Uwe, Großmann, Vera, Brody, Jennifer A, Irvin, Marguerite R, Shah, Sanjiv J, Pramana, Setia, Lieb, Wolfgang, Schmidt, Reinhold, Stanton, Alice V, Malzahn, Dörthe, Smith, Albert Vernon, Sundström, Johan, Minelli, Cosetta, Ruggiero, Daniela, Lyytikäinen, Leo-Pekka, Tiller, Daniel, Smith, J Gustav, Monnereau, Claire, Di Tullio, Marco R, Musani, Solomon K, Morrison, Alanna C, Pers, Tune H, Morley, Michael, Kleber, Marcus E, Aragam, Jayashri, Benjamin, Emelia J, Bis, Joshua C, Bisping, Egbert, Broeckel, Ulrich, Cheng, Susan, Deckers, Jaap W, Del Greco M, Fabiola, Edelmann, Frank, Fornage, Myriam, Franke, Lude, Friedrich, Nele, Harris, Tamara B, Hofer, Edith, Hofman, Albert, Huang, Jie, Hughes, Alun D, Kähönen, Mika, investigators, KNHI, Kruppa, Jochen, Lackner, Karl J, Lannfelt, Lars, Laskowski, Rafael, Launer, Lenore J, Leosdottir, Margrét, Lin, Honghuang, Lindgren, Cecilia M, Loley, Christina, MacRae, Calum A, Mascalzoni, Deborah, Mayet, Jamil, Medenwald, Daniel, Morris, Andrew P, Müller, Christian, Müller-Nurasyid, Martina, Nappo, Stefania, Nilsson, Peter M, Nuding, Sebastian, Nutile, Teresa, Peters, Annette, Pfeufer, Arne, Pietzner, Diana, Pramstaller, Peter P, Raitakari, Olli T, Rice, Kenneth M, Rivadeneira, Fernando, Rotter, Jerome I, Ruohonen, Saku T, Sacco, Ralph L, Samdarshi, Tandaw E, Schmidt, Helena, Sharp, Andrew SP, Shields, Denis C, Sorice, Rossella, Sotoodehnia, Nona, Stricker, Bruno H, Surendran, Praveen, Thom, Simon, Töglhofer, Anna M, Uitterlinden, André G, Wachter, Rolf, Völzke, Henry, Ziegler, Andreas, Münzel, Thomas, März, Winfried, Cappola, Thomas P, Hirschhorn, Joel N, Mitchell, Gary F, Smith, Nicholas L, and Fox, Ervin R

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Clinical Research, Prevention, Heart Disease, Cardiovascular, 2.1 Biological and endogenous factors, Aetiology, Female, Genetic Loci, Genome-Wide Association Study, Heart Diseases, Humans, Male, Myocardium, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundUnderstanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.MethodsA GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.ResultsThe discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.ConclusionThe additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.FundingFor detailed information per study, see Acknowledgments.

Published
2017

25. The cross-sectional association between vasomotor symptoms and hemostatic parameter levels in postmenopausal women

Author

Harrington, Laura B, Blondon, Marc, Cushman, Mary, Kaunitz, Andrew M, Rossouw, Jacques E, Allison, Matthew A, Martin, Lisa W, Johnson, Karen C, Rosing, Jan, Woods, Nancy F, LaCroix, Andrea Z, Heckbert, Susan R, McKnight, Barbara, and Smith, Nicholas L

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Cardiovascular, Hematology, Aging, Contraception/Reproduction, Aged, Antigens, Antithrombin Proteins, Cross-Sectional Studies, Female, Fibrin Fibrinogen Degradation Products, Hemostasis, Hot Flashes, Humans, Lipoproteins, Middle Aged, Plasminogen Activator Inhibitor 1, Postmenopause, Protein C, Protein S, Severity of Illness Index, Sweating, Symptom Assessment, Thrombin, Epidemiology, Hot flashes, Menopause, Medical and Health Sciences, Obstetrics & Reproductive Medicine, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

ObjectiveVasomotor symptoms (VMS) may be a marker of cardiovascular risk. We aimed to evaluate the cross-sectional association of VMS presence and severity with hemostatic parameter levels measured at baseline among Women's Health Initiative (WHI) Hormone Therapy trial postmenopausal participants.MethodsThis cross-sectional analysis included 2,148 postmenopausal women with measures of VMS presence and severity reported in the 4 weeks before WHI baseline, who were not using warfarin or hormone therapy and for whom the following baseline hemostatic parameters were measured within the WHI Cardiovascular Disease Biomarker Case-Control Study: antithrombin, plasminogen activator inhibitor-1, protein C antigen, total and free protein S antigen, total and free tissue factor pathway inhibitor, D-dimer, normalized activated protein C sensitivity ratio, and thrombin generation. Using multiple linear regression, we estimated the adjusted average difference in each hemostatic parameter associated with VMS presence and severity. A multiple comparisons-corrected P value was computed using the P-min procedure to determine statistical significance of our smallest observed P value.ResultsWomen were 67 years of age on average and 33% reported VMS presence at baseline. There was some suggestion that VMS presence may be associated with a -0.34 adjusted difference in normalized activated protein C sensitivity ratio compared with no VMS (95% CI, -0.60 to -0.087; P = 0.009), but this association was not significant after correction for multiple comparisons (P = 0.073). VMS presence or severity was not significantly associated with the other hemostatic parameters.ConclusionsWe found no convincing evidence that VMS presence or severity was associated with levels of hemostatic parameters among postmenopausal women.

Published
2017

26. Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study

Author

de Vries, Paul S, Sabater-Lleal, Maria, Chasman, Daniel I, Trompet, Stella, Ahluwalia, Tarunveer S, Teumer, Alexander, Kleber, Marcus E, Chen, Ming-Huei, Wang, Jie Jin, Attia, John R, Marioni, Riccardo E, Steri, Maristella, Weng, Lu-Chen, Pool, Rene, Grossmann, Vera, Brody, Jennifer A, Venturini, Cristina, Tanaka, Toshiko, Rose, Lynda M, Oldmeadow, Christopher, Mazur, Johanna, Basu, Saonli, Frånberg, Mattias, Yang, Qiong, Ligthart, Symen, Hottenga, Jouke J, Rumley, Ann, Mulas, Antonella, de Craen, Anton JM, Grotevendt, Anne, Taylor, Kent D, Delgado, Graciela E, Kifley, Annette, Lopez, Lorna M, Berentzen, Tina L, Mangino, Massimo, Bandinelli, Stefania, Morrison, Alanna C, Hamsten, Anders, Tofler, Geoffrey, de Maat, Moniek PM, Draisma, Harmen HM, Lowe, Gordon D, Zoledziewska, Magdalena, Sattar, Naveed, Lackner, Karl J, Völker, Uwe, McKnight, Barbara, Huang, Jie, Holliday, Elizabeth G, McEvoy, Mark A, Starr, John M, Hysi, Pirro G, Hernandez, Dena G, Guan, Weihua, Rivadeneira, Fernando, McArdle, Wendy L, Slagboom, P Eline, Zeller, Tanja, Psaty, Bruce M, Uitterlinden, André G, de Geus, Eco JC, Stott, David J, Binder, Harald, Hofman, Albert, Franco, Oscar H, Rotter, Jerome I, Ferrucci, Luigi, Spector, Tim D, Deary, Ian J, März, Winfried, Greinacher, Andreas, Wild, Philipp S, Cucca, Francesco, Boomsma, Dorret I, Watkins, Hugh, Tang, Weihong, Ridker, Paul M, Jukema, Jan W, Scott, Rodney J, Mitchell, Paul, Hansen, Torben, O'Donnell, Christopher J, Smith, Nicholas L, Strachan, David P, and Dehghan, Abbas

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Genome-Wide Association Study, HapMap Project, Humans, General Science & Technology
Abstract

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

Published
2017

27. Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

Author

Postmus, Iris, Warren, Helen R, Trompet, Stella, Arsenault, Benoit J, Avery, Christy L, Bis, Joshua C, Chasman, Daniel I, de Keyser, Catherine E, Deshmukh, Harshal A, Evans, Daniel S, Feng, QiPing, Li, Xiaohui, Smit, Roelof AJ, Smith, Albert V, Sun, Fangui, Taylor, Kent D, Arnold, Alice M, Barnes, Michael R, Barratt, Bryan J, Betteridge, John, Boekholdt, S Matthijs, Boerwinkle, Eric, Buckley, Brendan M, Chen, Y-D Ida, de Craen, Anton JM, Cummings, Steven R, Denny, Joshua C, Dubé, Marie Pierre, Durrington, Paul N, Eiriksdottir, Gudny, Ford, Ian, Guo, Xiuqing, Harris, Tamara B, Heckbert, Susan R, Hofman, Albert, Hovingh, G Kees, Kastelein, John JP, Launer, Leonore J, Liu, Ching-Ti, Liu, Yongmei, Lumley, Thomas, McKeigue, Paul M, Munroe, Patricia B, Neil, Andrew, Nickerson, Deborah A, Nyberg, Fredrik, O'Brien, Eoin, O'Donnell, Christopher J, Post, Wendy, Poulter, Neil, Vasan, Ramachandran S, Rice, Kenneth, Rich, Stephen S, Rivadeneira, Fernando, Sattar, Naveed, Sever, Peter, Shaw-Hawkins, Sue, Shields, Denis C, Slagboom, P Eline, Smith, Nicholas L, Smith, Joshua D, Sotoodehnia, Nona, Stanton, Alice, Stott, David J, Stricker, Bruno H, Stürmer, Til, Uitterlinden, André G, Wei, Wei-Qi, Westendorp, Rudi GJ, Whitsel, Eric A, Wiggins, Kerri L, Wilke, Russell A, Ballantyne, Christie M, Colhoun, Helen M, Cupples, L Adrienne, Franco, Oscar H, Gudnason, Vilmundur, Hitman, Graham, Palmer, Colin NA, Psaty, Bruce M, Ridker, Paul M, Stafford, Jeanette M, Stein, Charles M, Tardif, Jean-Claude, Caulfield, Mark J, Jukema, J Wouter, Rotter, Jerome I, and Krauss, Ronald M

Subjects
Atherosclerosis, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Stroke, Good Health and Well Being, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Female, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Treatment Outcome, White People, Genome-wide association study, HDL-cholesterol, Statins, pharmacogenetics, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

BackgroundIn addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.Methods and resultsWe performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p

Published
2016

28. Prior hysterectomy and oophorectomy and incident venous thrombosis risk among postmenopausal women

Author

Harrington, Laura B, Weiss, Noel S, Wiggins, Kerri L, Heckbert, Susan R, McKnight, Barbara, Blondon, Marc, Woods, Nancy F, LaCroix, Andrea Z, Psaty, Bruce M, and Smith, Nicholas L

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Contraception/Reproduction, Clinical Research, Prevention, Aging, Estrogen, Case-Control Studies, Causality, Confidence Intervals, Estrogen Replacement Therapy, Female, Humans, Hysterectomy, Logistic Models, Middle Aged, Odds Ratio, Ovariectomy, Postmenopause, Risk Factors, Salpingectomy, Venous Thrombosis, Cardiovascular diseases, Hormones, Thrombosis, Women, Medical and Health Sciences, Obstetrics & Reproductive Medicine, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

ObjectiveHysterectomy and bilateral salpingo-oophorectomy (BSO) are associated with changes in endogenous hormone levels, yet the risk of venous thrombosis (VT) associated with hysterectomy and BSO is incompletely characterized. This study evaluated the risk of incident VT among postmenopausal women associated with combined prior hysterectomy/oophorectomy status and current use of hormone therapy (HT).MethodsIn a case-control study, we identified incident VT cases (n = 1,623) among postmenopausal Group Health Cooperative enrollees without reproductive cancer, defining their "index date" as their VT diagnosis date (1995-2010). Matched controls had not experienced a prior VT (n = 4,480). Multiple logistic regression models estimated adjusted relative risks for VT associated with combinations of prior hysterectomy/oophorectomy status and HT use at the index date.ResultsCompared with women with an intact uterus who were not using HT, there was no suggestion of greater VT risk in women with prior hysterectomy without BSO, whether they were (adjusted odds ratio [aOR] = 0.80 [95% CI: 0.57, 1.12]) or were not using HT (aOR = 1.09 [95% CI: 0.89, 1.35]). Women with prior hysterectomy and BSO who were using HT were not at a greater VT risk (OR = 1.00 [95% CI: 0.78, 1.27]), but there was evidence of a 25% greater risk associated with prior hysterectomy with BSO and no current HT use (OR = 1.25 [95% CI: 1.05, 1.49]).ConclusionsCollectively, these and prior data do not suggest a substantial impact of hysterectomy, with or without BSO, on the risk of VT among postmenopausal women.

Published
2016

29. Prior hysterectomy and oophorectomy and incident venous thrombosis risk among postmenopausal women: a population-based, case-control study.

Author

Harrington, Laura B, Weiss, Noel S, Wiggins, Kerri L, Heckbert, Susan R, McKnight, Barbara, Blondon, Marc, Woods, Nancy F, LaCroix, Andrea Z, Psaty, Bruce M, and Smith, Nicholas L

Subjects
Humans, Venous Thrombosis, Estrogen Replacement Therapy, Ovariectomy, Hysterectomy, Confidence Intervals, Logistic Models, Odds Ratio, Risk Factors, Case-Control Studies, Causality, Postmenopause, Middle Aged, Female, Salpingectomy, Clinical Research, Aging, Contraception/Reproduction, Estrogen, Prevention, Medical And Health Sciences, Obstetrics & Reproductive Medicine, Medical and Health Sciences
Abstract

ObjectiveHysterectomy and bilateral salpingo-oophorectomy (BSO) are associated with changes in endogenous hormone levels, yet the risk of venous thrombosis (VT) associated with hysterectomy and BSO is incompletely characterized. This study evaluated the risk of incident VT among postmenopausal women associated with combined prior hysterectomy/oophorectomy status and current use of hormone therapy (HT).MethodsIn a case-control study, we identified incident VT cases (n = 1,623) among postmenopausal Group Health Cooperative enrollees without reproductive cancer, defining their "index date" as their VT diagnosis date (1995-2010). Matched controls had not experienced a prior VT (n = 4,480). Multiple logistic regression models estimated adjusted relative risks for VT associated with combinations of prior hysterectomy/oophorectomy status and HT use at the index date.ResultsCompared with women with an intact uterus who were not using HT, there was no suggestion of greater VT risk in women with prior hysterectomy without BSO, whether they were (adjusted odds ratio [aOR] = 0.80 [95% CI: 0.57, 1.12]) or were not using HT (aOR = 1.09 [95% CI: 0.89, 1.35]). Women with prior hysterectomy and BSO who were using HT were not at a greater VT risk (OR = 1.00 [95% CI: 0.78, 1.27]), but there was evidence of a 25% greater risk associated with prior hysterectomy with BSO and no current HT use (OR = 1.25 [95% CI: 1.05, 1.49]).ConclusionsCollectively, these and prior data do not suggest a substantial impact of hysterectomy, with or without BSO, on the risk of VT among postmenopausal women.

Published
2016

30. Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium

Author

Dehghan, Abbas, Bis, Joshua C, White, Charles C, Smith, Albert Vernon, Morrison, Alanna C, Cupples, L Adrienne, Trompet, Stella, Chasman, Daniel I, Lumley, Thomas, Völker, Uwe, Buckley, Brendan M, Ding, Jingzhong, Jensen, Majken K, Folsom, Aaron R, Kritchevsky, Stephen B, Girman, Cynthia J, Ford, Ian, Dörr, Marcus, Salomaa, Veikko, Uitterlinden, André G, Eiriksdottir, Gudny, Vasan, Ramachandran S, Franceschini, Nora, Carty, Cara L, Virtamo, Jarmo, Demissie, Serkalem, Amouyel, Philippe, Arveiler, Dominique, Heckbert, Susan R, Ferrières, Jean, Ducimetière, Pierre, Smith, Nicholas L, Wang, Ying A, Siscovick, David S, Rice, Kenneth M, Wiklund, Per-Gunnar, Taylor, Kent D, Evans, Alun, Kee, Frank, Rotter, Jerome I, Karvanen, Juha, Kuulasmaa, Kari, Heiss, Gerardo, Kraft, Peter, Launer, Lenore J, Hofman, Albert, Markus, Marcello RP, Rose, Lynda M, Silander, Kaisa, Wagner, Peter, Benjamin, Emelia J, Lohman, Kurt, Stott, David J, Rivadeneira, Fernando, Harris, Tamara B, Levy, Daniel, Liu, Yongmei, Rimm, Eric B, Jukema, J Wouter, Völzke, Henry, Ridker, Paul M, Blankenberg, Stefan, Franco, Oscar H, Gudnason, Vilmundur, Psaty, Bruce M, Boerwinkle, Eric, and O'Donnell, Christopher J

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Heart Disease - Coronary Heart Disease, Prevention, Human Genome, Cardiovascular, Heart Disease, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Aetiology, Good Health and Well Being, Aged, Cohort Studies, Cooperative Behavior, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies, General Science & Technology
Abstract

BackgroundData are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.MethodsWe performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.ResultsIn Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value

Published
2016

31. A genetic risk score comprising known venous thromboembolism loci is associated with chronic venous disease in a multi-ethnic cohort

Author

Wassel, Christina L, Rasmussen-Torvik, Laura J, Callas, Peter W, Denenberg, Julie O, Durda, J Peter, Reiner, Alexander P, Smith, Nicholas L, Allison, Matthew A, Rosendaal, Frits R, Criqui, Michael H, and Cushman, Mary

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Clinical Research, Genetics, Prevention, Adult, Aged, Aged, 80 and over, Chronic Disease, Cohort Studies, Ethnicity, Female, Genetic Loci, Humans, Male, Middle Aged, Venous Thromboembolism, Chronic venous disease, Venous thromboembolism, Race/ethnicity, Genetic risk score, Single nucleotide polymorphisms, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundChronic venous disease is common and shares some risk factors with venous thromboembolism (VTE). Several genetic loci have been discovered and well-replicated for VTE in European descent populations. We examined associations of a genetic risk score (GRS), comprising known VTE loci, with chronic venous disease.MethodsThe San Diego Population Study (SDPS) is a multi-ethnic cohort that evaluated 2404 men and women aged 29-91 from 1994 to 1998 for chronic venous disease. The current study includes 1447 participants genotyped for 33 variants in 22 established VTE risk loci. Using these variants, unweighted and weighted GRS were constructed. Logistic regression was used to examine associations with venous disease.ResultsIn non-Hispanic whites, African-Americans, Hispanics, and Asians, each standard deviation increment higher of the unweighted 33-SNP GRS was associated with a 1.45-fold (95% CI (1.26, 1.67)), 1.74-fold (1.18, 2.55), a 1.80-fold (1.30, 2.51), and 1.88-fold (1.30, 2.73) greater odds, respectively, for moderate plus severe disease. The difference in c-statistics was significant between a known venous risk factor model and a model adding the 33-SNP GRS for whites (p=0.008), African-Americans (0.03), and Hispanics (p=0.04), with marginal significance in Asians (p=0.06).ConclusionsGRS comprising variants primarily from VTE findings in European descent populations were associated with chronic venous disease across all race/ethnic groups, and contributed significantly to prediction, indicating some level of generalizability to other race/ethnic groups. Future work should focus on more in depth examination of racial/ethnic group genetic architecture in relation to chronic venous disease.

