Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure–raising genetic variants on future cardiovascular disease risk.

He Gao | Andres Metspalu | Fotios Drenos | Borbala Mifsud | Alice Stanton | Simon Thom | Marie Loh | Evangelos Evangelou | Nilesh J Samani | Reedik Mägi | Danish Saleheen | Caroline Hayward | Bernard Keavney | Ioanna Ntalla | Stephan J L Bakker | Ibrahim Karaman | Tõnu Esko | Harold Snieder | Praveen Surendran | Aravinda Chakravarti | Daniel Levy | Louise V Wain | Martin D Tobin | Martin Farrall | Sandosh Padmanabhan | Lorna M. Lopez | John C Chambers | Jiang He | Norihiro Kato | Daniel I Chasman | Pim van der Harst | Aude Saint Pierre | Denis C Shields | Jonathan Marten | Paul F O'Reilly | M. Jarvelin | M. Nalls | C. Gieger | O. Franco | D. Levy | I. Deary | L. Wain | N. Shrine | I. Ntalla | J. Cook | R. Mägi | E. Zeggini | D. Strachan | M. Tobin | G. Abecasis | K. Kristiansson | T. Lehtimäki | V. Salomaa | M. Perola | C. Lindgren | Z. Kutalik | M. Boehnke | P. Ridker | D. Chasman | N. Samani | P. Braund | M. Mangino | Morris J. Brown | J. Connell | P. Munroe | M. Caulfield | M. Farrall | T. Ferreira | V. Gudnason | D. Conen | A. Chakravarti | P. Munson | E. Tai | Stefan Enroth | A. James | Yongmei Liu | B. Psaty | D. Siscovick | A. Stanton | S. Wild | B. Penninx | G. Willemsen | D. Arking | A. Kraja | A. Palotie | S. Ripatti | A. Metspalu | T. Esko | H. Snieder | E. Ingelsson | A. Jackson | J. Tuomilehto | A. Doney | S. Kathiresan | C. Newton-Cheh | K. Taylor | J. Rotter | I. Karaman | R. Chowdhury | A. Havulinna | P. Jousilahti | T. Harris | I. Rudan | D. Boomsma | E. D. de Geus | M. Swertz | D. Porteous | A. Gow | A. Pattie | J. Starr | H. Cordell | N. Wareham | Antti-Pekka Sarin | A. Mahajan | J. Hottenga | J. Ried | C. Nelson | J. Deelen | A. Hamsten | C. V. van Duijn | A. Jula | Xiuqing Guo | C. Tzourio | H. Schmidt | A. Teumer | U. Völker | S. Harris | A. Wright | D. Saleheen | H. Watkins | R. Joehanes | J. Bis | B. Oostra | J. Kooner | E. Bottinger | J. Howson | A. Morgan | G. Davies | D. Liewald | L. Lopez | N. Amin | C. Hayward | P. Joshi | I. Kolčić | O. Polašek | V. Vitart | E. Holliday | M. Kähönen | L. Launer | P. Vollenweider | C. Hartman | J. Marten | A. Campbell | A. Goel | J. Luan | I. Nolte | S. Padmanabhan | A. Robino | R. Scott | P. J. van der Most | H. Warren | Weihua Zhang | Jinghua Zhao | M. Brumat | R. de Mutsert | G. Ehret | E. Evangelou | I. Gandin | He Gao | C. Langenberg | B. Lehne | M. Loh | Y. Milaneschi | N. Poulter | L. Rose | P. Sever | J. Chambers | N. Kato | A. Oldehinkel | P. van der Harst | D. Mook-Kanamori | W. Palmas | A. Morrison | G. Verwoert | B. Keavney | R. Loos | R. Strawbridge | C. Palmer | K. Khaw | Å. Johansson | L. Lyytikäinen | M. Bochud | U. Gyllensten | P. Pramstaller | I. Tzoulaki | J. Jukema | D. Shields | G. Paré | J. Marrugat | M. Dörr | R. Rettig | G. Chauhan | S. Debette | S. Trompet | V. Giedraitis | Yingchang Lu | C. Menni | D. Stott | J. Sundström | N. Verweij | S. Bakker | R. Gansevoort | M. Cocca | F. Drenos | G. Girotto | R. Li-Gao | P. Surendran | P. Knekt | R. Jansen | E. Org | M. Laan | B. Prins | E. Hofer | M. Abedi | Jiang He | S. Thériault | A. Vergnaud | D. Toniolo | H. Riese | C. Batini | M. Traglia | J. Huffman | T. Nutile | M. D. de Borst | C. Cabrera | N. Shah | Chunyu Liu | Andrew A. Hicks | Mattias Frånberg | J. Knight | C. Sala | C. Barbieri | T. Niiranen | M. Ciullo | D. Ruggiero | R. Sorice | D. Vuckovic | D. Siscovick | Ahmad Vaez | Andrew P. Morris | P. Nandakumar | K. Ayers | S. Thom | M. Seelen | R. Scott | Y. Saba | S. Sõber | M. Tomaszewski | L. Lin | Christopher Newton-Cheh | Neil Poulter | Niek Verweij | Rajiv Chowdhury | Cecilia M Lindgren | Peter Sever | Meixia Ren | Ron T Gansevoort | Aldi T Kraja | E Shyong Tai | M. Ren | Patricia B Munroe | Jaspal S Kooner | Maciej Tomaszewski | Joanne Knight | Chrysovalanto Mamasoula | Morris Brown | C. Oldmeadow | A. Erzurumluoglu | Joanna M M Howson | Annette Peters | Chunyu Liu | Helen R Warren | Claudia P Cabrera | James P Cook | Marcelo P Segura Lepe | M Abdullah Said | David Porteous | Maris Alver | John Connell | Georg B Ehret | T. Blake | J. Damman | Peter J. van der Most | J. Knight | F. Mach | M. Larson | J. Yao | C. Lindgren | U. Gyllensten | A. Smith | O. Raitakari | Harry Campbell | A. Johnson | Simon A Thom | Kenneth M. Rice | M. P. S. Lepe | M. A. Said | S. Kathiresan | R. Elosúa | D. Porteous | L. Lind | S. Koskinen | James F. Wilson | Maris Alver | Evangelos A. Evangelou | Franco Giulianini | Paul Elliott | Andrew D. Morris | A. Hofman | R. Schmidt | P. Gasparini | U. Völker | A. Uitterlinden | P. van der harst | T. Spector | Borbála Mifsud | Shih-Jen Hwang | P. O’Reilly | Francis S. Collins | Yusuf Demirkale | Louise V Ahmad Rick Roby Peter J A Mesut Paul Claudia P H Wain Vaez Jansen Joehanes van der Most Erz | Fabiola Del Greco M | Tatijana Zemonik | Michael R Barnes | Quang Tri Nguyen | A. John | Michael R Ioanna Mark J Paul Barnes Tzoulaki Caulfield Elliott | E. Tai | Rodney J. Scott | A. Smith | L. Rose | Weihua Zhang | Rajiv Chowdhury | M. Kähönen | Michela Traglia | M. Said | T. Harris | A. Goel | B. Oostra | F. Collins | François Mach | Michael A. Nalls | Andrew D. Johnson | MartinD. Tobin | Cristina Menni | Roberto Elosua | Alice Stanton | Igor Rudan | Ruth J. F. Loos | Jerome I. Rotter | Alan F. Wright | John M. Starr | B.W.J.H. Penninx | Johan Sundström | A. Palotie | Alan L. James | Robert A. Scott | Olli T. Raitakari | Hugh Watkins | A. Jackson | Morris J. Brown | M. Tomaszewski | Colin N. A. Palmer | George B. Ehret | Paul F. O’Reilly | Yongmei Liu | N. Wareham | B. Keavney | Terho Lehtimäki | J. Tuomilehto | Elizabeth G. Holliday | Rodney J. Scott | A. Campbell | P. Elliott | G. Abecasis | Guillaume Paré | Anders Hamsten | Timothy D. Spector | Cecilia M. Lindgren | D. Stott | A. Uitterlinden | Cornelia M. van Duijn | J. Connell | Aravinda Chakravarti | Sarah E. Harris | Andrew P. Morris | Heather J. Cordell | Kenneth M. Rice | R. Gansevoort | Rick Jansen | Andrew D. Morris | A. Peters | Denis C. Shields | Claudia P. Cabrera | C. Newton‐Cheh | R. Elosua | Helena Schmidt | M. Dörr | B. Psaty | Kent D. Taylor | Oscar Franco | Albert V. Smith | Erwin P. Bottinger | Lars Lind | Kristin L. Ayers | Peter J. Munson | Alex S. F. Doney | Nilesh J. Samani | Pekka Jousilahti | P. Vollenweider | David P. Strachan | Paul M. Ridker | Daniel Levy | Antti Jula | Massimo Mangino | Nabi Shah | Albert Hofman | Marcus Dörr | Åsa Johansson | Rainer Rettig | Heather J Cordell | Shih-Jen Hwang | Oscar H. Franco | Christopher P. Nelson | J. Marrugat | V. Gudnason | A. Smith | Stephan J. L. Bakker | Michael R Barnes | Sarah H Wild | K. Khaw | P. Sever | Erik Ingelsson | Chunyu Liu | H. Snieder | Norihiro Kato | Neil Poulter | Fabiola Del Greco M | Kristin L Ayers | Tatijana Zemonik | Maryam Abedi | Gail Davies | François Mach | Aude Saint Pierre | C. Tzourio | D. Conen | Attia John | C. M. Lindgren | C. Hartman | Michael R Ioanna Mark J Paul Barnes Tzoulaki Caulfield Elliott | Nilesh J. Samani | B. Penninx | Shih-Jen Hwang | V. Salomaa | T. Lehtimäki | Joanna M. M. Howson | Paolo Gasparini | P. Ridker | J. Zhao | David P Strachan | Jaakko Tuomilehto | Gonçalo R. Abecasis | I. Deary | J. Jukema | A. D. Morris | Jerome I. Rotter | J. Luan | Evangelos Evangelou | L. Lin | Neil Poulter | Peter Sever | Bernard D Keavney | Fabiola Del Greco M | Sarah E. Harris | Tatijana Zemonik | Maryam Abedi | Attia John | John Starr | C. V. van Duijn | Michael R Ioanna Mark J Paul Barnes Tzoulaki Caulfield Elliott