Published
2015

32. Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

Author

Huffman, Jennifer E, de Vries, Paul S, Morrison, Alanna C, Sabater-Lleal, Maria, Kacprowski, Tim, Auer, Paul L, Brody, Jennifer A, Chasman, Daniel I, Chen, Ming-Huei, Guo, Xiuqing, Lin, Li-An, Marioni, Riccardo E, Müller-Nurasyid, Martina, Yanek, Lisa R, Pankratz, Nathan, Grove, Megan L, de Maat, Moniek PM, Cushman, Mary, Wiggins, Kerri L, Qi, Lihong, Sennblad, Bengt, Harris, Sarah E, Polasek, Ozren, Riess, Helene, Rivadeneira, Fernando, Rose, Lynda M, Goel, Anuj, Taylor, Kent D, Teumer, Alexander, Uitterlinden, André G, Vaidya, Dhananjay, Yao, Jie, Tang, Weihong, Levy, Daniel, Waldenberger, Melanie, Becker, Diane M, Folsom, Aaron R, Giulianini, Franco, Greinacher, Andreas, Hofman, Albert, Huang, Chiang-Ching, Kooperberg, Charles, Silveira, Angela, Starr, John M, Strauch, Konstantin, Strawbridge, Rona J, Wright, Alan F, McKnight, Barbara, Franco, Oscar H, Zakai, Neil, Mathias, Rasika A, Psaty, Bruce M, Ridker, Paul M, Tofler, Geoffrey H, Völker, Uwe, Watkins, Hugh, Fornage, Myriam, Hamsten, Anders, Deary, Ian J, Boerwinkle, Eric, Koenig, Wolfgang, Rotter, Jerome I, Hayward, Caroline, Dehghan, Abbas, Reiner, Alex P, O'Donnell, Christopher J, and Smith, Nicholas L

Subjects
Biological Sciences, Genetics, Human Genome, Hematology, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Cohort Studies, Factor VII, Factor VIII, Fibrinogen, Gene Frequency, Genetic Association Studies, Genetic Variation, Humans, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, Potassium Channels, Sodium-Activated, von Willebrand Factor, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Immunology, Biochemistry and cell biology, Cardiovascular medicine and haematology, Paediatrics
Abstract

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and

Published
2015

33. The effect of calcium plus vitamin D supplementation on the risk of venous thromboembolism

Author

Blondon, Marc, Rodabough, Rebecca J, Budrys, Nicole, Johnson, Karen C, Berger, Jeffrey S, Shikany, James M, Raiesdana, Azad, Heckbert, Susan R, Manson, JoAnn E, LaCroix, Andrea Z, Siscovick, David, Kestenbaum, Bryan, Smith, Nicholas L, and de Boer, Ian H

Subjects
Hematology, Clinical Trials and Supportive Activities, Nutrition, Complementary and Integrative Health, Prevention, Aging, Clinical Research, Evaluation of treatments and therapeutic interventions, 3.3 Nutrition and chemoprevention, 6.1 Pharmaceuticals, Prevention of disease and conditions, and promotion of well-being, Administration, Oral, Aged, Calcium Carbonate, Colorectal Neoplasms, Dietary Supplements, Double-Blind Method, Female, Follow-Up Studies, Hip Fractures, Humans, Middle Aged, Proportional Hazards Models, Venous Thromboembolism, Vitamin D, Venous thrombosis, risk factors, clinical studies, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract

Experimental and epidemiological studies suggest that vitamin D may be implicated in haemostatic regulations and influence the risk of venous thromboembolism (VTE). The aim of this study was to investigate whether oral supplementation of vitamin D3 combined with calcium reduces the risk of VTE. In the randomised, double-blind, placebo-controlled Women's Health Initiative Calcium Plus Vitamin D trial, 36,282 postmenopausal women aged 50-79 years were randomised to receive 1,000 mg of calcium carbonate and 400 IU of vitamin D3 per day (n=18,176) or a matching placebo (n=18,106) during an average of seven years. This secondary analysis of the trial compared the incidence of VTE by treatment group using an intention-to-treat Cox regression analysis. The incidence of VTE did not differ between women randomised to calcium plus vitamin D and women randomised to placebo (320 vs 348 VTE events, respectively; hazard ratio (HR) 0.92, 95 % confidence interval (CI) 0.79-1.07). Results were not modified in an analysis using inverse-probability weights to take non-adherence into account (HR 0.94, 95 %CI 0.73-1.22) or in multiple subgroups. Whereas the risk of a non-idiopathic VTE was similar between groups, the risk of idiopathic VTE was lower in women randomised to calcium plus vitamin D (40 vs 65 events; HR 0.62, 95 %CI 0.42-0.92). In conclusion, daily supplementation with 1,000 mg of calcium and 400 IU of vitamin D did not reduce the overall incidence of VTE in generally healthy postmenopausal women. However, the observed reduced risk of idiopathic VTE in women randomised to calcium and vitamin D warrants further investigations.

Published
2015

34. Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.

Author

Bis, Joshua C, Sitlani, Colleen, Irvin, Ryan, Avery, Christy L, Smith, Albert Vernon, Sun, Fangui, Evans, Daniel S, Musani, Solomon K, Li, Xiaohui, Trompet, Stella, Krijthe, Bouwe P, Harris, Tamara B, Quibrera, P Miguel, Brody, Jennifer A, Demissie, Serkalem, Davis, Barry R, Wiggins, Kerri L, Tranah, Gregory J, Lange, Leslie A, Sotoodehnia, Nona, Stott, David J, Franco, Oscar H, Launer, Lenore J, Stürmer, Til, Taylor, Kent D, Cupples, L Adrienne, Eckfeldt, John H, Smith, Nicholas L, Liu, Yongmei, Wilson, James G, Heckbert, Susan R, Buckley, Brendan M, Ikram, M Arfan, Boerwinkle, Eric, Chen, Yii-Der Ida, de Craen, Anton JM, Uitterlinden, Andre G, Rotter, Jerome I, Ford, Ian, Hofman, Albert, Sattar, Naveed, Slagboom, P Eline, Westendorp, Rudi GJ, Gudnason, Vilmundur, Vasan, Ramachandran S, Lumley, Thomas, Cummings, Steven R, Taylor, Herman A, Post, Wendy, Jukema, J Wouter, Stricker, Bruno H, Whitsel, Eric A, Psaty, Bruce M, and Arnett, Donna

Subjects
Humans, Cardiovascular Diseases, Hypertension, Antihypertensive Agents, Treatment Outcome, Incidence, Polymorphism, Single Nucleotide, Aged, Middle Aged, African Americans, European Continental Ancestry Group, Female, Male, Genome-Wide Association Study, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

BackgroundHypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.MethodsUsing a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).ResultsAlthough drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

Published
2015

35. Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study

Author

Shores, Molly M, Arnold, Alice M, Biggs, Mary L, Longstreth, WT, Smith, Nicholas L, Kizer, Jorge R, Cappola, Anne R, Hirsch, Calvin H, Marck, Brett T, and Matsumoto, Alvin M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Aging, Urologic Diseases, Stroke, Cardiovascular, Brain Disorders, Good Health and Well Being, Aged, Aged, 80 and over, Brain Ischemia, Cardiovascular Physiological Phenomena, Dihydrotestosterone, Health, Humans, Incidence, Longitudinal Studies, Male, Testosterone, Paediatrics and Reproductive Medicine, Endocrinology & Metabolism, Clinical sciences
Abstract

ObjectiveIschaemic stroke is a major cause of morbidity and mortality in elderly men. Our main objective was to examine whether testosterone (T) or dihydrotestosterone (DHT) was associated with incident ischaemic stroke in elderly men.DesignCohort study.ParticipantsElderly men in the Cardiovascular Health Study who had no history of stroke, heart disease or prostate cancer as of 1994 and were followed until December 2010.MeasurementsAdjudicated ischaemic stroke.ResultsAmong 1032 men (mean age 76, range 66-97), followed for a median of 10 years, 114 had an incident ischaemic stroke. Total T and free T were not significantly associated with stroke risk, while DHT had a nonlinear association with incident stroke (P = 0·006) in analyses adjusted for stroke risk factors. The lowest risk of stroke was at DHT levels of 50-75 ng/dl, with greater risk of stroke at DHT levels above 75 ng/dl or below 50 ng/dl. Results were unchanged when SHBG was added to the model. Calculated free DHT had an inverse linear association with incident ischaemic stroke with HR 0·77 (95% CI, 0·61, 0·98) per standard deviation in analyses adjusted for stroke risk factors.ConclusionsDihydrotestosterone had a nonlinear association with stroke risk in which there was an optimal DHT level associated with the lowest stroke risk. Further studies are needed to confirm these results and to clarify whether there is an optimal androgen range associated with the least risk of adverse outcomes in elderly men.

Published
2014

36. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.

Author

Postmus, Iris, Trompet, Stella, Deshmukh, Harshal A, Barnes, Michael R, Li, Xiaohui, Warren, Helen R, Chasman, Daniel I, Zhou, Kaixin, Arsenault, Benoit J, Donnelly, Louise A, Wiggins, Kerri L, Avery, Christy L, Griffin, Paula, Feng, QiPing, Taylor, Kent D, Li, Guo, Evans, Daniel S, Smith, Albert V, de Keyser, Catherine E, Johnson, Andrew D, de Craen, Anton JM, Stott, David J, Buckley, Brendan M, Ford, Ian, Westendorp, Rudi GJ, Slagboom, P Eline, Sattar, Naveed, Munroe, Patricia B, Sever, Peter, Poulter, Neil, Stanton, Alice, Shields, Denis C, O'Brien, Eoin, Shaw-Hawkins, Sue, Chen, Y-D Ida, Nickerson, Deborah A, Smith, Joshua D, Dubé, Marie Pierre, Boekholdt, S Matthijs, Hovingh, G Kees, Kastelein, John JP, McKeigue, Paul M, Betteridge, John, Neil, Andrew, Durrington, Paul N, Doney, Alex, Carr, Fiona, Morris, Andrew, McCarthy, Mark I, Groop, Leif, Ahlqvist, Emma, Welcome Trust Case Control Consortium, Bis, Joshua C, Rice, Kenneth, Smith, Nicholas L, Lumley, Thomas, Whitsel, Eric A, Stürmer, Til, Boerwinkle, Eric, Ngwa, Julius S, O'Donnell, Christopher J, Vasan, Ramachandran S, Wei, Wei-Qi, Wilke, Russell A, Liu, Ching-Ti, Sun, Fangui, Guo, Xiuqing, Heckbert, Susan R, Post, Wendy, Sotoodehnia, Nona, Arnold, Alice M, Stafford, Jeanette M, Ding, Jingzhong, Herrington, David M, Kritchevsky, Stephen B, Eiriksdottir, Gudny, Launer, Leonore J, Harris, Tamara B, Chu, Audrey Y, Giulianini, Franco, MacFadyen, Jean G, Barratt, Bryan J, Nyberg, Fredrik, Stricker, Bruno H, Uitterlinden, André G, Hofman, Albert, Rivadeneira, Fernando, Emilsson, Valur, Franco, Oscar H, Ridker, Paul M, Gudnason, Vilmundur, Liu, Yongmei, Denny, Joshua C, Ballantyne, Christie M, Rotter, Jerome I, Adrienne Cupples, L, Psaty, Bruce M, Palmer, Colin NA, Tardif, Jean-Claude, and Colhoun, Helen M

Subjects
Welcome Trust Case Control Consortium, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pharmacogenetics, Polymorphism, Single Nucleotide, Cholesterol, LDL, Genome-Wide Association Study, Cholesterol, LDL, Polymorphism, Single Nucleotide
Abstract

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

Published
2014

37. Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans

Author

Fox, Ervin R, Musani, Solomon K, Barbalic, Maja, Lin, Honghuang, Yu, Bing, Ogunyankin, Kofo O, Smith, Nicholas L, Kutlar, Abdullah, Glazer, Nicole L, Post, Wendy S, Paltoo, Dina N, Dries, Daniel L, Farlow, Deborah N, Duarte, Christine W, Kardia, Sharon L, Meyers, Kristin J, Sun, Yan V, Arnett, Donna K, Patki, Amit A, Sha, Jin, Cui, Xiangqui, Samdarshi, Tandaw E, Penman, Alan D, Bibbins-Domingo, Kirsten, Bková, Petra, Benjamin, Emelia J, Bluemke, David A, Morrison, Alanna C, Heiss, Gerardo, Carr, J Jeffrey, Tracy, Russell P, Mosley, Thomas H, Taylor, Herman A, Psaty, Bruce M, Heckbert, Susan R, Cappola, Thomas P, and Vasan, Ramachandran S

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Heart Disease, Cardiovascular, Human Genome, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, African Americans, Aged, Cohort Studies, Diastole, Echocardiography, Female, Genome-Wide Association Study, Genotype, Heart, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Systole, Whites, echocardiography, ethnic, genome-wide association studies, left atrium genetics, left ventricular mass genetics, White People, Black or African American, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundUsing data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.Methods and resultsAmong 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.ConclusionsIn the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

Published
2013

38. Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism

Author

Iglesias, Maria Jesus, Sanchez-Rivera, Laura, Ibrahim-Kosta, Manal, Naudin, Clément, Munsch, Gaëlle, Goumidi, Louisa, Farm, Maria, Smith, Philip M, Thibord, Florian, Kral-Pointner, Julia Barbara, Hong, Mun-Gwan, Suchon, Pierre, Germain, Marine, Schottmaier, Waltraud, Dusart, Philip, Boland, Anne, Kotol, David, Edfors, Fredrik, Koprulu, Mine, Pietzner, Maik, Langenberg, Claudia, Damrauer, Scott M, Johnson, Andrew D, Klarin, Derek M, Smith, Nicholas L, Smadja, David M, Holmström, Margareta, Magnusson, Maria, Silveira, Angela, Uhlén, Mathias, Renné, Thomas, Martinez-Perez, Angel, Emmerich, Joseph, Deleuze, Jean-Francois, Antovic, Jovan, Soria Fernandez, Jose Manuel, Assinger, Alice, Schwenk, Jochen M, Souto Andres, Joan Carles, Morange, Pierre-Emmanuel, Butler, Lynn Marie, Trégouët, David-Alexandre, Odeberg, Jacob, Naudin, Clément [0000-0002-6777-9587], Munsch, Gaëlle [0000-0003-1564-9825], Goumidi, Louisa [0000-0003-4164-8471], Hong, Mun-Gwan [0000-0001-8603-8293], Schottmaier, Waltraud [0000-0003-0550-4120], Dusart, Philip [0000-0003-2747-3214], Kotol, David [0000-0002-5388-3826], Edfors, Fredrik [0000-0002-0017-7987], Koprulu, Mine [0000-0001-6870-4539], Pietzner, Maik [0000-0003-3437-9963], Langenberg, Claudia [0000-0002-5017-7344], Damrauer, Scott M [0000-0001-8009-1632], Johnson, Andrew D [0000-0001-6369-5178], Klarin, Derek M [0000-0002-4636-5780], Silveira, Angela [0000-0003-2063-4935], Uhlén, Mathias [0000-0002-4858-8056], Martinez-Perez, Angel [0000-0002-5934-1454], Deleuze, Jean-Francois [0000-0002-5358-4463], Assinger, Alice [0000-0002-5670-5910], Schwenk, Jochen M [0000-0001-8141-8449], Souto Andres, Joan Carles [0000-0003-2092-5142], Morange, Pierre-Emmanuel [0000-0002-9065-722X], Butler, Lynn Marie [0000-0002-2352-8217], Trégouët, David-Alexandre [0000-0001-9084-7800], Odeberg, Jacob [0000-0003-0996-1644], and Apollo - University of Cambridge Repository

Subjects
Complement Factor H, Humans, Factor V, Complement System Proteins, Venous Thromboembolism, Complement Activation, Biomarkers
Abstract

Venous thromboembolism (VTE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. Here we show, using proteomics profiling to screen plasma from patients with suspected acute VTE, and several case-control studies for VTE, how Complement Factor H Related 5 protein (CFHR5), a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker. In plasma, higher CFHR5 levels are associated with increased thrombin generation potential and recombinant CFHR5 enhanced platelet activation in vitro. GWAS analysis of ~52,000 participants identifies six loci associated with CFHR5 plasma levels, but Mendelian randomization do not demonstrate causality between CFHR5 and VTE. Our results indicate an important role for the regulation of the alternative pathway of complement activation in VTE and that CFHR5 represents a potential diagnostic and/or risk predictive plasma biomarker.

Published
2023

39. Genetically predicted cortisol levels and risk of venous thromboembolism

Author

Allarai, Elias, Lee, Wei-Hsuan, Burgess, Stephen, Larsson, Susanna C., Lindstrom, Sara, Wang, Lu, Smith, Erin N., Gordon, William, Van Hylckama Vlieg, Astrid, De Andrade, Mariza, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben Michael, Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., Macdonald, James, Brækkan, Sigrid Kufaas, Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rabecca D., Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Bammler, Theo K., Frazer, Kelly A., Mccauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken Elvestad, Deleuze, Jean-Francois, O'Donnell, Chris J., Kim, Jihye, Mcknight, Barbara, Kraft, Peter, Hansen, John Bjarne, Rosendaal, Frits Richard, Heit, John A., Psaty, Bruce M., Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, Alexandretrégouët, David, Smith, Nicholas L., Allara, Elias [0000-0002-1634-8330], Burgess, Stephen [0000-0001-5365-8760], and Apollo - University of Cambridge Repository

Subjects
Medicine and health sciences, Multidisciplinary, Kardiologi, Hydrocortisone, Biology and life sciences, FOS: Social sciences, Venous Thromboembolism, Mendelian Randomization Analysis, Endocrinology and Diabetes, Social sciences, Risk Factors, Endokrinologi och diabetes, Humans, Cardiac and Cardiovascular Systems, Pulmonary Embolism, Medical Genetics, Medicinsk genetik, Research Article
Abstract

Introduction In observational studies, venous thromboembolism (VTE) has been associated with Cushing’s syndrome and with persistent mental stress, two conditions associated with higher cortisol levels. However, it remains unknown whether high cortisol levels within the usual range are causally associated with VTE risk. We aimed to assess the association between plasma cortisol levels and VTE risk using Mendelian randomization. Methods Three genetic variants in the SERPINA1/SERPINA6 locus (rs12589136, rs11621961 and rs2749527) were used to proxy plasma cortisol. The associations of the cortisol-associated genetic variants with VTE were acquired from the INVENT (28 907 cases and 157 243 non-cases) and FinnGen (6913 cases and 169 986 non-cases) consortia. Corresponding data for VTE subtypes were available from the FinnGen consortium and UK Biobank. Two-sample Mendelian randomization analyses (inverse-variance weighted method) were performed. Results Genetic predisposition to higher plasma cortisol levels was associated with a reduced risk of VTE (odds ratio [OR] per one standard deviation increment 0.73, 95% confidence interval [CI] 0.62–0.87, p Conclusions This study provides evidence that genetically predicted plasma cortisol levels in the high end of the normal range are associated with a decreased risk of VTE and that this association may be mediated by blood pressure. This study has implications for the planning of observational studies of cortisol and VTE, suggesting that blood pressure traits should be measured and accounted for.

Published
2022

40. Genetic diversity fuels gene discovery for tobacco and alcohol use

Author

Saunders, Gretchen R. B., Wang, Xingyan, Chen, Fang, Jang, Seon-Kyeong, Liu, Mengzhen, Wang, Chen, Gao, Shuang, Jiang, Yu, Khunsriraksakul, Chachrit, Otto, Jacqueline M., Addison, Clifton, Akiyama, Masato, Albert, Christine M., Aliev, Fazil, Alonso, Alvaro, Arnett, Donna K., Ashley-Koch, Allison E., Ashrani, Aneel A., Barnes, Kathleen C., Barr, R. Graham, Bartz, Traci M., Becker, Diane M., Bielak, Lawrence F., Benjamin, Emelia J., Bis, Joshua C., Bjornsdottir, Gyda, Blangero, John, Bleecker, Eugene R., Boardman, Jason D., Boerwinkle, Eric, Boomsma, Dorret, Boorgula, Meher Preethi, Bowden, Donald W., Brody, Jennifer A., Cade, Brian E., Chasman, Daniel, Chavan, Sameer, Chen, Yii-Der Ida, Chen, Zhengming, Cheng, Iona, Cho, Michael H., Choquet, Helene, Cole, John W., Cornelis, Marilyn C., Cucca, Francesco, Curran, Joanne E., de Andrade, Mariza, Dick, Danielle M., Docherty, Anna R., Duggirala, Ravindranath, Eaton, Charles B., Ehringer, Marissa A., Esko, Tonu, Faul, Jessica D., Silva, Lilian Fernandes, Fiorillo, Edoardo, Fornage, Myriam, Freedman, Barry, Gabrielsen, Maiken E., Garrett, Melanie E., Gharib, Sina A., Gieger, Christian, Gillespie, Nathan, Glahn, David C., Gordon, Scott D., Gu, Charles C., Gu, Dongfeng, Gudbjartsson, Daniel F., Guo, Xiuqing, Haessler, Jeffrey, Hall, Michael E., Haller, Toomas, Harris, Kathleen Mullan, He, Jiang, Herd, Pamela, Hewitt, John K., Hickie, Ian, Hidalgo, Bertha, Hokanson, John E., Hopfer, Christian, Hottenga, JoukeJan, Hou, Lifang, Huang, Hongyan, Hung, Yi-Jen, Hunter, David J., Hveem, Kristian, Hwang, Shih-Jen, Hwu, Chii-Min, Iacono, William, Irvin, Marguerite R., Jee, Yon Ho, Johnson, Eric O., Joo, Yoonjung Y., Jorgenson, Eric, Justice, Anne E., Kamatani, Yoichiro, Kaplan, Robert C., Kaprio, Jaakko, Kardia, Sharon L. R., Keller, Matthew C., Kelly, Tanika N., Kooperberg, Charles, Korhonen, Tellervo, Kraft, Peter, Krauter, Kenneth, Kuusisto, Johanna, Laakso, Markku, Lasky-Su, Jessica, Lee, Wen-Jane, Lee, James J., Levy, Daniel, Li, Liming, Li, Kevin, Li, Yuqing, Lin, Kuang, Lind, Penelope A., Liu, Chunyu, Lloyd-Jones, Donald M., Lutz, Sharon M., Ma, Jiantao, Magi, Reedik, Manichaikul, Ani, Martin, Nicholas G., Mathur, Ravi, Matoba, Nana, McArdle, Patrick F., McGue, Matt, McQueen, Matthew B., Medland, Sarah E., Metspalu, Andres, Meyers, Deborah A., Millwood, Iona Y., Mitchell, Braxton D., Mohlke, Karen L., Moll, Matthew, Montasser, May E., Morrison, Alanna C., Mulas, Antonella, Nielsen, Jonas B., North, Kari E., Oelsner, Elizabeth C., Okada, Yukinori, Orru, Valeria, Palmer, Nicholette D., Palviainen, Teemu, Pandit, Anita, Park, S. Lani, Peters, Ulrike, Peters, Annette, Peyser, Patricia A., Polderman, Tinca J. C., Rafaels, Nicholas, Redline, Susan, Reed, Robert M., Reiner, Alex P., Rice, John P., Rich, Stephen S., Richmond, Nicole E., Roan, Carol, Rotter, Jerome, Rueschman, Michael N., Runarsdottir, Valgerdur, Saccone, Nancy L., Schwartz, David A., Shadyab, Aladdin H., Shi, Jingchunzi, Shringarpure, Suyash S., Sicinski, Kamil, Skogholt, Anne Heidi, Smith, Jennifer A., Smith, Nicholas L., Sotoodehnia, Nona, Stallings, Michael C., Stefansson, Hreinn, Stefansson, Kari, Stitzel, Jerry A., Sun, Xiao, Syed, Moin, Tal-Singer, Ruth, Taylor, Amy E., Taylor, Kent D., Telen, Marilyn J., Thai, Khanh K., Tiwari, Hemant, Turman, Constance, Tyrfingsson, Thorarinn, Wall, Tamara L., Walters, Robin G., Weir, David R., Weiss, Scott T., White, Wendy B., Whitfield, John B., Wiggins, Kerri L., Willemsen, Gonneke, Willer, Cristen J., Winsvold, Bendik S., Xu, Huichun, Yanek, Lisa R., Yin, Jie, Young, Kristin L., Young, Kendra A., Yu, Bing, Zhao, Wei, Zhou, Wei, Zollner, Sebastian, Zuccolo, Luisa, Project, The Biobank Japan, Batini, Chiara, Bergen, Andrew W., Bierut, Laura J., David, Sean P., Taliun, Sarah A. Gagliano, Hancock, Dana B., Jiang, Bibo, Munafo, Marcus R., Thorgeirsson, Thorgeir E., Liu, Dajiang J., Vrieze, Scott, Pediatrics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Clinical Developmental Psychology, Institute for Molecular Medicine Finland, University Management, Tellervo Korhonen / Principal Investigator, Genetic Epidemiology, and University of Helsinki

Subjects
Multidisciplinary, Internationality, Protein, Genetic Predisposition to Disease/genetics, 1184 Genetics, developmental biology, physiology, Neurotrophic factors, Alcohol Drinking/genetics, Europe/ethnology, Genetic Variation/genetics, Tobacco Use/genetics, SDG 3 - Good Health and Well-being, Risk Factors, Sample Size, Genetic Loci/genetics, Genome-Wide Association Study/methods, Humans, Disease, 3111 Biomedicine, Prediction, Transcriptome, Multifactorial Inheritance/genetics, Model
Abstract

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

Published
2022

41. Cerebral small vessel disease genomics and its implications across the lifespan

Author

Sargurupremraj, Muralidharan, Suzuki, Hideaki, Zhao, Wei, Okada, Yukinori, Mazoyer, Bernard, Wardlaw, Joanna M, Nyquist, Paul A, Mather, Karen A, Grabe, Hans, Schmidt, Helena, Van Duijn, Cornelia M, Gudnason, Vilmundur, Longstreth, William T, Armstrong, Nicola J, Launer, Lenore J, Lathrop, Mark, Seshadri, Sudha, Tzourio, Christophe, Adams, Hieab H, Matthews, Paul M, Fornage, Myriam, Debette, Stéphanie, Amouyel, Philippe, de Andrade, Mariza, Hofer, Edith, Basu, Saonli, Berr, Claudine, Brody, Jennifer A, Chasman, Daniel I, Dartigues, Jean-Francois, Folsom, Aaron R, Germain, Marine, de Haan, Hugoline, Heit, John, Houwing-Duitermaat, Jeanine, Yanek, Lisa R, Kabrhel, Christopher, Kraft, Peter, Legal, Grégoire, Lindström, Sara, Monajemi, Ramin, Morange, Pierre-Emmanuel, Psaty, Bruce M, Reitsma, Pieter H, Ridker, Paul M, Rose, Lynda M, Hagenaars, Saskia P, Rosendaal, Frits R, Saut, Noémie, Slagboom, Eline, Smadja, David, Smith, Nicholas L, Suchon, Pierre, Tang, Weihong, Taylor, Kent D, Trégouët, David-Alexandre, Kumar, Rajan B, de Visser, Marieke C H, van Hylckama Vlieg, Astrid, Weng, Lu-Chen, Wiggins, Kerri L, Gormley, Padhraig, Anttila, Verneri, Winsvold, Bendik S, Palta, Priit, Esko, Tonu, Pers, Tune H, van den Akker, Erik B, Farh, Kai-How, Cuenca-Leon, Ester, Muona, Mikko, Furlotte, Nicholas A, Kurth, Tobias, Ingason, Andres, McMahon, George, Ligthart, Lannie, Terwindt, Gisela M, Kallela, Mikko, McWhirter, Rebekah E, Freilinger, Tobias M, Ran, Caroline, Gordon, Scott G, Stam, Anine H, Steinberg, Stacy, Borck, Guntram, Koiranen, Markku, Quaye, Lydia, Adams, Hieab H H, Lehtimäki, Terho, Trompet, Stella, Sarin, Antti-Pekka, Wedenoja, Juho, Hinds, David A, Buring, Julie E, Schürks, Markus, Gudlaug Hrafnsdottir, Maria, Stefansson, Hreinn, Ring, Susan M, Hottenga, Jouke-Jan, Mishra, Aniket, Penninx, Brenda W J H, Färkkilä, Markus, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Malik, Rainer, Heath, Andrew C, Madden, Pamela A F, Martin, Nicholas G, Montgomery, Grant W, Jian, Xueqiu, Saba, Yasaman, Kurki, Mitja, Kals, Mart, Mägi, Reedik, Pärn, Kalle, Hämäläinen, Eija, Huang, Hailiang, Byrnes, Andrea E, Franke, Lude, Huang, Jie, Stergiakouli, Evie, Satizabal, Claudia L, Lee, Phil H, Sandor, Cynthia, Webber, Caleb, Cader, Zameel, Muller-Myhsok, Bertram, Schreiber, Stefanie, Meitinger, Thomas, Eriksson, Johan G, Salomaa, Veikko, Heikkilä, Kauko, Beaudet, Gregory, Loehrer, Elizabeth, Uitterlinden, Andre G, Hofman, Albert, van Duijn, Cornelia M, Cherkas, Lynn, Pedersen, Linda M, Stubhaug, Audun, Nielsen, Christopher S, Männikkö, Minna, Mihailov, Evelin, Petit, Laurent, Milani, Lili, Göbel, Hartmut, Esserlind, Ann-Louise, Francke Christensen, Anne, Folkmann Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Aromaa, Arpo J, Raitakari, Olli, Ikram, M Arfan, Tsuchida, Ami, Spector, Tim, Järvelin, Marjo-Riitta, Metspalu, Andres, Kubisch, Christian, Strachan, David P, Ferrari, Michel D, Belin, Andrea C, Dichgans, Martin, Wessman, Maija, van den Maagdenberg, Arn M J M, Zago, Laure, Zwart, John-Anker, Boomsma, Dorret I, Davey Smith, George, Stefansson, Kari, Eriksson, Nicholas, Daly, Mark J, Neale, Benjamin M, Olesen, Jes, Nyholt, Dale R, Schilling, Sabrina, Palotie, Aarno, Sigurdsson, Sigurdur, Gottesman, Rebecca F, Lewis, Cora E, Sarnowski, Chloé, Aggarwal, Neelum T, Lopez, Oscar L, Smith, Jennifer A, Valdés Hernández, Maria C, van der Grond, Jeroen, Wright, Margaret J, Knol, Maria J, Dörr, Marcus, Thomson, Russell J, Bordes, Constance, Evans, Tavia E, Le Grand, Quentin, Duperron, Marie-Gabrielle, Smith, Albert V, Knopman, David S, Schreiner, Pamela J, Evans, Denis A, Rotter, Jerome I, Beiser, Alexa S, Maniega, Susana Muñoz, Beekman, Marian, Bis, Joshua C, Trollor, Julian, Stott, David J, Vernooij, Meike W, Wittfeld, Katharina, Niessen, Wiro J, Soumaré, Aicha, Boerwinkle, Eric, Sidney, Stephen, Turner, Stephen T, Davies, Gail, Eiriksdottir, Gudny, Thalamuthu, Anbupalam, Völker, Uwe, van Buchem, Mark A, Bryan, R Nick, Dupuis, Josée, Bastin, Mark E, Ames, David, Teumer, Alexander, Kwok, John B, Sakaue, Saori, Bülow, Robin, Deary, Ian J, Schofield, Peter R, Brodaty, Henry, Jiang, Jiyang, Tabara, Yasuharu, Setoh, Kazuya, Miyamoto, Susumu, Yoshida, Kazumichi, Nagata, Manabu, Terzikhan, Natalie, Kamatani, Yoichiro, Matsuda, Fumihiko, Bennett, David A, De Jager, Philip L, Mosley, Thomas H, Sachdev, Perminder S, Schmidt, Reinhold, Warren, Helen R, Evangelou, Evangelos, Habes, Mohamad, Thrombosis, International Network against, Consortium, International Headache Genomics, Ikram, Mohammad A, Wen, Wei, DeCarli, Charles, Srikanth, Velandai K, Jukema, J Wouter, Slagboom, Eline P, Kardia, Sharon L R, Equipe VINTAGE - Inserm U1219 [Bordeaux], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), and Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Adult, Male, epidemiology [Alzheimer Disease], genetics [Alzheimer Disease], diagnosis [Cerebral Small Vessel Diseases], epidemiology [Hypertension], Genome-wide association studies, behavioral disciplines and activities, Risk Assessment, Article, diagnostic imaging [White Matter], Young Adult, Alzheimer Disease, Risk Factors, White matter disease, mental disorders, Humans, Medical History Taking, Aged, Aged, 80 and over, [SCCO.NEUR]Cognitive science/Neuroscience, Mendelian Randomization Analysis, Middle Aged, White Matter, Stroke, Diffusion Tensor Imaging, Genetic Loci, Cerebral Small Vessel Diseases, complications [Cerebral Small Vessel Diseases], Hypertension, genetics [Stroke], genetics [Cerebral Small Vessel Diseases], Female, genetics [Hypertension], ddc:500, epidemiology [Stroke], Genome-Wide Association Study
Abstract

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials., White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

Published
2020

42. Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study

Author

Georgakis, Marios K, Malik, Rainer, Gordon, William, Davey-Smith, George, Morrison, Alanna C, Hicks, Andrew, van Duijn, Cornelia M, Ward-Caviness, Cavin, Boerwinkle, Eric, Rotter, J., Rice, Ken, Lange, Leslie, Perola, Markus, van Hylckama Vlieg, Astrid, de Geus, Eco, Morris, Andrew P, Makela, Kari Matti, Stacey, David, Eriksson, Johan, Frayling, Tim M, Slagboom, Eline P, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Chen, Ming-Huei, Gill, Dipender, Turman, Constance, Germain, Marine, Wiggins, Kerri L, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Pankratz, Nathan, Jackson, Rabecca D, Nielsen, Jonas B, Giulianini, Franco, Franceschini, Nora, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Damrauer, Scott M, Natarajan, Pradeep, Klarin, Derek, de Vries, Paul S, SabaterLleal, Maria, Huffman, Jennifer E, Bammler, Theo K, Sudlow, Cathie L M, Frazer, Kelly A, McCauley, Bryan M, Taylor, Kent, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean-François, O'Donnell, Chris J, Kim, Jihye, McKnight, Barbara, Dichgans, Martin, Kraft, Peter, Hansen, JohnBjarne, Rosendaal, Frits R, Heit, John A, Psaty, Bruce M, Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M, Morange, Pierre Emmanuel, INVENT Consortium, CHARGE Inflammation Working Group, Johnson, Andrew D, Kabrhel, Christopher, Trégouët, David-Alexandre, Smith, Nicholas L, Benjamin, Emelia, Dehghan, Abbas, Ahluwalia, Tarunveer Singh, Meigs, James, Tracy, Russell, Lindstrom, Sara, Alizadeh, Behrooz Z, Ligthart, Symen, Bis, Josh, Eiriksdottir, Gudny, Gross, Myron, Rainer, Alex, Snieder, Harold, Wilson, James G, Wang, Lu, Dupuis, Josee, Prins, Bram, Vaso, Urmo, Stathopoulou, Maria, Franke, Lude, Lehtimaki, Terho, Koenig, Wolfgang, Jamshidi, Yalda, Siest, Sophie, Abbasi, Ali, Smith, Erin N, Uitterlinden, Andre G, Abdollahi, Mohammadreza, Schnabel, Renate, Schick, Ursula M, Nolte, Ilja M, Kraja, Aldi, Hsu, Yi-Hsiang, Tylee, Daniel S, Zwicker, Alyson, Uher, Rudolf, Environmental Geography (former), and Biological Psychology

Subjects
Male, Genome-wide association study, Disease, 030204 cardiovascular system & hematology, Coronary artery disease, 0302 clinical medicine, Medicine, genetics, Myocardial infarction, Stroke, diagnostic imaging [Ischemic Stroke], 0303 health sciences, Atrial fibrillation, General Medicine, stroke, 3. Good health, Cardiology, Female, coronary artery disease, INVENT Consortium,CHARGE Inflammation Working Group, Signal Transduction, medicine.medical_specialty, genetics [Interleukin-6], Lower risk, genetics [Signal Transduction], 03 medical and health sciences, Internal medicine, Mendelian randomization, Research Letter, Humans, Genetic Predisposition to Disease, ddc:610, Ischemic Stroke, 030304 developmental biology, Interleukin-6, business.industry, Odds ratio, genetics [Ischemic Stroke], Mendelian Randomization Analysis, medicine.disease, cardiovascular diseases, inflammation, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