[1]  R. Knight,et al.  miR-146a is modulated in human endothelial cell with aging. , 2011, Atherosclerosis.

[2]  J W DEVORE,et al.  The school of medicine. , 1957, The Journal of the Oklahoma State Medical Association.

[3]  Nilesh Samani,et al.  Genome-wide mapping of human loci for essential hypertension , 2003, The Lancet.

[4]  Avner Schlessinger,et al.  ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI , 2012 .

[5]  Dan J Stein,et al.  Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 , 2015, BDJ.

[6]  Søren Balling Engelsen,et al.  Quantification of lipoprotein subclasses by proton nuclear magnetic resonance-based partial least-squares regression models. , 2005, Clinical chemistry.

[7]  Ashutosh Kumar Singh,et al.  Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015 , 2016, Lancet.

[8]  T. Davis,et al.  Targeting transporters: Promoting blood–brain barrier repair in response to oxidative stress injury , 2015, Brain Research.

[9]  C. Sing,et al.  The influence of genetics and household environment upon the variability of normal blood pressure: the Montreal Adoption Survey. , 1986, Clinical and experimental hypertension. Part A, Theory and practice.

[10]  M. Daly,et al.  LD Score regression distinguishes confounding from polygenicity in genome-wide association studies , 2014, Nature Genetics.

[11]  N. Risch,et al.  Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation , 2016, Nature Genetics.

[12]  M. Woodward,et al.  Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data , 2014, The Lancet.