BackgroundStudies in humans and experimental models highlight a role of interleukin-6 (IL-6) in cardiovascular disease. Indirect evidence suggests that inhibition of IL-6 signaling could lower risk of coronary artery disease. However, whether such an approach would be effective for ischemic stroke and other cardiovascular outcomes remains unknown.MethodsIn a genome-wide association study (GWAS) of 204,402 European individuals, we identified genetic proxies for downregulated IL-6 signaling as genetic variants in the IL-6 receptor (IL6R) locus that were associated with lower C-reactive protein (CRP) levels, a downstream effector of IL-6 signaling. We then applied two-sample Mendelian randomization (MR) to explore associations with ischemic stroke and its major subtypes (large artery stroke, cardioembolic stroke, small vessel stroke) in the MEGASTROKE dataset (34,217 cases and 404,630 controls), with coronary artery disease in the CARDIoGRAMplusC4D dataset (60,801 cases and 123,504 control), and with other cardiovascular outcomes in the UK Biobank (up to 321,406 individuals) and in phenotype-specific GWAS datasets. All effect estimates were scaled to the CRP-decreasing effects of tocilizumab, a monoclonal antibody targeting IL-6R.ResultsWe identified 7 genetic variants as proxies for downregulated IL-6 signaling, which showed effects on upstream regulators (IL-6 and soluble IL-6R levels) and downstream effectors (CRP and fibrinogen levels) of the pathway that were consistent with pharmacological blockade of IL-6R. In MR, proxies for downregulated IL-6 signaling were associated with lower risk of ischemic stroke (Odds Ratio [OR]: 0.89, 95%CI: 0.82-0.97) and coronary artery disease (OR: 0.84, 95%CI: 0.77-0.90). Focusing on ischemic stroke subtypes, we found significant associations with risk of large artery (OR: 0.76, 95%CI: 0.62-0.93) and small vessel stroke (OR: 0.71, 95%CI: 0.59-0.86), but not cardioembolic stroke (OR: 0.95, 95%CI: 0.74-1.22). Proxies for IL-6 signaling inhibition were further associated with a lower risk of myocardial infarction, aortic aneurysm, atrial fibrillation and carotid plaque.ConclusionsWe provide evidence for a causal effect of IL-6 signaling on ischemic stroke, particularly large artery and small vessel stroke, and a range of other cardiovascular outcomes. IL-6R blockade might represent a valid therapeutic target for lowering cardiovascular risk and should thus be investigated in clinical trials.CLINICAL PERSPECTIVEWhat is newWe identified genetic proxies for downregulated IL-6 signaling that had effects on upstream and downstream regulators of the IL-6 signaling pathway consistent with those of pharmacological IL-6R blockadeGenetically downregulated IL-6 signaling was associated with a lower risk of ischemic stroke, and in particular large artery and small vessel strokeSimilar associations were obtained for a broad range of other cardiovascular outcomesWhat are the clinical implicationsInhibition of IL-6 signaling is a promising therapeutic target for lowering risk of stroke and other cardiovascular outcomes and should be further investigated in clinical trials

Published
2020

43. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Anderson, Christopher D, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie L M, Tanislav, Christian, Tatlisumak, Turgut, Chong, Michael, Taylor, Kent D, Thijs, Vincent N S, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Adams, Hieab H H, Wassertheil-Smoller, Sylvia, Wilson, James G, Wiggins, Kerri L, Yang, Qiong, Yusuf, Salim, Consortium, AFGen, Epidemiology, Cohorts for Heart and Aging Research in Genomic, Pressure, International Genomics of Blood, Consortium, INVENT, STARNET, Ago, Tetsuro, Bis, Joshua C, Pastinen, Tomi, Ruusalepp, Arno, Schadt, Eric E, Koplev, Simon, Björkegren, Johan L M, Codoni, Veronica, Civelek, Mete, Smith, Nicholas L, Trégouët, David A, Almgren, Peter, Christophersen, Ingrid E, Roselli, Carolina, Lubitz, Steven A, Ellinor, Patrick T, Tai, E Shyong, Kooner, Jaspal S, Kato, Norihiro, He, Jiang, van der Harst, Pim, Elliott, Paul, Amouyel, Philippe, Chambers, John C, Takeuchi, Fumihiko, Johnson, Andrew D, Group, BioBank Japan Cooperative Hospital, Consortium, COMPASS, Consortium, EPIC-CVD, Consortium, EPIC-InterAct, Consortium, International Stroke Genetics, Consortium, METASTROKE, Consortium, Neurology Working Group of the CHARGE, Ay, Hakan, Network, NINDS Stroke Genetics, Study, UK Young Lacunar DNA, Consortium, MEGASTROKE, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez-Cadenas, Israel, Longstreth, W. T., Rolfs, Arndt, Bartz, Traci M, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Benavente, Oscar R, Fornage, Myriam, Markus, Hugh S, Howson, Joanna M M, Kamatani, Yoichiro, Debette, Stephanie, Dichgans, Martin, Traylor, Matthew, Sargurupremraj, Muralidharan, Bevan, Steve, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei-Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul I W, DeStefano, Anita L, Hoed, Marcel den, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I, Ikram, M Arfan, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei-Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O'Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Amin, Najaf, Aparicio, Hugo S, Arnett, Donna K, Attia, John, Beiser, Alexa S, Berr, Claudine, Buring, Julie E, Bustamante, Mariana, Caso, Valeria, Cheng, Yu-Ching, Choi, Seung Hoan, Chowhan, Ayesha, Cullell, Natalia, Dartigues, Jean-François, Delavaran, Hossein, Delgado, Pilar, Dörr, Marcus, Engström, Gunnar, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Heitsch, Laura, Hozawa, Atsushi, Ibanez, Laura, Ilinca, Andreea, Ingelsson, Martin, Iwasaki, Motoki, Jackson, Rebecca D, Jood, Katarina, den Hoed, Marcel, Jousilahti, Pekka, Kaffashian, Sara, Kalra, Lalit, Kamouchi, Masahiro, Kitazono, Takanari, Kjartansson, Olafur, Kloss, Manja, Koudstaal, Peter J, Krupinski, Jerzy, Labovitz, Daniel L, Laurie, Cathy C, Levi, Christopher R, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Lioutas, Vasileios, Liu, Yong Mei, Lopez, Oscar L, Makoto, Hirata, Martinez-Majander, Nicolas, Matsuda, Koichi, Minegishi, Naoko, Montaner, Joan, Morris, Andrew P, Muiño, Elena, Müller-Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Peddareddygari, Leema Reddy, Pedersen, Nancy L, Pera, Joanna, Perola, Markus, Pezzini, Alessandro, Pileggi, Silvana, Rabionet, Raquel, Riba-Llena, Iolanda, Ribasés, Marta, Romero, Jose R, Roquer, Jaume, Rudd, Anthony G, Sarin, Antti-Pekka, Sarju, Ralhan, Sarnowski, Chloe, Sasaki, Makoto, Satizabal, Claudia L, Satoh, Mamoru, Sattar, Naveed, Sawada, Norie, Sibolt, Gerli, Sigurdsson, Ásgeir, Smith, Albert, Sobue, Kenji, Soriano-Tárraga, Carolina, Stanne, Tara, Stine, O Colin, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Tanno, Kozo, Teumer, Alexander, Tomppo, Liisa, Torres-Aguila, Nuria P, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Völzke, Henry, Wakai, Kenji, Weir, David, Williams, Stephen R, Wolfe, Charles D A, Wong, Quenna, Xu, Huichun, Yamaji, Taiki, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathology, Epidemiology, Radiology & Nuclear Medicine, Cardiovascular Centre (CVC), Universitat de Barcelona, Traylor, Matthew [0000-0001-6624-8621], Okada, Yukinori [0000-0002-0311-8472], Rutten-Jacobs, Loes [0000-0003-3223-885X], van der Laan, Sander W [0000-0001-6888-1404], Adams, Hieab HH [0000-0003-3687-2508], Almgren, Peter [0000-0002-0473-0241], Amouyel, Philippe [0000-0001-9088-234X], Correa, Adolfo [0000-0002-9501-600X], Cruchaga, Carlos [0000-0002-0276-2899], den Hoed, Marcel [0000-0001-8081-428X], Gustafsson, Stefan [0000-0001-5894-0351], Havulinna, Aki S [0000-0002-4787-8959], Ikram, M Arfan [0000-0003-0372-8585], Jukema, J Wouter [0000-0002-3246-8359], Kanai, Masahiro [0000-0001-5165-4408], Lewis, Cathryn M [0000-0002-8249-8476], Lin, Wei-Yu [0000-0002-9267-7988], Magnusson, Patrik K [0000-0002-7315-7899], Pulit, Sara L [0000-0002-2502-3669], Wiggins, Kerri L [0000-0003-2749-1279], Yang, Qiong [0000-0002-3658-1375], Schadt, Eric E [0000-0002-7892-8808], Koplev, Simon [0000-0002-8586-5614], Civelek, Mete [0000-0002-8141-0284], Trégouët, David A [0000-0001-9084-7800], Christophersen, Ingrid E [0000-0002-6141-4712], Roselli, Carolina [0000-0001-5267-6756], Ellinor, Patrick T [0000-0002-2067-0533], van der Harst, Pim [0000-0002-2713-686X], Elliott, Paul [0000-0002-7511-5684], Takeuchi, Fumihiko [0000-0003-3185-5661], Jern, Christina [0000-0002-7531-2354], Saleheen, Danish [0000-0001-6193-020X], Kamatani, Yoichiro [0000-0001-8748-5597], Dichgans, Martin [0000-0002-0654-387X], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, COMPASS Consortium, Linkage disequilibrium, Candidate gene, UK Young Lacunar DNA Study, Genome-wide association study, SEPIA, Linkage Disequilibrium, Epigenesis, Genetic, classification [Stroke], International Stroke Genetics Consortium (ISGC), 0302 clinical medicine, INDEL Mutation, HEMORRHAGIC STROKE, Risk Factors, Pleiotropy, Databases, Genetic, Neurology Working Group of the CHARGE Consortium, WHITE-MATTER HYPERINTENSITIES, Gene Regulatory Networks, Stroke, Genetics & Heredity, Genetics, International Genomics of Blood Pressure (iGEN-BP) Consortium, physiopathology [Stroke], AFGen Consortium, 11 Medical And Health Sciences, Genomics, 3. Good health, [MEGASTROKE Consortium], ISCHEMIC-STROKE, VINTAGE, genetics [Stroke], CORONARY-ARTERY-DISEASE, Medical genetics, Female, EPIC-InterAct Consortium, MEGASTROKE Consortium, Life Sciences & Biomedicine, Gens, medicine.medical_specialty, SUSCEPTIBILITY LOCI, STARNET, INVENT Consortium, SMALL-VESSEL DISEASE, Biology, Polymorphism, Single Nucleotide, EPIC-CVD Consortium, Article, Chromosomes, HUMAN GENETIC-VARIATION, NINDS Stroke Genetics Network (SiGN), 03 medical and health sciences, ddc:570, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Science & Technology, Models, Genetic, COMPLEX TRAITS, Computational Biology, 06 Biological Sciences, medicine.disease, METASTROKE Consortium, Human genetics, Cromosomes, BioBank Japan Cooperative Hospital Group, Genòmica, 030104 developmental biology, Genes, Genetic Loci, ATRIAL-FIBRILLATION, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, SUDDEN CARDIAC DEATH, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke sub-types. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Published
2018

44. Respiratory Health after Military Service in Southwest Asia and Afghanistan. An Official American Thoracic Society Workshop Report

Author

Yiallouros, Panayiotis, Garshick, Eric, Abraham, Joseph H., Baird, Coleen P., Ciminera, Paul, Downey, Gregory P., Falvo, Michael J., Hart, Jaime E., Jackson, David A., Jerrett, Michael, Kuschner, Ware, Helmer, Drew A., Jones, Kirk D., Krefft, Silpa D., Mallon, Timothy, Miller, Robert F., Morris, Michael J., Proctor, Susan P., Redlich, Carrie A., Rose, Cecile S., Rull, Rudolph P., Saers, Johannes, Schneiderman, Aaron I., Smith, Nicholas L., Blanc, Paul D., and Yiallouros, Panayiotis [0000-0002-8339-9285]

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Military service, Respiratory Tract Diseases, Burn pit, Pulmonary function testing, Middle East, Confidence Intervals, Humans, deployment, Medicine, Bronchitis, Iraq War, 2003-2011, Lung, Societies, Medical, Respiratory health, Asthma, American Thoracic Society Documents, particulate matter, Afghan Campaign 2001, business.industry, Constrictive Bronchiolitis, medicine.disease, United States, Military personnel, Dyspnea, Military Personnel, Cough, Emergency medicine, Female, business, Airway, constrictive bronchiolitis
Abstract

Since 2001, more than 2.7 million U.S. military personnel have been deployed in support of operations in Southwest Asia and Afghanistan. Land-based personnel experienced elevated exposures to particulate matter and other inhalational exposures from multiple sources, including desert dust, burn pit combustion, and other industrial, mobile, or military sources. A workshop conducted at the 2018 American Thoracic Society International Conference had the goals of: 1) identifying key studies assessing postdeployment respiratory health, 2) describing emerging research, and 3) highlighting knowledge gaps. The workshop reviewed epidemiologic studies that demonstrated more frequent encounters for respiratory symptoms postdeployment compared with nondeployers and for airway disease, predominantly asthma, as well as case series describing postdeployment dyspnea, asthma, and a range of other respiratory tract findings. On the basis of particulate matter effects in other populations, it also is possible that deployers experienced reductions in pulmonary function as a result of such exposure. The workshop also gave particular attention to constrictive bronchiolitis, which has been reported in lung biopsies of selected deployers. Workshop participants had heterogeneous views regarding the definition and frequency of constrictive bronchiolitis and other small airway pathologic findings in deployed populations. The workshop concluded that the relationship of airway disease, including constrictive bronchiolitis, to exposures experienced during deployment remains to be better defined. Future clinical and epidemiologic research efforts should address better characterization of deployment exposures carry out longitudinal assessment of potentially related adverse health conditions, including lung function and other physiologic changes and use rigorous histologic, exposure, and clinical characterization of patients with respiratory tract abnormalities. 16 8 e1 e16

Published
2019

45. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Author

Wain, Louise V, Verwoert, Germaine C, O'Reilly, Paul F, Shi, Gang, Johnson, Toby, Johnson, Andrew D, Bochud, Murielle, Rice, Kenneth M, Henneman, Peter, Smith, Albert V, Ehret, Georg B, Amin, Najaf, Larson, Martin G, Mooser, Vincent, Hadley, David, Dörr, Marcus, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile JW, Zhao, Jing Hua, Heath, Simon, Laan, Maris, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'an, Arora, Pankaj, Lucas, Gavin, Pirastu, Nicola, Pichler, Irene, Jackson, Anne U, Webster, Rebecca J, Zhang, Feng, Peden, John F, Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I, Trompet, Stella, Bragg-Gresham, Jennifer L, Alizadeh, Behrooz Z, Chambers, John C, Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M, Polašek, Ozren, Boban, Mladen, Nelson, Christopher P, Morrison, Alanna C, Pihur, Vasyl, Ganesh, Santhi K, Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco US, Rivadeneira, Fernando, Sijbrands, Eric JG, Uitterlinden, Andre G, Hwang, Shih-Jen, Vasan, Ramachandran S, Wang, Thomas J, Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, McArdle, Wendy L, Kroemer, Heyo K, Völker, Uwe, Völzke, Henry, Glazer, Nicole L, Taylor, Kent D, Harris, Tamara B, Alavere, Helene, Haller, Toomas, Keis, Aime, Tammesoo, Mari-Liis, Aulchenko, Yurii, Barroso, Inês, Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M, Penninx, Brenda W, Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, D'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco, Fabiola M, Facheris, Maurizio, Collins, Francis S, Bergman, Richard N, Beilby, John P, Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Anders, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S, Navarro, Pau, Wild, Sarah H, Corsi, Anna Maria, Singleton, Andrew, De Geus, Eco JC, Willemsen, Gonneke, Parker, Alex N, Rose, Lynda M, Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, LifeLines Cohort Study, Van Der Klauw, Melanie M, Zhang, Weihua, Li, Xinzhong, Scott, James, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thomas, Davies, Gail, Starr, John M, Emilsson, Valur, Plump, Andrew, Lindeman, Jan H, Hoen, Peter AC 'T, König, Inke R, EchoGen Consortium, Felix, Janine F, Clarke, Robert, Hopewell, Jemma C, Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L, Fornage, Myriam, AortaGen Consortium, Mitchell, Gary F, CHARGE Consortium Heart Failure Working Group, Smith, Nicholas L, KidneyGen Consortium, Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, CKDGen Consortium, Cardiogenics Consortium, CardioGram, Samani, Nilesh J, Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J, Wichmann, H-Erich, Raitakari, Olli T, Palmas, Walter, Kooner, Jaspal S, Stolk, Ronald P, Jukema, J Wouter, Wright, Alan F, Boomsma, Dorret I, Bandinelli, Stefania, Gyllensten, Ulf B, Wilson, James F, Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D, Palmer, Lyle J, Tuomilehto, Jaakko, Pfeufer, Arne, Gasparini, Paolo, Siscovick, David, Altshuler, David, Loos, Ruth JF, Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J, Oostra, Ben A, Metspalu, Andres, Launer, Lenore, Rettig, Rainer, Strachan, David P, Beckmann, Jacques S, Witteman, Jacqueline CM, Erdmann, Jeanette, Van Dijk, Ko Willems, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M, Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R, Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B, Psaty, Bruce M, Caulfield, Mark J, Rao, Dabeeru C, Tobin, Martin D, Elliott, Paul, and Van Duijn, Cornelia M

Subjects
Genetic Loci, Case-Control Studies, Hypertension, Humans, Blood Pressure, cardiovascular diseases, Arteries, Polymorphism, Single Nucleotide, Linkage Disequilibrium, circulatory and respiratory physiology, Follow-Up Studies, Genome-Wide Association Study
Abstract

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

Published
2018
Full Text
View/download PDF

46. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Author

Wain, Louise V., Verwoert, Germaine C., O'Reilly, Paul F., Shi, Gang, Johnson, Toby, Johnson, Andrew D., Bochud, Murielle, Rice, Kenneth M., Henneman, Peter, Smith, Albert V., Ehret, Georg B., Amin, Najaf, Larson, Martin G., Mooser, Vincent, Hadley, David, Dörr, Marcus, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile J. W., Zhao, Jing Hua, Heath, Simon, Laan, Maris, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'An, Arora, Pankaj, Lucas, Gavin, Pirastu, Nicola, Pichler, Irene, Jackson, Anne U., Webster, Rebecca J., Zhang, Feng, Peden, John F., Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I., Trompet, Stella, Bragg-Gresham, Jennifer L., Alizadeh, Behrooz Z., Chambers, John C., Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M., Polašek, Ozren, Boban, Mladen, Nelson, Christopher P., Morrison, Alanna C., Pihur, Vasyl, Ganesh, Santhi K., Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco U. S., Rivadeneira, Fernando, Sijbrands, Eric J. G., Uitterlinden, Andre G., Hwang, Shih-Jen, Vasan, Ramachandran S., Wang, Thomas J., Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, McArdle, Wendy L., Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Glazer, Nicole L., Taylor, Kent D., Harris, Tamara B., Alavere, Helene, Haller, Toomas, Keis, Aime, Tammesoo, Mari-Liis, Aulchenko, Yurii, Barroso, In S., Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M., Penninx, Brenda W., Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, D'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco M, Fabiola, Facheris, Maurizio, Collins, Francis S., Bergman, Richard N., Beilby, John P., Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Anders, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S., Navarro, Pau, Wild, Sarah H., Corsi, Anna Maria, Singleton, Andrew, De Geus, Eco J. C., Willemsen, Gonneke, Parker, Alex N., Rose, Lynda M., Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, Van Der Klauw, Melanie M., Zhang, Weihua, Li, Xinzhong, Scott, James, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thomas, Davies, Gail, Starr, John M., Emilsson, Valur, Plump, Andrew, Lindeman, Jan H., Hoen, Peter A. C. T., König, Inke R., Felix, Janine F., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L., Fornage, Myriam, Mitchell, Gary F., Smith, Nicholas L., Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Samani, Nilesh J., Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J., Wichmann, H-Erich, Raitakari, Olli T., Palmas, Walter, Kooner, Jaspal S., Stolk, Ronald P., Jukema, J Wouter, Wright, Alan F., Boomsma, Dorret I., Bandinelli, Stefania, Gyllensten, Ulf B., Wilson, James F., Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D., Palmer, Lyle J., Tuomilehto, Jaakko, Pfeufer, Arne, Gasparini, Paolo, Siscovick, David, Altshuler, David, Loos, Ruth J. F., Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J., Oostra, Ben A., Metspalu, Andres, Launer, Lenore, Rettig, Rainer, Strachan, David P., Beckmann, Jacques S., Witteman, Jacqueline C. M., Erdmann, Jeanette, Van Dijk, Ko Willems, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M., Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R., Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B., Psaty, Bruce M., Caulfield, Mark J., Rao, Dabeeru C., Tobin, Martin D., Elliott, Paul, Van Duijn, Cornelia M. McEniery CM, Wilkinson IB, Cockcroft JR, O'Shaughnessy KM, Newhouse SJ, Yasmin, Smith AV, Eiriksdottir G, Launer LJ, Sigurdsson S, Aspelund T, Gudnason V, De Bacquer D, Rietzschel ER, De Backer GG, Van Bortel L, De Buyzere ML, Segers P, Bekaert S, Gillebert TC, De Meyer T, Ferrucci L, Tanaka T, Johnson AD, Levy D, Benjamin EJ, Mitchell GF, Vita JA, Larson MG, Hamburg NM, Vasan RS, Isaacs A, Schut AF, Oostra BA, van Duijn CM, van Rijn MJ, Sie MP, Newman AB, Herrington DM, Andrews JS, Ding J, Sutton-Tyrrell KC, Harris TB, Howard TD, Liu Y, Parsa A, Shuldiner AR, McArdle PF, Gibson Q, Post WS, Dehghan A, Hofman A, Uitterlinden AG, Sijbrands EJ, Rivadeneira F, Mattace-Raso FU, Verwoert GC, Witteman JC, Scuteri A, Lakatta EG, Jewell E, Abecasis GR, Tarasov KV, Uda M, Najjar SS, Sanna S, Attwood T, Belz S, Braund P, Cambien F, Cooper J, Crisp-Hihn A, Deloukas P, Foad N, Eardman J, Goodall AH, Gracey J, Gray E, Gulde S, Gwilliams R, Heimerl S, Hengstenberg C, Jolley J, Krishnan U, Linsel-Nitschke P, Lloyd-Jones H, Lugauer I, Lundmark P, Maouche S, Moore JS, Muir D, Murray E, Nelson CP, Neudert J, Niblett D, O'Leary K, Ouwehand WH, Pollard H, Rankin A, Rice CM, Sager H, Samani NJ, Sambrook J, Schmitz G, Scholz M, Schroeder L, Schunkert H, Syvannen AC, Wallace C, Kathiresan S, Reilly MP, Erdmann J, Assimes TL, Boerwinkle E, Hall A, König IR, Laaksonen R, McPherson R, Thompson JR, Thorsteinsdottir U, Ziegler A, Absher D, Chen L, Cupples LA, Halperin E, Li M, Musunuru K, Preuss M, Schillert A, Thorleifsson G, Voight BF, Wells GA, Assime TL, Holm H, Roberts R, Stewart AF, Fortmann S, Go A, Hlatky M, Iribarren C, Knowles J, Myers R, Quertermous T, Sidney S, Risch N, Tang H, Blankenberg S, Zeller T, Wild P, Schnabel R, Sinning C, Lackner K, Tiret L, Nicaud V, Bickel C, Rupprecht HJ, Perret C, Proust C, Münzel T, Barbalic M, Bis J, Chen IY, Cupples L, Demissie-Banjaw S, Folsom A, Glazer N, Harris T, Heckbert S, Lumley T, Marciante K, Morrison A, O' Donnell CJ, Psaty BM, Rice K, Rotter JI, Siscovick DS, Smith N, Smith A, Taylor KD, van Duijn C, Volcik K, Whitteman J, Ramachandran V, Uitterlinden A, Gretarsdottir S, Gulcher JR, Kong A, Stefansson K, Thorgeirsson G, Andersen K, Fischer M, Grosshennig A, Lieb W, Stark K, Schreiber S, Wichmann HE, Aherrahrou Z, Bruse P, Doering A, Illig T, Klopp N, Loley C, Medack A, Meisinger C, Meitinger T, Nahrstedt J, Peters A, Wagner AK, Willenborg C, Böhm BO, Dobnig H, Grammer TB, Hoffmann MM, Kleber M, März W, Meinitzer A, Winkelmann BR, Pilz S, Renner W, Scharnagl H, Stojakovic T, Tomaschitz A, Winkler K, Guiducci C, Burtt N, Gabriel SB, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Dandona S, Jarinova O, Qu L, Wilensky R, Matthai W, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Mooser V, Epstein SE, Rader DJ, Braund PS, Wright BJ, Balmforth AJ, Ball SG, Hall AS, Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, Rosamond WD, Bis JC, Folsom AR, Benjamin E, Aulchenko YS, Haritunians T, Couper D, Murabito J, Yang YA, Stricker BH, Gottdiener JS, Chang PP, Wang TJ, Rice KM, Heckbert SR, Fox ER, Willerson JT, Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Gao X, Yang Q, O'Connell JR, Schmidt H, Ketkar S, Hwang SJ, Teumer A, Paré G, Atkinson EJ, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tönjes A, Hayward C, Rampersaud E, Mitchell BD, Arking DE, Struchalin M, Cavalieri M, Singleton A, Giallauria F, Metter J, de Boer IH, Siscovick D, Zillikens MC, Feitosa M, Province M, de Andrade M, Turner ST, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Imboden M, Nitsch D, Brandstätter A, Kollerits B, Kedenko L, Mägi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Völzke H, Kroemer HK, Nauck M, Völker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Coresh J, Schmidt R, Shlipak MG, Borecki I, Krämer BK, Rudan I, Gyllensten U, Wilson JF, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS, Felix SB, Watzinger N, Homuth G, Aragam J, Dörr M, Zweiker R, Lind L, Rodeheffer RJ, Greiser KH, Deckers JW, Stritzke J, Lackner KJ, Ingelsson E, Kullo I, Haerting J, Reffelmann T, Redfield MM, Werdan K, Arnett DK, Blettner M, Friedrich N, Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, Gale DP, Wass MN, Ahmadi KR, Bakker SJ, Beckmann J, Bilo HJ, Bochud M, Brown MJ, Caulfield MJ, Connell JM, Cook HT, Cotlarciuc I, Davey Smith G, de Silva R, Deng G, Devuyst O, Dikkeschei LD, Dimkovic N, Dockrell M, Dominiczak A, Ebrahim S, Eggermann T, Farrall M, Floege J, Forouhi NG, Gansevoort RT, Han X, Hedblad B, Homan van der Heide JJ, Hepkema BG, Hernandez-Fuentes M, Hypponen E, Johnson T, de Jong PE, Kleefstra N, Lagou V, Lapsley M, Li Y, Loos RJ, Luan J, Luttropp K, Maréchal C, Munroe PB, Nordfors L, Penninx BW, Perucha E, Pouta A, Roderick PJ, Ruokonen A, Schalling M, Schlessinger D, Schlieper G, Seelen MA, Sjögren M, Smit JH, Snieder H, Soranzo N, Spector TD, Stenvinkel P, Sternberg MJ, Swaminathan R, Ubink-Veltmaat LJ, Vollenweider P, Waterworth D, Zerres K, Waeber G, Wareham NJ, Maxwell PH, McCarthy MI, Jarvelin MR, Lightstone L, Scott J, Navis G, Elliott P, Kooner JS., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), University of Leicester, Department of Genetics [Leicester], Erasmus University Rotterdam, Netherlands Genomics Initiative, Department of Epidemiology and Biostatistics, School of Public Health, Zahedan University of Medical Sciences, Washington University in Saint Louis (WUSTL), Queen Mary University of London (QMUL), National Heart, Lung and Blood Institute, Partenaires INRAE, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne = University of Lausanne (UNIL), Department of Biostatistics [Oslo], Institute of Basic Medical Sciences [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Leiden University Medical Center (LUMC), Universiteit Leiden, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], Johns Hopkins University, School of Medicine, Hôpitaux Universitaires de Genève (HUG), Department of Epidemiology, The Netherlands Cancer Institute, Department of Mathematics, Boston University [Boston] (BU), GlaxoSmithKline, Division of Community Health Sciences, St. George's, University of South Florida [Tampa] (USF), Universität Greifswald - University of Greifswald, University of Washington [Seattle], University of Tartu, Institute of Molecular and Cell Biology, Medical Research Council, Institut de Génomique, Centre National de Génotypage, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University Medical Center Groningen, Department of Genetics, University Medical Center Groningen [Groningen] (UMCG), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Massachusetts General Hospital [Boston], Centro de Regulación Genómica (CRG), Universitat Pompeu Fabra [Barcelona] (UPF), Università degli studi di Trieste = University of Trieste, Universität zu Lübeck = University of Lübeck [Lübeck], Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, The University of Western Australia (UWA), Department of Twin Research and Genetic Epidemiology, King's College London, London, University of Oxford, Medical University Graz, National Institute on Aging, Centre for population Health Sciences, University of Edinburgh, Uppsala University, Vrije Universiteit Amsterdam [Amsterdam] (VU), Western General Hospital, Harvard Medical School [Boston] (HMS), Brigham and Women's Hospital [Boston], University of Michigan System, University of Groningen, Ealing Hospital, School of Public Health - Department of Epidemiology and Biostatistics, Imperial College London, Medical Genetics Institute, Cedars-Sinai Medical Center, University of Tampere, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Split, The University of Texas Health Science Center at Houston (UTHealth), Johns Hopkins University (JHU), Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Swiss Institute of Bioinformatics [Lausanne] (SIB), Finnish Institute of Occupational Health, National Institute of Health and Welfare, University of Oulu, Lapland Central Hospital, University of Bristol [Bristol], Institute for Community Medicine, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), US National Institutes of Health, National Heart, Lung, and Blood Institute, European, Epidemiology, Internal Medicine, Public Health, Clinical Genetics, Université de Lausanne (UNIL), LeidenUniversity Medical Centre, University of Iceland, Università degli studi di Trieste, Universität zu Lübeck [Lübeck], University of Western Australia, University of Oxford [Oxford], VU University Amsterdam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Human genetics, Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Epidemiology and Data Science, Medical Research Council (MRC), Louise V., Wain, Germaine C., Verwoert, Paul F., O'Reilly, Gang, Shi, Toby, Johnson, Andrew D., Johnson, Murielle, Bochud, Kenneth M., Rice, Peter, Henneman, Albert V., Smith, Georg B., Ehret, Najaf, Amin, Martin G., Larson, Vincent, Mooser, David, Hadley, Marcus, Dörr, Joshua C., Bi, Thor, Aspelund, Tõnu, Esko, A. Cecile J. W., Janssen, Jing Hua, Zhao, Simon, Heath, Maris, Laan, Jingyuan, Fu, Giorgio, Pisti, Jian'An, Luan, Pankaj, Arora, Gavin, Luca, Pirastu, Nicola, Irene, Pichler, Anne U., Jackson, Rebecca J., Webster, Feng, Zhang, John F., Peden, Helena, Schmidt, Toshiko, Tanaka, Harry, Campbell, Wilmar, Igl, Yuri, Milaneschi, Jouke Jan, Hottenga, Veronique, Vitart, Daniel I., Chasman, Stella, Trompet, Jennifer L., Bragg Gresham, Behrooz Z., Alizadeh, John C., Chamber, Xiuqing, Guo, Terho, Lehtimäki, Brigitte, Kühnel, Lorna M., Lopez, Ozren, Polašek, Mladen, Boban, Christopher P., Nelson, Alanna C., Morrison, Vasyl, Pihur, Santhi K., Ganesh, Albert, Hofman, Suman, Kundu, Francesco U. S., Mattace Raso, Fernando, Rivadeneira, Eric J. G., Sijbrand, Andre G., Uitterlinden, Shih Jen, Hwang, Ramachandran S., Vasan, Thomas J., Wang, Sven, Bergmann, Peter, Vollenweider, Gérard, Waeber, Jaana, Laitinen, Anneli, Pouta, Paavo, Zitting, Wendy L., Mcardle, Heyo K., Kroemer, Uwe, Völker, Henry, Völzke, Nicole L., Glazer, Kent D., Taylor, Tamara B., Harri, Helene, Alavere, Toomas, Haller, Aime, Kei, Mari Liis, Tammesoo, Yurii, Aulchenko, Inês, Barroso, Kay Tee, Khaw, Pilar, Galan, Serge, Hercberg, Mark, Lathrop, Susana, Eyheramendy, Elin, Org, Siim, Sõber, Xiaowen, Lu, Ilja M., Nolte, Brenda W., Penninx, Tanguy, Corre, Corrado, Masciullo, Cinzia, Sala, Leif, Groop, Benjamin F., Voight, Olle, Melander, Christopher J., O'Donnell, Veikko, Salomaa, D'Adamo, ADAMO PIO, Antonella, Fabretto, Flavio, Faletra, Sheila, Ulivi, Fabiola Del Greco, M, Maurizio, Facheri, Francis S., Collin, Richard N., Bergman, John P., Beilby, Joseph, Hung, A., William Musk, Massimo, Mangino, So Youn, Shin, Nicole, Soranzo, Hugh, Watkin, Anuj, Goel, Anders, Hamsten, Pierre, Gider, Marisa, Loitfelder, Marion, Zeginigg, Dena, Hernandez, Samer S., Najjar, Pau, Navarro, Sarah H., Wild, Anna Maria, Corsi, Andrew, Singleton, Eco J. C., de Geu, Gonneke, Willemsen, Alex N., Parker, Lynda M., Rose, Brendan, Buckley, David, Stott, Marco, Orru, Manuela, Uda, Melanie M., van der Klauw, Weihua, Zhang, Xinzhong, Li, James, Scott, Yii Der Ida, Chen, Gregory L., Burke, Mika, Kähönen, Jorma, Viikari, Angela, Döring, Thomas, Meitinger, Gail, Davie, John M., Starr, Valur, Emilsson, Andrew, Plump, Jan H., Lindeman, Peter A. C., 't Hoen, Inke R., König, Janine F., Felix, Robert, Clarke, Jemma C., Hopewell, Halit, Ongen, Monique, Breteler, Stéphanie, Debette, Anita L., Destefano, Myriam, Fornage, Gary F., Mitchell, Nicholas L., Smith, Hilma, Holm, Kari, Stefansson, Gudmar, Thorleifsson, Unnur, Thorsteinsdottir, Nilesh J., Samani, Michael, Preu, Igor, Rudan, Caroline, Hayward, Ian J., Deary, H., Erich Wichmann, Olli T., Raitakari, Walter, Palma, Jaspal S., Kooner, Ronald P., Stolk, J., Wouter Jukema, Alan F., Wright, Dorret I., Boomsma, Stefania, Bandinelli, Ulf B., Gyllensten, James F., Wilson, Luigi, Ferrucci, Reinhold, Schmidt, Martin, Farrall, Tim D., Spector, Lyle J., Palmer, Jaakko, Tuomilehto, Arne, Pfeufer, Gasparini, Paolo, David, Siscovick, David, Altshuler, Ruth J. F., Loo, Daniela, Toniolo, Harold, Snieder, Christian, Gieger, Pierre, Meneton, Nicholas J., Wareham, Ben A., Oostra, Andres, Metspalu, Lenore, Launer, Rainer, Rettig, David P., Strachan, Jacques S., Beckmann, Jacqueline C. M., Witteman, Jeanette, Erdmann, Ko Willems van, Dijk, Eric, Boerwinkle, Michael, Boehnke, Paul M., Ridker, Marjo Riitta, Jarvelin, Aravinda, Chakravarti, Goncalo R., Abecasi, Vilmundur, Gudnason, Christopher Newton, Cheh, Daniel, Levy, Patricia B., Munroe, Bruce M., Psaty, Mark J., Caulfield, Dabeeru C., Rao, Martin D., Tobin, Paul, Elliott, Cornelia M., van Duijn, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Wain, Louise V., Verwoert, Germaine C., O'Reilly, Paul F., Shi, Gang, Johnson, Toby, Johnson, Andrew D., Bochud, Murielle, Rice, Kenneth M., Henneman, Peter, Smith, Albert V., Ehret, Georg B., Amin, Najaf, Larson, Martin G., Mooser, Vincent, Hadley, David, Dörr, Marcu, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile J. W., Zhao, Jing Hua, Heath, Simon, Laan, Mari, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'An, Arora, Pankaj, Lucas, Gavin, Pichler, Irene, Jackson, Anne U., Webster, Rebecca J., Zhang, Feng, Peden, John F., Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I., Trompet, Stella, Bragg-Gresham, Jennifer L., Alizadeh, Behrooz Z., Chambers, John C., Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M., Polašek, Ozren, Boban, Mladen, Nelson, Christopher P., Morrison, Alanna C., Pihur, Vasyl, Ganesh, Santhi K., Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco U. S., Rivadeneira, Fernando, Sijbrands, Eric J. G., Uitterlinden, Andre G., Hwang, Shih-Jen, Vasan, Ramachandran S., Wang, Thomas J., Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, Mcardle, Wendy L., Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Glazer, Nicole L., Taylor, Kent D., Harris, Tamara B., Alavere, Helene, Haller, Tooma, Keis, Aime, Tammesoo, Mari-Lii, Aulchenko, Yurii, Barroso, In S., Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M., Penninx, Brenda W., Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, D'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco M, Fabiola, Facheris, Maurizio, Collins, Francis S., Bergman, Richard N., Beilby, John P., Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Ander, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S., Navarro, Pau, Wild, Sarah H., Corsi, Anna Maria, Singleton, Andrew, De Geus, Eco J. C., Willemsen, Gonneke, Parker, Alex N., Rose, Lynda M., Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, Van Der Klauw, Melanie M., Zhang, Weihua, Li, Xinzhong, Scott, Jame, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thoma, Davies, Gail, Starr, John M., Emilsson, Valur, Plump, Andrew, Lindeman, Jan H., Hoen, Peter A. C. T., König, Inke R., Felix, Janine F., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L., Fornage, Myriam, Mitchell, Gary F., Smith, Nicholas L., Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Samani, Nilesh J., Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J., Wichmann, H-Erich, Raitakari, Olli T., Palmas, Walter, Kooner, Jaspal S., Stolk, Ronald P., Jukema, J Wouter, Wright, Alan F., Boomsma, Dorret I., Bandinelli, Stefania, Gyllensten, Ulf B., Wilson, James F., Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D., Palmer, Lyle J., Tuomilehto, Jaakko, Pfeufer, Arne, Siscovick, David, Altshuler, David, Loos, Ruth J. F., Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J., Oostra, Ben A., Metspalu, Andre, Launer, Lenore, Rettig, Rainer, Strachan, David P., Beckmann, Jacques S., Witteman, Jacqueline C. M., Erdmann, Jeanette, Van Dijk, Ko Willem, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M., Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R., Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B., Psaty, Bruce M., Caulfield, Mark J., Rao, Dabeeru C., Tobin, Martin D., Elliott, Paul, Van, Duijn, Cornelia M., McEniery CM, Wilkinson, Ib, Cockcroft, Jr, O'Shaughnessy, Km, Newhouse, Sj, Yasmin, Smith, Av, Eiriksdottir, G, Launer, Lj, Sigurdsson, S, Aspelund, T, Gudnason, V, De Bacquer, D, Rietzschel, Er, De Backer, Gg, Van Bortel, L, De Buyzere, Ml, Segers, P, Bekaert, S, Gillebert, Tc, De Meyer, T, Ferrucci, L, Tanaka, T, Johnson, Ad, Levy, D, Benjamin, Ej, Mitchell, Gf, Vita, Ja, Larson, Mg, Hamburg, Nm, Vasan, R, Isaacs, A, Schut, Af, Oostra, Ba, van Duijn, Cm, van Rijn, Mj, Sie, Mp, Newman, Ab, Herrington, Dm, Andrews, J, Ding, J, Sutton-Tyrrell, Kc, Harris, Tb, Howard, Td, Liu, Y, Parsa, A, Shuldiner, Ar, Mcardle, Pf, Gibson, Q, Post, W, Dehghan, A, Hofman, A, Uitterlinden, Ag, Sijbrands, Ej, Rivadeneira, F, Mattace-Raso, Fu, Verwoert, Gc, Witteman, Jc, Scuteri, A, Lakatta, Eg, Jewell, E, Abecasis, Gr, Tarasov, Kv, Uda, M, Najjar, S, Sanna, S, Attwood, T, Belz, S, Braund, P, Cambien, F, Cooper, J, Crisp-Hihn, A, Deloukas, P, Foad, N, Eardman, J, Goodall, Ah, Gracey, J, Gray, E, Gulde, S, Gwilliams, R, Heimerl, S, Hengstenberg, C, Jolley, J, Krishnan, U, Linsel-Nitschke, P, Lloyd-Jones, H, Lugauer, I, Lundmark, P, Maouche, S, Moore, J, Muir, D, Murray, E, Nelson, Cp, Neudert, J, Niblett, D, O'Leary, K, Ouwehand, Wh, Pollard, H, Rankin, A, Rice, Cm, Sager, H, Samani, Nj, Sambrook, J, Schmitz, G, Scholz, M, Schroeder, L, Schunkert, H, Syvannen, Ac, Wallace, C, Kathiresan, S, Reilly, Mp, Erdmann, J, Assimes, Tl, Boerwinkle, E, Hall, A, König, Ir, Laaksonen, R, Mcpherson, R, Thompson, Jr, Thorsteinsdottir, U, Ziegler, A, Absher, D, Chen, L, Cupples, La, Halperin, E, Li, M, Musunuru, K, Preuss, M, Schillert, A, Thorleifsson, G, Voight, Bf, Wells, Ga, Assime, Tl, Holm, H, Roberts, R, Stewart, Af, Fortmann, S, Go, A, Hlatky, M, Iribarren, C, Knowles, J, Myers, R, Quertermous, T, Sidney, S, Risch, N, Tang, H, Blankenberg, S, Zeller, T, Wild, P, Schnabel, R, Sinning, C, Lackner, K, Tiret, L, Nicaud, V, Bickel, C, Rupprecht, Hj, Perret, C, Proust, C, Münzel, T, Barbalic, M, Bis, J, Chen, Iy, Cupples, L, Demissie-Banjaw, S, Folsom, A, Glazer, N, Harris, T, Heckbert, S, Lumley, T, Marciante, K, Morrison, A, O' Donnell, Cj, Psaty, Bm, Rice, K, Rotter, Ji, Siscovick, D, Smith, N, Smith, A, Taylor, Kd, van Duijn, C, Volcik, K, Whitteman, J, Ramachandran, V, Uitterlinden, A, Gretarsdottir, S, Gulcher, Jr, Kong, A, Stefansson, K, Thorgeirsson, G, Andersen, K, Fischer, M, Grosshennig, A, Lieb, W, Stark, K, Schreiber, S, Wichmann, He, Aherrahrou, Z, Bruse, P, Doering, A, Illig, T, Klopp, N, Loley, C, Medack, A, Meisinger, C, Meitinger, T, Nahrstedt, J, Peters, A, Wagner, Ak, Willenborg, C, Böhm, Bo, Dobnig, H, Grammer, Tb, Hoffmann, Mm, Kleber, M, März, W, Meinitzer, A, Winkelmann, Br, Pilz, S, Renner, W, Scharnagl, H, Stojakovic, T, Tomaschitz, A, Winkler, K, Guiducci, C, Burtt, N, Gabriel, Sb, O'Donnell, Cj, Elosua, R, Peltonen, L, Salomaa, V, Schwartz, Sm, Melander, O, Altshuler, D, Dandona, S, Jarinova, O, Qu, L, Wilensky, R, Matthai, W, Hakonarson, Hh, Devaney, J, Burnett, M, Pichard, Ad, Kent, Km, Satler, L, Lindsay, Jm, Waksman, R, Knouff, Cw, Waterworth, Dm, Walker, Mc, Mooser, V, Epstein, Se, Rader, Dj, Wright, Bj, Balmforth, Aj, Ball, Sg, Smith, Nl, Felix, Jf, Morrison, Ac, Demissie, S, Glazer, Nl, Loehr, Lr, Rosamond, Wd, Bis, Jc, Folsom, Ar, Benjamin, E, Aulchenko, Y, Haritunians, T, Couper, D, Murabito, J, Yang, Ya, Stricker, Bh, Gottdiener, J, Chang, Pp, Wang, Tj, Rice, Km, Heckbert, Sr, Fox, Er, Willerson, Jt, Köttgen, A, Pattaro, C, Böger, Ca, Fuchsberger, C, Olden, M, Gao, X, Yang, Q, O'Connell, Jr, Schmidt, H, Ketkar, S, Hwang, Sj, Teumer, A, Paré, G, Atkinson, Ej, Lohman, K, Cornelis, Mc, Probst-Hensch, Nm, Kronenberg, F, Tönjes, A, Hayward, C, Rampersaud, E, Mitchell, Bd, Arking, De, Struchalin, M, Cavalieri, M, Singleton, A, Giallauria, F, Metter, J, de Boer, Ih, Zillikens, Mc, Feitosa, M, Province, M, de Andrade, M, Turner, St, Schnabel, Rb, Wilde, S, Munzel, Tf, Leak, T, Koenig, W, Zgaga, L, Zemunik, T, Kolcic, I, Minelli, C, Hu, Fb, Johansson, A, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Imboden, M, Nitsch, D, Brandstätter, A, Kollerits, B, Kedenko, L, Mägi, R, Stumvoll, M, Kovacs, P, Boban, M, Campbell, S, Endlich, K, Völzke, H, Kroemer, Hk, Nauck, M, Völker, U, Polasek, O, Vitart, V, Badola, S, Parker, An, Ridker, Pm, Kardia, Sl, Curhan, Gc, Franke, A, Rochat, T, Paulweber, B, Prokopenko, I, Wang, W, Coresh, J, Schmidt, R, Shlipak, Mg, Borecki, I, Krämer, Bk, Rudan, I, Gyllensten, U, Wilson, Jf, Pramstaller, Pp, Rettig, R, Hastie, N, Chasman, Di, Kao, Wh, Heid, Im, Fox, C, Felix, Sb, Watzinger, N, Homuth, G, Aragam, J, Dörr, M, Zweiker, R, Lind, L, Rodeheffer, Rj, Greiser, Kh, Deckers, Jw, Stritzke, J, Lackner, Kj, Ingelsson, E, Kullo, I, Haerting, J, Reffelmann, T, Redfield, Mm, Werdan, K, Arnett, Dk, Blettner, M, Friedrich, N, Chambers, Jc, Zhang, W, Lord, Gm, van der Harst, P, Lawlor, Da, Sehmi, J, Gale, Dp, Wass, Mn, Ahmadi, Kr, Bakker, Sj, Beckmann, J, Bilo, Hj, Bochud, M, Brown, Mj, Caulfield, Mj, Connell, Jm, Cook, Ht, Cotlarciuc, I, Davey Smith, G, de Silva, R, Deng, G, Devuyst, O, Dikkeschei, Ld, Dimkovic, N, Dockrell, M, Dominiczak, A, Ebrahim, S, Eggermann, T, Farrall, M, Floege, J, Forouhi, Ng, Gansevoort, Rt, Han, X, Hedblad, B, Homan van der Heide, Jj, Hepkema, Bg, Hernandez-Fuentes, M, Hypponen, E, Johnson, T, de Jong, Pe, Kleefstra, N, Lagou, V, Lapsley, M, Li, Y, Loos, Rj, Luan, J, Luttropp, K, Maréchal, C, Munroe, Pb, Nordfors, L, Penninx, Bw, Perucha, E, Pouta, A, Roderick, Pj, Ruokonen, A, Schalling, M, Schlessinger, D, Schlieper, G, Seelen, Ma, Sjögren, M, Smit, Jh, Snieder, H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Ubink-Veltmaat, Lj, Vollenweider, P, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Lightstone, L, Scott, J, Navis, G, Elliott, P, and Kooner, Js.