[13]  R. Mägi,et al.  Cohort Profile Cohort Profile : Estonian Biobank of the Estonian Genome Center , University of Tartu , 2015 .

[14]  Xiaofeng Zhu,et al.  The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals , 2016, Nature Genetics.

[15]  John P. Overington,et al.  An atlas of genetic influences on human blood metabolites , 2014, Nature Genetics.

[16]  E. Boerwinkle,et al.  Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease. , 2016, The New England journal of medicine.

[17]  S. Anderson,et al.  Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis , 2016, The Lancet.

[18]  T. Ogihara,et al.  Accumulation of common polymorphisms is associated with development of hypertension: a 12-year follow-up from the Ohasama study , 2010, Hypertension Research.

[19]  L. Wain,et al.  Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank , 2015, The Lancet. Respiratory medicine.

[20]  Claude Bouchard,et al.  Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders , 2014 .

[21]  Hans L Hillege,et al.  Urinary Albumin Excretion Predicts Cardiovascular and Noncardiovascular Mortality in General Population , 2002, Circulation.

[22]  A. Deng,et al.  Retinoblastoma-associated protein 140 as a candidate for a novel etiological gene to hypertension , 2016, Clinical and experimental hypertension.

[23]  H. Cingolani,et al.  Phosphodiesterase 5A Inhibition Induces Na+/H+ Exchanger Blockade and Protection Against Myocardial Infarction , 2007, Hypertension.

[24]  He Zhang,et al.  Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension , 2016, Nature Genetics.

[25]  R. Touyz,et al.  Vascular Nox4: a multifarious NADPH oxidase. , 2012, Circulation research.

[26]  Philip Eaton,et al.  Endothelial Nox4 NADPH Oxidase Enhances Vasodilatation and Reduces Blood Pressure In Vivo , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[27]  G. Dusting,et al.  Nox4 modulates collagen production stimulated by transforming growth factor β1 in vivo and in vitro. , 2013, Biochemical and biophysical research communications.

[28]  M. Caulfield,et al.  ADAMTS7 cleavage and vascular smooth muscle cell migration is affected by a coronary-artery-disease-associated variant. , 2013, American journal of human genetics.

[29]  D. Kass,et al.  Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy , 2005, Nature Medicine.

[30]  D. Toncheva,et al.  Gene expression in peripheral blood of patients with hypertension and patients with type 2 diabetes , 2014, Journal of cardiovascular medicine.

[31]  P. Donnelly,et al.  A new multipoint method for genome-wide association studies by imputation of genotypes , 2007, Nature Genetics.

[32]  E. Topol,et al.  Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes , 2004, Journal of Medical Genetics.

[33]  Michael R Barnes,et al.  Exploring the landscape of the genome. , 2010, Methods in molecular biology.

[34]  Beau Dabbs,et al.  Summary and discussion of : “ Controlling the False Discovery Rate : A Practical and Powerful Approach to Multiple Testing , 2014 .

[35]  P. Elliott,et al.  UK Biobank: Current status and what it means for epidemiology , 2012 .

[36]  Mikhail G. Dozmorov,et al.  GenomeRunner: automating genome exploration , 2012, Bioinform..

[37]  P. Elliott,et al.  An Update on Nutrients and Blood Pressure. , 2016, Journal of atherosclerosis and thrombosis.

[38]  Orton,et al.  EFFECTS ON BLOOD PRESSURE OF REDUCED DIETARY SODIUM AND THE DIETARY APPROACHES TO STOP HYPERTENSION ( DASH ) DIET , 2000 .

[39]  D. Rizzoni,et al.  Structural abnormalities of small resistance arteries in essential hypertension , 2012, Internal and Emergency Medicine.

[40]  E. Fleck,et al.  ED-B fibronectin (ED-B) can be targeted using a novel single chain antibody conjugate and is associated with macrophage accumulation in atherosclerotic lesions , 2007, Basic Research in Cardiology.

[41]  T. Hansen,et al.  Cohort Profile: the Health2006 cohort, research centre for prevention and health. , 2014, International journal of epidemiology.