Subjects
Netherlands Twin Register (NTR), Linkage disequilibrium, pulse pressure, mean arterial pressure, genome-wide, [SDV]Life Sciences [q-bio], Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, 030204 cardiovascular system & hematology, Linkage Disequilibrium, 0302 clinical medicine, RELEVANCE, CardioGram, Medicine and Health Sciences, Genetics & Heredity, ddc:616, Genetics, 0303 health sciences, Genome-wide association, 11 Medical And Health Sciences, Arteries, ADRENERGIC-RECEPTOR TRAFFICKING, Pulse pressure, EchoGen consortium, Hypertension, HEART-FAILURE, arterial pressure, Case-Control Studie, Life Sciences & Biomedicine, Human, circulatory and respiratory physiology, medicine.medical_specialty, Mean arterial pressure, Arterie, AortaGen Consortium, Cardiogenics consortium, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, Follow-Up Studie, 03 medical and health sciences, Internal medicine, medicine, Humans, cardiovascular diseases, METAANALYSIS, 030304 developmental biology, Genetic association, Science & Technology, HYPERTENSION, MORTALITY, Case-control study, CARDIOVASCULAR-DISEASE RISK, 06 Biological Sciences, GENE, MICE, Endocrinology, Blood pressure, CKDGen consortium, Genetic Loci, Case-Control Studies, KidneyGen consortium, CHARGE Consortium Heart Failure Working Group, LifeLines Cohort Study, Developmental Biology, Follow-Up Studies, Genome-Wide Association Study
Abstract

Les affiliations des 100 premiers auteurs sont renseignées dans la notice. Les affiliations des autres auteurs sont disponibles à la fin de la publication.; International audience; Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans(1-3). We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 x 10(-8) to P = 2.3 x 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

Published
2016

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

Author

Ehret, Georg B., Munroe, Patricia B., Rice, Kenneth M., Bochud, Murielle, Johnson, Andrew D., Chasman, Daniel I., Smith, Albert V., Tobin, Martin D., Verwoert, Germaine C., Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O'Reilly, Paul F., Amin, Najaf, Bragg-Gresham, Jennifer L., Teumer, Alexander, Glazer, Nicole L., Launer, Lenore, Zhao, Jing Hua, Aulchenko, Yurii, Heath, Simon, Sober, Siim, Parsa, Afshin, Luan, Jian'an, Arora, Pankaj, Dehghan, Abbas, Zhang, Feng, Lucas, Gavin, Hicks, Andrew A., Jackson, Anne U., Peden, John F., Tanaka, Toshiko, Wild, Sarah H., Rudan, Igor, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N., Fava, Cristiano, Chambers, John C., Fox, Ervin R., Kumari, Meena, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Whincup, Peter H., Liu, Yongmei, Shi, Gang, Kuusisto, Johanna, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Hoang Nguyen, Khanh-Dung, Lehtimäki, Terho, Matullo, Giuseppe, Wu, Ying, Gaunt, Tom R., Charlotte Onland-Moret, N., Cooper, Matthew N., Platou, Carl G. P., Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Braund, Peter S., Kuznetsova, Tatiana, Uiterwaal, Cuno S. P. M., Adeyemo, Adebowale, Palmas, Walter, Campbell, Harry, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D., Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C., O'Connell, Jeffrey R., Steinle, Nanette I., Grobbee, Diederick E., Arking, Dan E., Kardia, Sharon L., Morrison, Alanna C., Hernandez, Dena, Najjar, Samer, McArdle, Wendy L., Hadley, David, Brown, Morris J., Connell, John M., Hingorani, Aroon D., Day, Ian N. M., Lawlor, Debbie A., Beilby, John P., Lawrence, Robert W., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Dreisbach, Albert W., Li, Yali, Hunter Young, J., Bis, Joshua C., Kähönen, Mika, Viikari, Jorma, Adair, Linda S., Lee, Nanette R., Chen, Ming-Huei, Olden, Matthias, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Frayling, Timothy M., Islam, Muhammad, Jafar, Tazeen H., Erdmann, Jeanette, Kulkarni, Smita R., Bornstein, Stefan R., Grässler, Jürgen, Groop, Leif, Voight, Benjamin F., Kettunen, Johannes, Howard, Philip, Taylor, Andrew, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Barroso, Inês, Khaw, Kay-Tee, Weder, Alan B., Hunt, Steven C., Sun, Yan V., Bergman, Richard N., Collins, Francis S., Bonnycastle, Lori L., Scott, Laura J., Stringham, Heather M., Peltonen, Leena, Perola, Markus, Vartiainen, Erkki, Brand, Stefan-Martin, Staessen, Jan A., Wang, Thomas J., Burton, Paul R., Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K., Rudock, Megan E., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margus, Kinra, Sanjay, Prabhakaran, Dorairaj, Tripathy, Vikal, Langefeld, Carl D., Rosengren, Annika, Thelle, Dag S., Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, McKenzie, Colin A., Salako, Tunde, Iwai, Naoharu, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thomas, Wichmann, H. -Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, James, Sehmi, Joban S., Zhang, Weihua, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Wong, Andrew, Narisu, Narisu, Stančáková, Alena, Raffel, Leslie J., Yao, Jie, Kathiresan, Sekar, O'Donnell, Christopher J., Schwartz, Stephen M., Arfan Ikram, M., Longstreth Jr. , W. T., Mosley, Thomas H., Seshadri, Sudha, Shrine, Nick R. G., Wain, Louise V., Morken, Mario A., Swift, Amy J., Laitinen, Jaana, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A., Humphries, Steve E., Danesh, John, Rasheed, Asif, Goel, Anuj, Hamsten, Anders, Watkins, Hugh, Bakker, Stephan J. L., van Gilst, Wiek H., Janipalli, Charles S., Radha Mani, K., Yajnik, Chittaranjan S., Hofman, Albert, Mattace-Raso, Francesco U. S., Oostra, Ben A., Demirkan, Ayse, Isaacs, Aaron, Rivadeneira, Fernando, Lakatta, Edward G., Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J., Lyytikäinen, Leo-Pekka, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Twee-HeeOng, Rick, Dörr, Marcus, Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Deloukas, Panos, Mangino, Massimo, Spector, Tim D., Zhai, Guangju, Meschia, James F., Nalls, Michael A., Sharma, Pankaj, Terzic, Janos, Kranthi Kumar, M. V., Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E., Fowkes, F. Gerald R., Charchar, Fadi J., Schwarz, Peter E. H., Hayward, Caroline, Guo, Xiuqing, Rotimi, Charles, Bots, Michiel L., Brand, Eva, Samani, Nilesh J., Polasek, Ozren, Talmud, Philippa J., Nyberg, Fredrik, Kuh, Diana, Laan, Maris, Hveem, Kristian, Palmer, Lyle J., van der Schouw, Yvonne T., Casas, Juan P., Mohlke, Karen L., Vineis, Paolo, Raitakari, Olli, Ganesh, Santhi K., Wong, Tien Y., Shyong Tai, E., Cooper, Richard S., Laakso, Markku, Rao, Dabeeru C., Harris, Tamara B., Morris, Richard W., Dominiczak, Anna F., Kivimaki, Mika, Marmot, Michael G., Miki, Tetsuro, Saleheen, Danish, Chandak, Giriraj R., Coresh, Josef, Navis, Gerjan, Salomaa, Veikko, Han, Bok-Ghee, Zhu, Xiaofeng, Kooner, Jaspal S., Melander, Olle, Ridker, Paul M., Bandinelli, Stefania, Gyllensten, Ulf B., Wright, Alan F., Wilson, James F., Ferrucci, Luigi, Farrall, Martin, Tuomilehto, Jaakko, Pramstaller, Peter P., Elosua, Roberto, Soranzo, Nicole, Sijbrands, Eric J. G., Altshuler, David, Loos, Ruth J. F., Shuldiner, Alan R., Gieger, Christian, Meneton, Pierre, Uitterlinden, Andre G., Wareham, Nicholas J., Gudnason, Vilmundur, Rotter, Jerome I., Rettig, Rainer, Uda, Manuela, Strachan, David P., Witteman, Jacqueline C. M., Hartikainen, Anna-Liisa, Beckmann, Jacques S., Boerwinkle, Eric, Vasan, Ramachandran S., Boehnke, Michael, Larson, Martin G., Järvelin, Marjo-Riitta, Psaty, Bruce M., Abecasis, Gonçalo R., Chakravarti, Aravinda, Elliott, Paul, van Duijn, Cornelia M., Newton-Cheh, Christopher, Levy, Daniel, Caulfield, Mark J., Johnson, Toby, Tang H, Knowles J, Hlatky M, Fortmann S, Assimes TL, Quertermous T, Go A, Iribarren C, Absher D, Risch N, Meyers R, Sidney S, Ziegler A, Schillert A, Bickel C, Sinning C, Rupprecht HJ, Lackner K, Wild P, Schnabel R, Blankenberg S, Zeller T, Münzel T, Perret C, Cambien F, Tiret L, Nicaud V, Proust C, Dehghan A, Hofman A, Uitterlinden A, van Duijn C, Levy D, Whitteman J, Cupples LA, Demissie-Banjaw S, Ramachandran V, Smith A, Gudnason V, Boerwinkle E, Folsom A, Morrison A, Psaty BM, Chen IY, Rotter JI, Bis J, Volcik K, Rice K, Taylor KD, Marciante K, Smith N, Glazer N, Heckbert S, Harris T, Lumley T, Kong A, Thorleifsson G, Thorgeirsson G, Holm H, Gulcher JR, Stefansson K, Andersen K, Gretarsdottir S, Thorsteinsdottir U, Preuss M, Schreiber S, Meitinger T, König IR, Lieb W, Hengstenberg C, Schunkert H, Erdmann J, Fisher M, Grosshennig A, Medack A, Stark K, Linsel-Nitschke P, Bruse P, Aherrahrou Z, Peters A, Loley C, Willenborg C, Nahrstedt J, Freyer J, Gulde S, Doering A, Meisinger C, Wichmann HE, Klopp N, Illig T, Meinitzer A, Tomaschitz A, Halperin E, Dobnig H, Scharnagl H, Kleber M, Laaksonen R, Pilz S, Grammer TB, Stojakovic T, Renner W, März W, Böhm BO, Winkelmann BR, Winkler K, Hoffmann M, O'Donnell CJ, Voight BF, Altshuler D, Siscovick DS, Musunuru K, Peltonen L, Barbalic M, Melander O, Elosua R, Kathiresan S, Schwartz SM, Salomaa V, Guiducci C, Burtt N, Gabriel SB, Stewart AF, Wells GA, Chen L, Jarinova O, Roberts R, McPherson R, Dandona S, Pichard AD, Rader DJ, Devaney J, Lindsay JM, Kent KM, Qu L, Satler L, Burnett MS, Li M, Reilly MP, Wilensky R, Waksman R, Epstein S, Mattha W, Knouf CW, Waterworth DM, Hakonarson HH, Walker M, Mooser V, Hall AS, Balmforth AJ, Wright BJ, Nelson C, Thompson JR, Samani NJ, Braund PS, Ball SG, Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, Rosamond WD, Rivadeneira F, Bis JC, Folsom AR, Benjamin E, Aulchenko YS, Haritunians T, Couper D, Murabito J, Wang YA, Stricker B, Gottdiener JS, Chang PP, Wang TJ, Rice KM, Heckbert SR, Fox ER, Uitterlinden AG, Willerson JT, van Duijn CM, Witteman JC, Vasan RS, Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Parsa A, Gao X, Yang Q, Smith AV, O'Connell JR, Schmidt H, Tanaka T, Isaacs A, Ketkar S, Hwang SJ, Johnson A, Teumer A, Paré G, Atkinson EJ, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tönjes A, Hayward C, Aspelund T, Eiriksdottir G, Launer LJ, Harris TB, Rampersaud E, Mitchell BD, Arking DE, Struchalin M, Cavalieri M, Singleton A, Giallauria, Francesco, Metter J, de Boer J, Siscovick D, Zillikens MC, Oostra BA, Feitosa M, Province M, de Andrade M, Turne ST, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Imboden M, Nitsch D, Brandstätter A, Kollerits B, Kedenko L, Mägi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Völzke H, Kroemer HK, Nauck M, Völker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Liu Y, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Shuldiner AR, Coresh J, Schmidt R, Ferrucci L, Shlipak MG, Borecki I, Krämer BK, Rudan I, Gyllensten U, Wilson JF, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS, Vasan R, Felix SB, Watzinger N, Larson MG, Homuth G, Aragam J, Dörr M, Zweiker R, Lind L, Rodeheffer RJ, Greiser KH, Deckers JW, Stritzke J, Lackner KJ, Ingelsson E, Kullo I, Haerting J, Stricker BH, Reffelmann T, Redfield MM, Werdan K, Mitchell GF, Arnett D, Blettner M, Friedrich N, Benjamin EJ, Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, Gale DP, Wass MN, Ahmadi KR, Bakker SJ, Beckmann J, Bilo HJ, Bochud M, Brown MJ, Caulfield MJ, Connell JM, Cook HT, Cotlarciuc I, Davey Smith G, de Silva R, Deng G, Devuyst O, Dikkeschei LD, Dimkovic T, Dockrell M, Dominiczak A, Ebrahim S, Eggermann T, Farrall M, Floege J, Forouhi NG, Gansevoort RT, Han X, Hedblad B, Homan van der Heide JJ, Hepkema BG, Hernandez-Fuentes M, Hypponen E, Johnson T, de Jong PE, Kleefstra N, Lagou V, Lapsley M, Li Y, Loos RJ, Luan J, Luttropp K, Maréchal C, Munroe PB, Nordfors L, Penninx BW, Perucha E, Pouta A, Roderick PJ, Ruokonen A, Sanna S, Schalling M, Schlessinger D, Schlieper G, Seelen MA, Sjögren M, Smit JH, Snieder H, Soranzo N, Spector TD, Stenvinkel P, Sternberg MJ, Swaminathan R, Ubink-Veltmaat LJ, Uda M, Vollenweider P, Wallace C, Waterworth D, Zerres K, Waeber G, Wareham NJ, Maxwell PH, McCarthy MI, Jarvelin MR, Abecasis GR, Lightstone L, Scott J, Navis G, Elliot P, Kooner JS., AII - Amsterdam institute for Infection and Immunity, Nephrology, Epidemiologie, RS: CARIM School for Cardiovascular Diseases, Epidemiology, Medical Microbiology & Infectious Diseases, Radiology & Nuclear Medicine, Cardiology, Internal Medicine, Clinical Genetics, Erasmus MC other, Obstetrics & Gynecology, International Consortium for Blood Pressure Genome-Wide Association Studies, CARDIoGRAM consortium, CKDGen Consortium, KidneyGen Consortium, EchoGen consortium, CHARGE-HF consortium, Zhao, Jing Hua [0000-0003-4930-3582], Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Khaw, Kay-Tee [0000-0002-8802-2903], Danesh, John [0000-0003-1158-6791], Soranzo, Nicole [0000-0003-1095-3852], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Clinical Pharmacology and The Genome Centre, Queen Mary University of London (QMUL), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Center for Human Genetic Research, Massachusetts General Hospital [Boston], Program in Medical and Population Genetics, Harvard University-Massachusetts Institute of Technology (MIT), Ehret, Georg B., Munroe, Patricia B., Rice, Kenneth M., Bochud, Murielle, Johnson, Andrew D., Chasman, Daniel I., Smith, Albert V., Tobin, Martin D., Verwoert, Germaine C., Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O'Reilly, Paul F., Amin, Najaf, Bragg-Gresham, Jennifer L., Teumer, Alexander, Glazer, Nicole L., Launer, Lenore, Zhao, Jing Hua, Aulchenko, Yurii, Heath, Simon, Sober, Siim, Parsa, Afshin, Luan, Jian'An, Arora, Pankaj, Dehghan, Abba, Zhang, Feng, Lucas, Gavin, Hicks, Andrew A., Jackson, Anne U., Peden, John F., Tanaka, Toshiko, Wild, Sarah H., Rudan, Igor, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N., Fava, Cristiano, Chambers, John C., Fox, Ervin R., Kumari, Meena, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Whincup, Peter H., Liu, Yongmei, Shi, Gang, Kuusisto, Johanna, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Hoang Nguyen, Khanh-Dung, Lehtimäki, Terho, Matullo, Giuseppe, Wu, Ying, Gaunt, Tom R., Charlotte Onland-Moret, N., Cooper, Matthew N., Platou, Carl G. P., Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Braund, Peter S., Kuznetsova, Tatiana, Uiterwaal, Cuno S. P. M., Adeyemo, Adebowale, Palmas, Walter, Campbell, Harry, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D., Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C., O'Connell, Jeffrey R., Steinle, Nanette I., Grobbee, Diederick E., Arking, Dan E., Kardia, Sharon L., Morrison, Alanna C., Hernandez, Dena, Najjar, Samer, Mcardle, Wendy L., Hadley, David, Brown, Morris J., Connell, John M., Hingorani, Aroon D., Day, Ian N. M., Lawlor, Debbie A., Beilby, John P., Lawrence, Robert W., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Dreisbach, Albert W., Li, Yali, Hunter Young, J., Bis, Joshua C., Kähönen, Mika, Viikari, Jorma, Adair, Linda S., Lee, Nanette R., Chen, Ming-Huei, Olden, Matthia, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Frayling, Timothy M., Islam, Muhammad, Jafar, Tazeen H., Erdmann, Jeanette, Kulkarni, Smita R., Bornstein, Stefan R., Grässler, Jürgen, Groop, Leif, Voight, Benjamin F., Kettunen, Johanne, Howard, Philip, Taylor, Andrew, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Barroso, Inê, Khaw, Kay-Tee, Weder, Alan B., Hunt, Steven C., Sun, Yan V., Bergman, Richard N., Collins, Francis S., Bonnycastle, Lori L., Scott, Laura J., Stringham, Heather M., Peltonen, Leena, Perola, Marku, Vartiainen, Erkki, Brand, Stefan-Martin, Staessen, Jan A., Wang, Thomas J., Burton, Paul R., Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K., Rudock, Megan E., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margu, Kinra, Sanjay, Prabhakaran, Dorairaj, Tripathy, Vikal, Langefeld, Carl D., Rosengren, Annika, Thelle, Dag S., Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, Mckenzie, Colin A., Salako, Tunde, Iwai, Naoharu, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thoma, Wichmann, H. -Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, Jame, Sehmi, Joban S., Zhang, Weihua, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Wong, Andrew, Narisu, Narisu, Stančáková, Alena, Raffel, Leslie J., Yao, Jie, Kathiresan, Sekar, O'Donnell, Christopher J., Schwartz, Stephen M., Arfan Ikram, M., Longstreth Jr., W. T., Mosley, Thomas H., Seshadri, Sudha, Shrine, Nick R. G., Wain, Louise V., Morken, Mario A., Swift, Amy J., Laitinen, Jaana, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A., Humphries, Steve E., Danesh, John, Rasheed, Asif, Goel, Anuj, Hamsten, Ander, Watkins, Hugh, Bakker, Stephan J. L., van Gilst, Wiek H., Janipalli, Charles S., Radha Mani, K., Yajnik, Chittaranjan S., Hofman, Albert, Mattace-Raso, Francesco U. S., Oostra, Ben A., Demirkan, Ayse, Isaacs, Aaron, Rivadeneira, Fernando, Lakatta, Edward G., Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J., Lyytikäinen, Leo-Pekka, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Twee-HeeOng, Rick, Dörr, Marcu, Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Deloukas, Pano, Mangino, Massimo, Spector, Tim D., Zhai, Guangju, Meschia, James F., Nalls, Michael A., Sharma, Pankaj, Terzic, Jano, Kranthi Kumar, M. V., Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E., Fowkes, F. Gerald R., Charchar, Fadi J., Schwarz, Peter E. H., Hayward, Caroline, Guo, Xiuqing, Rotimi, Charle, Bots, Michiel L., Brand, Eva, Samani, Nilesh J., Polasek, Ozren, Talmud, Philippa J., Nyberg, Fredrik, Kuh, Diana, Laan, Mari, Hveem, Kristian, Palmer, Lyle J., van der Schouw, Yvonne T., Casas, Juan P., Mohlke, Karen L., Vineis, Paolo, Raitakari, Olli, Ganesh, Santhi K., Wong, Tien Y., Shyong Tai, E., Cooper, Richard S., Laakso, Markku, Rao, Dabeeru C., Harris, Tamara B., Morris, Richard W., Dominiczak, Anna F., Kivimaki, Mika, Marmot, Michael G., Miki, Tetsuro, Saleheen, Danish, Chandak, Giriraj R., Coresh, Josef, Navis, Gerjan, Salomaa, Veikko, Han, Bok-Ghee, Zhu, Xiaofeng, Kooner, Jaspal S., Melander, Olle, Ridker, Paul M., Bandinelli, Stefania, Gyllensten, Ulf B., Wright, Alan F., Wilson, James F., Ferrucci, Luigi, Farrall, Martin, Tuomilehto, Jaakko, Pramstaller, Peter P., Elosua, Roberto, Soranzo, Nicole, Sijbrands, Eric J. G., Altshuler, David, Loos, Ruth J. F., Shuldiner, Alan R., Gieger, Christian, Meneton, Pierre, Uitterlinden, Andre G., Wareham, Nicholas J., Gudnason, Vilmundur, Rotter, Jerome I., Rettig, Rainer, Uda, Manuela, Strachan, David P., Witteman, Jacqueline C. M., Hartikainen, Anna-Liisa, Beckmann, Jacques S., Boerwinkle, Eric, Vasan, Ramachandran S., Boehnke, Michael, Larson, Martin G., Järvelin, Marjo-Riitta, Psaty, Bruce M., Abecasis, Gonçalo R., Chakravarti, Aravinda, Elliott, Paul, van Duijn, Cornelia M., Newton-Cheh, Christopher, Levy, Daniel, Caulfield, Mark J., Johnson, Toby, Tang, H, Knowles, J, Hlatky, M, Fortmann, S, Assimes, Tl, Quertermous, T, Go, A, Iribarren, C, Absher, D, Risch, N, Meyers, R, Sidney, S, Ziegler, A, Schillert, A, Bickel, C, Sinning, C, Rupprecht, Hj, Lackner, K, Wild, P, Schnabel, R, Blankenberg, S, Zeller, T, Münzel, T, Perret, C, Cambien, F, Tiret, L, Nicaud, V, Proust, C, Dehghan, A, Hofman, A, Uitterlinden, A, van Duijn, C, Levy, D, Whitteman, J, Cupples, La, Demissie-Banjaw, S, Ramachandran, V, Smith, A, Gudnason, V, Boerwinkle, E, Folsom, A, Morrison, A, Psaty, Bm, Chen, Iy, Rotter, Ji, Bis, J, Volcik, K, Rice, K, Taylor, Kd, Marciante, K, Smith, N, Glazer, N, Heckbert, S, Harris, T, Lumley, T, Kong, A, Thorleifsson, G, Thorgeirsson, G, Holm, H, Gulcher, Jr, Stefansson, K, Andersen, K, Gretarsdottir, S, Thorsteinsdottir, U, Preuss, M, Schreiber, S, Meitinger, T, König, Ir, Lieb, W, Hengstenberg, C, Schunkert, H, Erdmann, J, Fisher, M, Grosshennig, A, Medack, A, Stark, K, Linsel-Nitschke, P, Bruse, P, Aherrahrou, Z, Peters, A, Loley, C, Willenborg, C, Nahrstedt, J, Freyer, J, Gulde, S, Doering, A, Meisinger, C, Wichmann, He, Klopp, N, Illig, T, Meinitzer, A, Tomaschitz, A, Halperin, E, Dobnig, H, Scharnagl, H, Kleber, M, Laaksonen, R, Pilz, S, Grammer, Tb, Stojakovic, T, Renner, W, März, W, Böhm, Bo, Winkelmann, Br, Winkler, K, Hoffmann, M, O'Donnell, Cj, Voight, Bf, Altshuler, D, Siscovick, D, Musunuru, K, Peltonen, L, Barbalic, M, Melander, O, Elosua, R, Kathiresan, S, Schwartz, Sm, Salomaa, V, Guiducci, C, Burtt, N, Gabriel, Sb, Stewart, Af, Wells, Ga, Chen, L, Jarinova, O, Roberts, R, Mcpherson, R, Dandona, S, Pichard, Ad, Rader, Dj, Devaney, J, Lindsay, Jm, Kent, Km, Qu, L, Satler, L, Burnett, M, Li, M, Reilly, Mp, Wilensky, R, Waksman, R, Epstein, S, Mattha, W, Knouf, Cw, Waterworth, Dm, Hakonarson, Hh, Walker, M, Mooser, V, Hall, A, Balmforth, Aj, Wright, Bj, Nelson, C, Thompson, Jr, Samani, Nj, Braund, P, Ball, Sg, Smith, Nl, Felix, Jf, Morrison, Ac, Demissie, S, Glazer, Nl, Loehr, Lr, Rosamond, Wd, Rivadeneira, F, Bis, Jc, Folsom, Ar, Benjamin, E, Aulchenko, Y, Haritunians, T, Couper, D, Murabito, J, Wang, Ya, Stricker, B, Gottdiener, J, Chang, Pp, Wang, Tj, Rice, Km, Heckbert, Sr, Fox, Er, Uitterlinden, Ag, Willerson, Jt, van Duijn, Cm, Witteman, Jc, Vasan, R, Köttgen, A, Pattaro, C, Böger, Ca, Fuchsberger, C, Olden, M, Parsa, A, Gao, X, Yang, Q, Smith, Av, O'Connell, Jr, Schmidt, H, Tanaka, T, Isaacs, A, Ketkar, S, Hwang, Sj, Johnson, A, Teumer, A, Paré, G, Atkinson, Ej, Lohman, K, Cornelis, Mc, Probst-Hensch, Nm, Kronenberg, F, Tönjes, A, Hayward, C, Aspelund, T, Eiriksdottir, G, Launer, Lj, Harris, Tb, Rampersaud, E, Mitchell, Bd, Arking, De, Struchalin, M, Cavalieri, M, Singleton, A, Giallauria, Francesco, Metter, J, de Boer, J, Zillikens, Mc, Oostra, Ba, Feitosa, M, Province, M, de Andrade, M, Turne, St, Schnabel, Rb, Wilde, S, Munzel, Tf, Leak, T, Koenig, W, Zgaga, L, Zemunik, T, Kolcic, I, Minelli, C, Hu, Fb, Johansson, A, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Imboden, M, Nitsch, D, Brandstätter, A, Kollerits, B, Kedenko, L, Mägi, R, Stumvoll, M, Kovacs, P, Boban, M, Campbell, S, Endlich, K, Völzke, H, Kroemer, Hk, Nauck, M, Völker, U, Polasek, O, Vitart, V, Badola, S, Parker, An, Ridker, Pm, Kardia, Sl, Liu, Y, Curhan, Gc, Franke, A, Rochat, T, Paulweber, B, Prokopenko, I, Wang, W, Shuldiner, Ar, Coresh, J, Schmidt, R, Ferrucci, L, Shlipak, Mg, Borecki, I, Krämer, Bk, Rudan, I, Gyllensten, U, Wilson, Jf, Pramstaller, Pp, Rettig, R, Hastie, N, Chasman, Di, Kao, Wh, Heid, Im, Fox, C, Felix, Sb, Watzinger, N, Larson, Mg, Homuth, G, Aragam, J, Dörr, M, Zweiker, R, Lind, L, Rodeheffer, Rj, Greiser, Kh, Deckers, Jw, Stritzke, J, Lackner, Kj, Ingelsson, E, Kullo, I, Haerting, J, Stricker, Bh, Reffelmann, T, Redfield, Mm, Werdan, K, Mitchell, Gf, Arnett, D, Blettner, M, Friedrich, N, Benjamin, Ej, Chambers, Jc, Zhang, W, Lord, Gm, van der Harst, P, Lawlor, Da, Sehmi, J, Gale, Dp, Wass, Mn, Ahmadi, Kr, Bakker, Sj, Beckmann, J, Bilo, Hj, Bochud, M, Brown, Mj, Caulfield, Mj, Connell, Jm, Cook, Ht, Cotlarciuc, I, Davey Smith, G, de Silva, R, Deng, G, Devuyst, O, Dikkeschei, Ld, Dimkovic, T, Dockrell, M, Dominiczak, A, Ebrahim, S, Eggermann, T, Farrall, M, Floege, J, Forouhi, Ng, Gansevoort, Rt, Han, X, Hedblad, B, Homan van der Heide, Jj, Hepkema, Bg, Hernandez-Fuentes, M, Hypponen, E, Johnson, T, de Jong, Pe, Kleefstra, N, Lagou, V, Lapsley, M, Li, Y, Loos, Rj, Luan, J, Luttropp, K, Maréchal, C, Munroe, Pb, Nordfors, L, Penninx, Bw, Perucha, E, Pouta, A, Roderick, Pj, Ruokonen, A, Sanna, S, Schalling, M, Schlessinger, D, Schlieper, G, Seelen, Ma, Sjögren, M, Smit, Jh, Snieder, H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Ubink-Veltmaat, Lj, Uda, M, Vollenweider, P, Wallace, C, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Abecasis, Gr, Lightstone, L, Scott, J, Navis, G, Elliot, P, and Kooner, Js.