[42]  M. Zile,et al.  Primary culture of avian embryonic heart forming region cells to study the regulation of vertebrate early heart morphogenesis by vitamin A , 2014, BMC Developmental Biology.

[43]  Ewan Birney,et al.  FORGE: A tool to discover cell specific enrichments of GWAS associated SNPs in regulatory regions , 2014 .

[44]  J. Hirschhorn,et al.  Biological interpretation of genome-wide association studies using predicted gene functions , 2015, Nature Communications.

[45]  Hong-Mei Zhang,et al.  Genome‐wide identification of SNPs in microRNA genes and the SNP effects on microRNA target binding and biogenesis , 2012, Human mutation.

[46]  Nuala A Sheehan,et al.  Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure , 2005, Statistics in medicine.

[47]  R. Collins,et al.  Anglo-Scandinavian Cardiac Outcomes Trial: a brief history, rationale and outline protocol , 2001, Journal of Human Hypertension.

[48]  Andrew D. Johnson,et al.  Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. , 2013, The American journal of clinical nutrition.

[49]  Tom R. Gaunt,et al.  Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel , 2015, Nature Communications.

[50]  P. O’Reilly,et al.  Genome-wide association study identifies eight loci associated with blood pressure , 2009, Nature Genetics.

[51]  Ricardo Pong-Wong,et al.  Evaluating the contribution of genetic and familial shared environment to common disease using the UK Biobank , 2016, Nature Genetics.

[52]  Piero Carninci,et al.  FANTOM5 transcriptome catalog of cellular states based on Semantic MediaWiki , 2016, Database J. Biol. Databases Curation.

[53]  J. Rosenfeld,et al.  Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. , 2012, Blood.

[54]  G. Scally.  Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Intersalt Cooperative Research Group. , 1988, BMJ.

[55]  D. Cines,et al.  Determinants of binding and internalization of tissue-type plasminogen activator by human vascular smooth muscle and endothelial cells. , 1993, The Journal of biological chemistry.

[56]  Jeanette Spear,et al.  The Airwave Health Monitoring Study of police officers and staff in Great Britain: rationale, design and methods. , 2014, Environmental research.

[57]  P. Elliott,et al.  UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age , 2015, PLoS medicine.

[58]  J. Gulliver,et al.  The LifeLines Cohort Study: a resource providing new opportunities for environmental epidemiology , 2016, Archives of Public Health.

[59]  L. Farrer,et al.  Autosomal dominant orthostatic hypotensive disorder maps to chromosome 18q. , 1998, American journal of human genetics.

[60]  P. Munroe,et al.  Exploring hypertension genome‐wide association studies findings and impact on pathophysiology, pathways, and pharmacogenetics , 2015, Wiley interdisciplinary reviews. Systems biology and medicine.

[61]  P. Munroe,et al.  Advances in blood pressure genomics. , 2013, Circulation research.

[62]  D. Webb,et al.  Effect of Regular Phosphodiesterase Type 5 Inhibition in Hypertension , 2006, Hypertension.

[63]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[64]  Cory Y. McLean,et al.  GREAT improves functional interpretation of cis-regulatory regions , 2010, Nature Biotechnology.

[65]  Alok J. Saldanha,et al.  Java Treeview - extensible visualization of microarray data , 2004, Bioinform..

[66]  Andrew D. Johnson,et al.  Genome-wide association study of blood pressure and hypertension , 2009, Nature Genetics.

[67]  D. Keene,et al.  Fibrillins 1 and 2 Perform Partially Overlapping Functions during Aortic Development* , 2006, Journal of Biological Chemistry.

[68]  Tien Yin Wong,et al.  Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians , 2011, Nature Genetics.

[69]  Stephan Ripke,et al.  Genome-wide association study of coronary and aortic calcification implicates risk loci for coronary artery disease and myocardial infarction. , 2013, Atherosclerosis.

[70]  Ewan Birney,et al.  FORGE: A tool to discover cell specific enrichments of GWAS associated SNPs in regulatory regions , 2014, bioRxiv.