Subjects
novel loci, Kidney Disease, Polymorphism, Single Nucleotide/*genetics, [SDV]Life Sciences [q-bio], left ventricular wall thickness, LOCI, Genome-wide association study, Blood Pressure, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Coronary artery disease, 0302 clinical medicine, RELEVANCE, Africa/ethnology, Cardiovascular Disease, genetics, Kidney Diseases/genetics, Stroke, genome wide association study, POPULATION, ta118, Blood pressure, hypertension, stroke, coronary artery disease, ddc:616, 0303 health sciences, education.field_of_study, Asia/ethnology, Multidisciplinary, Coronary Artery Disease/genetics, COMMON VARIANTS, Genetic Predisposition to Disease/*genetics, 3. Good health, Europe, Cardiovascular Diseases, Hypertension, Cardiology, Kidney Diseases, HEALTH, Human, medicine.medical_specialty, Asia, Population, Renal function, Polymorphism, Single Nucleotide, Europe/ethnology, Article, CLONING, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Stroke/genetics, Internal medicine, medicine, Humans, Cardiovascular Diseases/*genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, METAANALYSIS, 030304 developmental biology, RECEPTOR, genes, blood pressure, cardiovascular disease risk, medicine.disease, Africa, Blood Pressure/*genetics/physiology, Hypertension/genetics, Kidney disease, Genome-Wide Association Study
Abstract

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. ispartof: Nature vol:478 issue:7367 pages:103-109 ispartof: location:England status: published

Published
2011

48. Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci

Author

Paul, Ds, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Akkerman, Jan Willem N., Albers, Cornelis A., Ale, Algra, Abtehale Al Hussani, Hooman, Allayee, Franco, Anni, Asselbergs, Folkert W., Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Baumeister, Sebastian E., Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Bis, Joshua C., Lorenzo, Bomba, Amélie, Bonnefond, Boomsma, Dorret I., Bradley, John R., François, Cambien, Chambers, John C., Marina, Ciullo, Cookson, William O., Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Das, Gail, Davies, Paul IW de Bakker, de Boer, Rudolf A., Eco JC de Geus, Deary, Ian J., Dedoussis, George V., Panos, Deloukas, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghaus, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, Evans, David M., Eyjolfsson, Gudmundur I., Mario, Falchi, Wei, Feng, Ferreira, Manuel A., Luigi, Ferrucci, Krista, Fischer, Folsom, Aaron R., Paolo, Fortina, Andre, Franke, Lude, Franke, Frazer, Ian H., Philippe, Froguel, Renzo, Galanello, Ganesh, Santhi K., Garner, Stephen F., Gasparini, Paolo, Bernd, Genser, Gibson, Quince D., Christian, Gieger, Girotto, Giorgia, Glazer, Nicole L., Martin, Gögele, Goodall, Alison H., Andreas, Greinacher, Gudbjartsson, Daniel F., Chris, Hammond, Harris, Sarah E., Jaana, Hartiala, Anna Liisa Hartikainen, Hazen, Stanley L., Heckbert, Susan R., Hedblad, Bo, Christian, Hengstenberg, Micha, Hersch, Hicks, Andrew A., Hilma, Holm, Jouke Jan Hottenga, Thomas, Illig, Marjo Riitta Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Kema, Ido P., Kemp, John P., Jyoti, Khadake, Kay Tee Khaw, Kleber, Marcus E., Kooner, Jaspal S., Peter, Kovacs, Brigitte, Kühnel, Marie Christine Kyrtsonis, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort Study, Heather Lloyd Jones, Ruth JF Loos, Lopez, Lorna M., Thomas, Lumley, Leo Pekka Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Martin, Nicholas G., Andrea, Maschio, Irene Mateo Leach, Barbara, Mcknight, Stuart, Meacham, Medland, Sarah E., Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Mitchell, Braxton D., Moffatt, Miriam F., Montgomery, Grant W., Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navis, Nolte, Ilja M., Ute, Nöthlings, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Onundarson, Pall T., O’Reilly, Paul F., Ouwehand, Willem H., Debora, Parracciani, Afshin, Parsa, Paul, Dirk S., Penninger, Josef M., Penninx, Brenda W., Mario, Pirastu, Pirastu, Nicola, Giorgio, Pistis, Eleonora, Porcu, Laura, Portas, David, Porteous, Anneli, Pouta, Pramstaller, Peter P., Inga, Prokopenko, Psaty, Bruce M., Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez Solis, Augusto, Rendon, Ried, Janina S., Ring, Susan M., Robino, Antonietta, Rotter, Jerome I., Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Saluments, Samani, Nilesh J., Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Schmidt, Carsten O., Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic Canic, So Youn Shin, Shuldiner, Alan R., Rob, Sladek, Smit, Johannes H., George Davey Smith, Gustav Smith, J., Smith, Nicholas L., Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Spector, Timothy D., Starr, John M., Kari, Stefansson, Derek, Stemple, Jonathan, Stephens, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönjes, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der Harst, Ellen van der Schoot, C., van Gilst, Wiek H., Joost van Pelt, L., van Veldhuisen, Dirk J., Niek, Verweij, Visscher, Peter M., Uwe, Völker, Peter, Vollenweider, Katrin, Voss, Wareham, Nicholas J., Lorenz, Wernisch, Harm Jan Westra, Whitfield, John B., Herich, Wichmann, Wiggins, Kerri L., Gonneke, Willemsen, Winkelmann, Bernhard R., Gerald, Wirnsberger, Bruce HR Wolffenbuttel, Jian, Yang, Tsun Po Yang, Weihua, Zhang, Jing Hua Zhao, Paavo, Zitting, Jaap Jan Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Paul, D, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Jan Willem N., Akkerman, Cornelis A., Alber, Ale, Algra, Abtehale Al, Hussani, Hooman, Allayee, Franco, Anni, Folkert W., Asselberg, Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Sebastian E., Baumeister, Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Joshua C., Bi, Lorenzo, Bomba, Amélie, Bonnefond, Dorret I., Boomsma, John R., Bradley, François, Cambien, John C., Chamber, Marina, Ciullo, William O., Cookson, Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Da, Gail, Davie, Paul IW de, Bakker, Rudolf A., de Boer, Eco JC de, Geu, Ian J., Deary, George V., Dedoussi, Panos, Delouka, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghau, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, David M., Evan, Gudmundur I., Eyjolfsson, Mario, Falchi, Wei, Feng, Manuel A., Ferreira, Luigi, Ferrucci, Krista, Fischer, Aaron R., Folsom, Paolo, Fortina, Andre, Franke, Lude, Franke, Ian H., Frazer, Philippe, Froguel, Renzo, Galanello, Santhi K., Ganesh, Stephen F., Garner, Gasparini, Paolo, Bernd, Genser, Quince D., Gibson, Christian, Gieger, Girotto, Giorgia, Nicole L., Glazer, Martin, Gögele, Alison H., Goodall, Andreas, Greinacher, Daniel F., Gudbjartsson, Chris, Hammond, Sarah E., Harri, Jaana, Hartiala, Anna Liisa, Hartikainen, Stanley L., Hazen, Susan R., Heckbert, Bo, Hedblad, Christian, Hengstenberg, Micha, Hersch, Andrew A., Hick, Hilma, Holm, Jouke Jan, Hottenga, Thomas, Illig, Marjo Riitta, Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Ido P., Kema, John P., Kemp, Jyoti, Khadake, Kay Tee, Khaw, Marcus E., Kleber, Jaspal S., Kooner, Peter, Kovac, Brigitte, Kühnel, Marie Christine, Kyrtsoni, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort, Study, Heather Lloyd, Jone, Ruth JF, Loo, Lorna M., Lopez, Thomas, Lumley, Leo Pekka, Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Nicholas G., Martin, Andrea, Maschio, Irene Mateo, Leach, Barbara, Mcknight, Stuart, Meacham, Sarah E., Medland, Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Braxton D., Mitchell, Miriam F., Moffatt, Grant W., Montgomery, Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navi, Ilja M., Nolte, Ute, Nöthling, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Pall T., Onundarson, Paul F., O’Reilly, Willem H., Ouwehand, Debora, Parracciani, Afshin, Parsa, Dirk S., Paul, Josef M., Penninger, Brenda W., Penninx, Mario, Pirastu, Pirastu, Nicola, Giorgio, Pisti, Eleonora, Porcu, Laura, Porta, David, Porteou, Anneli, Pouta, Peter P., Pramstaller, Inga, Prokopenko, Bruce M., Psaty, Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez, Soli, Augusto, Rendon, Janina S., Ried, Susan M., Ring, Robino, Antonietta, Jerome I., Rotter, Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Salument, Nilesh J., Samani, Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Carsten O., Schmidt, Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic, Canic, So Youn, Shin, Alan R., Shuldiner, Rob, Sladek, Johannes H., Smit, George Davey, Smith, J., Gustav Smith, Nicholas L., Smith, Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Timothy D., Spector, John M., Starr, Kari, Stefansson, Derek, Stemple, Jonathan, Stephen, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung, Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson, Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay, Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönje, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der, Harst, C., Ellen van der Schoot, Wiek H., van Gilst, L., Joost van Pelt, Dirk J., van Veldhuisen, Niek, Verweij, Peter M., Visscher, Uwe, Völker, Peter, Vollenweider, Katrin, Vo, Nicholas J., Wareham, Lorenz, Wernisch, Harm Jan, Westra, John B., Whitfield, Herich, Wichmann, Kerri L., Wiggin, Gonneke, Willemsen, Bernhard R., Winkelmann, Gerald, Wirnsberger, Bruce HR, Wolffenbuttel, Jian, Yang, Tsun Po, Yang, Weihua, Zhang, Jing Hua, Zhao, Paavo, Zitting, Jaap Jan, Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England, UCL, UCL Canc Inst, London WC1E 6BT, England, Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, Natl Hlth Serv NHS Blood & Transplant, Cambridge CB2 0PT, England, Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands, Inst Publ Hlth, MRC Biostat Unit, Cambridge CB2 0SR, England, NIHR Biomed Res Ctr, Cambridge CB2 0PT, England, Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands, Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands, Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1NY, England, Hammersmith Hosp, Imperial Coll Healthcare NHS Trust, London W12 0HS, England, Royal Brompton & Harefield Hosp NHS Trust, London SW3 6NP, England, Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England, Psychiatry, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, and Cardiovascular Centre (CVC)

Subjects
Netherlands Twin Register (NTR), Erythrocytes, Genome-wide association study, UNCERTAINTY, Regulatory Sequences, Nucleic Acid, VARIANTS, ANNOTATION, COLORECTAL-CANCER, Histones, 0302 clinical medicine, BINDING, Cluster Analysis, Myeloid Cells, Genetics (clinical), Genetics, hematological trait, 0303 health sciences, Chromosome Mapping, MRP4 ABCC4, Chromatin, Nucleosomes, Phenotype, Organ Specificity, 030220 oncology & carcinogenesis, Blood Platelets, Quantitative Trait Loci, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, DYNAMIN 3, 03 medical and health sciences, Quantitative Trait, Heritable, MEGAKARYOCYTES, Humans, Cell Lineage, ddc:610, GENOME-WIDE ASSOCIATION, Enhancer, Transcription factor, Gene, ChIA-PET, 030304 developmental biology, Research, Genetic Variation, DNA, Chromatin Assembly and Disassembly, Genetic architecture, Gene Expression Regulation, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510

Published
2013

49. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Author

Postmus, Iris, Trompet, Stella, Deshmukh, Harshal A., Barnes, Michael R., Li, Xiaohui, Warren, Helen R., Chasman, Daniel I., Zhou, Kaixin, Arsenault, Benoit J., Donnelly, Louise A., Wiggins, Kerri L., Avery, Christy L., Griffin, Paula, Feng, QiPing, Taylor, Kent D., Li, Guo, Evans, Daniel S., Smith, Albert V., de Keyser, Catherine E., Johnson, Andrew D., de Craen, Anton J.M., Stott, David J., Buckley, Brendan M., Ford, Ian, Westendorp, Rudi G. J., Eline Slagboom, P., Sattar, Naveed, Munroe, Patricia B., Sever, Peter, Poulter, Neil, Stanton, Alice, Shields, Denis C., O’Brien, Eoin, Shaw-Hawkins, Sue, Ida Chen, Y.-D., Nickerson, Deborah A., Smith, Joshua D., Pierre Dubé, Marie, Matthijs Boekholdt, S., Kees Hovingh, G., Kastelein, John J.P., McKeigue, Paul M., Betteridge, John, Neil, Andrew, Durrington, Paul N., Doney, Alex, Carr, Fiona, Morris, Andrew, McCarthy, Mark I., Groop, Leif, Ahlqvist, Emma, Bis, Joshua C., Rice, Kenneth, Smith, Nicholas L., Lumley, Thomas, Whitsel, Eric A., Stürmer, Til, Boerwinkle, Eric, Ngwa, Julius S., O’Donnell, Christopher J., Vasan, Ramachandran S., Wei, Wei-Qi, Wilke, Russell A., Liu, Ching-Ti, Sun, Fangui, Guo, Xiuqing, Heckbert, Susan R, Post, Wendy, Sotoodehnia, Nona, Arnold, Alice M., Stafford, Jeanette M., Ding, Jingzhong, Herrington, David M., Kritchevsky, Stephen B., Eiriksdottir, Gudny, Launer, Leonore J., Harris, Tamara B., Chu, Audrey Y., Giulianini, Franco, MacFadyen, Jean G., Barratt, Bryan J., Nyberg, Fredrik, Stricker, Bruno H., Uitterlinden, André G., Hofman, Albert, Rivadeneira, Fernando, Emilsson, Valur, Franco, Oscar H., Ridker, Paul M., Gudnason, Vilmundur, Liu, Yongmei, Denny, Joshua C., Ballantyne, Christie M., Rotter, Jerome I., Adrienne Cupples, L., Psaty, Bruce M., Palmer, Colin N.A., Tardif, Jean-Claude, Colhoun, Helen M., Hitman, Graham, Krauss, Ronald M., Wouter Jukema, J, Caulfield, Mark J., Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M., Bramon, Elvira, Brown, Matthew A., Casas, Juan P., Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S., Mathew, Christopher G., Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J., Trembath, Richard C., Viswanathan, Ananth C., Wood, Nicholas W., Spencer, Chris C.A., Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E., Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J., Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T., Liddle, Jennifer, Potter, Simon C., Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Erasmus MC other, Epidemiology, Internal Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, and Vascular Medicine

Subjects
Apolipoprotein E, BLOOD, LOCI, General Physics and Astronomy, Genome-wide association study, VARIANTS, 030204 cardiovascular system & hematology, Pharmacology, Bioinformatics, THERAPY, DISEASE, chemistry.chemical_compound, 0302 clinical medicine, GENE-EXPRESSION, 0303 health sciences, Multidisciplinary, biology, 3. Good health, Multidisciplinary Sciences, Meta-analysis, WHOLE-GENOME, Science & Technology - Other Topics, lipids (amino acids, peptides, and proteins), Statin, medicine.drug_class, Endocrinology and Diabetes, Polymorphism, Single Nucleotide, INDUCED MYOPATHY, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Humans, cardiovascular diseases, 030304 developmental biology, Genetic association, Science & Technology, Cholesterol, business.industry, HUMAN PREFRONTAL CORTEX, nutritional and metabolic diseases, General Chemistry, Cholesterol, LDL, A300, chemistry, Pharmacogenetics, biology.protein, PLASMA LIPOPROTEIN(A) LEVELS, Hydroxymethylglutaryl-CoA Reductase Inhibitors, SLCO1B1, business, Genome-Wide Association Study
Abstract

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response., Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.

Published
2016

50. Long-Term Trajectories of PTSD in Vietnam-Era Veterans: The Course and Consequences of PTSD in Twins

Author

Magruder, Kathryn M., Goldberg, Jack, Forsberg, Christopher W., Friedman, Matthew J., Litz, Brett T., Vaccarino, Viola, Heagerty, Patrick J., Gleason, Theresa C., Huang, Grant D., and Smith, Nicholas L.

Subjects
Adult, Male, education, Middle Aged, behavioral disciplines and activities, humanities, Article, United States, Vietnam Conflict, Diagnostic and Statistical Manual of Mental Disorders, Stress Disorders, Post-Traumatic, Vietnam, Surveys and Questionnaires, mental disorders, Diseases in Twins, Humans, Prospective Studies, Registries, Self Report, health care economics and organizations, Aged, Follow-Up Studies, Veterans
Abstract

We estimated the temporal course of posttraumatic stress disorder (PTSD) in Vietnam-era veterans using a national sample of male twins with a 20-year follow-up. The complete sample included those twins with a PTSD diagnostic assessment in 1992 and who completed a DSM-IV PTSD diagnostic assessment and a self-report PTSD checklist in 2012 (n = 4,138). Using PTSD diagnostic data, we classified veterans into 5 mutually exclusive groups, including those who never had PTSD, and 4 PTSD trajectory groups: (a) early recovery, (b) late recovery, (c) late onset, and (d) chronic. The majority of veterans remained unaffected by PTSD throughout their lives (79.05% of those with theater service, 90.85% of those with nontheater service); however, an important minority (10.50% of theater veterans, 4.45% of nontheater veterans) in 2012 had current PTSD that was either late onset (6.55% theater, 3.29% nontheater) or chronic (3.95% theater, 1.16% nontheater). The distribution of trajectories was significantly different by theater service (p < .001). PTSD remains a prominent issue for many Vietnam-era veterans, especially for those who served in Vietnam.

Published
2016

Catalog

Books, media, physical & digital resources
See catalog results