[71]  Jiang He,et al.  Primary prevention of hypertension: clinical and public health advisory from The National High Blood Pressure Education Program. , 2002, JAMA.

[72]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[73]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[74]  W. Seeger,et al.  Phosphodiesterase 10A Upregulation Contributes to Pulmonary Vascular Remodeling , 2010, PloS one.

[75]  K. Hsu,et al.  Transcriptional Upregulation of Brain-Derived Neurotrophic Factor in Rostral Ventrolateral Medulla by Angiotensin II: Significance in Superoxide Homeostasis and Neural Regulation of Arterial Pressure , 2010, Circulation research.

[76]  A. Dominiczak,et al.  Superoxide Excess in Hypertension and Aging: A Common Cause of Endothelial Dysfunction , 2001, Hypertension.

[77]  J C Christian,et al.  The NHLBI twin study of cardiovascular disease risk factors: methodology and summary of results. , 1977, American journal of epidemiology.

[78]  A. Yao,et al.  Sodium calcium exchanger plays a key role in alteration of cardiac function in response to pressure overload , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[79]  Ravi Karra,et al.  Fibronectin is deposited by injury-activated epicardial cells and is necessary for zebrafish heart regeneration. , 2013, Developmental biology.

[80]  Claude Bouchard,et al.  Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci , 2016, Nature Genetics.

[81]  Y. Benjamini,et al.  THE CONTROL OF THE FALSE DISCOVERY RATE IN MULTIPLE TESTING UNDER DEPENDENCY , 2001 .

[82]  P. Elliott,et al.  The UK Biobank sample handling and storage protocol for the collection, processing and archiving of human blood and urine. , 2008, International journal of epidemiology.

[83]  Marc Chadeau-Hyam,et al.  Metabolic profiling and the metabolome-wide association study: significance level for biomarker identification. , 2010, Journal of proteome research.

[84]  M. Zhang,et al.  Nox4 and redox signaling mediate TGF-β-induced endothelial cell apoptosis and phenotypic switch , 2014, Cell Death and Disease.

[85]  Jing He,et al.  Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation , 2015, Nature Genetics.

[86]  T. Komori,et al.  A coronary artery disease-associated gene product, JCAD/KIAA1462, is a novel component of endothelial cell-cell junctions. , 2011, Biochemical and biophysical research communications.

[87]  J. Brooks-Gunn.  The university of texas graduate school of biomedical sciences at houston , 1963 .

[88]  Leif Groop,et al.  The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants , 2016, European Journal of Human Genetics.

[89]  Alan D. Lopez,et al.  The Global Burden of Disease Study , 2003 .

[90]  Stephen Burgess,et al.  PhenoScanner: a database of human genotype–phenotype associations , 2016, Bioinform..

[91]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[92]  Viachaslau Barodka,et al.  Vascular Stiffness and Increased Pulse Pressure in the Aging Cardiovascular System , 2011, Cardiology research and practice.

[93]  I. Sjaastad,et al.  Elevated levels of activin A in clinical and experimental pulmonary hypertension. , 2009, Journal of applied physiology.

[94]  Cynthia A. Kalita,et al.  Which Genetics Variants in DNase-Seq Footprints Are More Likely to Alter Binding? , 2016, PLoS genetics.

[95]  L. Hayward,et al.  Brain-derived neurotrophic factor modulates angiotensin signaling in the hypothalamus to increase blood pressure in rats. , 2015, American journal of physiology. Heart and circulatory physiology.

[96]  AM Fernandes-Pujals.  Heritability of Major Depressive Disorder , stratified by age of onset , sex , and illness course in Generation Scotland : Scottish Family Health Study ( GS : SFHS ) , 2015 .

[97]  C. Bartram,et al.  Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF 2 , 2008 .

[98]  Christian Gieger,et al.  Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality , 2015, PLoS genetics.

[99]  L. R. Macfarlane,et al.  Department of pathology , 1961, Journal of the Royal Army Medical Corps.