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| Open AccessIntegrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation
Here the authors report 20 novel genomic risk loci for calcific aortic valve stenosis, the most common heart valve disorder. Using RNA sequencing in 500 human aortic valves, they prioritize candidate causal genes including TWIST1, a gene involved in endothelial-mesenchymal transition.
- Sébastien Thériault
- , Zhonglin Li
- & Yohan Bossé
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Article
| Open AccessBlood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension
Pulmonary arterial hypertension is a complex disease characterised by high morbidity and mortality. Here, the authors report methylation profiling of patients, finding disease associations in genes CTSZ, COG6 and ZNF678.
- Anna Ulrich
- , Yukyee Wu
- & Christopher J. Rhodes
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Article
| Open AccessGenome-wide association analysis of left ventricular imaging-derived phenotypes identifies 72 risk loci and yields genetic insights into hypertrophic cardiomyopathy
Changes of left ventricular structure are used to predict morbidity and mortality in cardiovascular diseases. Here the authors conducted a study using advanced deep learning technology to analyze left ventricular regional wall thickness (LVRWT) in a large population, identifying 72 significant genetic loci linked to LVRWT traits.
- Caibo Ning
- , Linyun Fan
- & Xiaoping Miao
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Article
| Open AccessSingle-nucleus DNA sequencing reveals hidden somatic loss-of-heterozygosity in Cerebral Cavernous Malformations
Here the authors establish somatic loss-of-heterozygosity as a genetic underpinning of Cerebral Cavernous Malformations (CCMs): using single-nucleus DNA sequencing, they show homozygosity of chromosomes 7p and/or 7q leads to biallelic inactivation of CCM genes in resected lesions.
- Andrew K. Ressler
- , Daniel A. Snellings
- & Douglas A. Marchuk
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Article
| Open AccessEnvironmental and genetic predictors of human cardiovascular ageing
Cardiovascular ageing is characterised by a progressive decline in function, which contributes to multi-morbidity. Here, the authors use machine learning to predict biological age and identify key genetic risk factors.
- Mit Shah
- , Marco H. de A. Inácio
- & Declan P. O’Regan
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Article
| Open AccessGenetic insights into resting heart rate and its role in cardiovascular disease
The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke.
- Yordi J. van de Vegte
- , Ruben N. Eppinga
- & Pim van der Harst
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Article
| Open AccessGenome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure
Here, the authors perform a large-scale meta-analysis of genome-wide association studies and cis-MR proteomics to identify protein biomarkers and drug targets for heart failure.
- Danielle Rasooly
- , Gina M. Peloso
- & Juan P. Casas
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Article
| Open AccessClinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass
A genome-wide association study of cardiac magnetic resonance-derived left ventricular mass index including 43,000 UK Biobank participants reveals 12 associations (11 novel), implicating genes involved in cardiac contractility and cardiomyopathy.
- Shaan Khurshid
- , Julieta Lazarte
- & Steven A. Lubitz
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Article
| Open AccessMultiple pkd and piezo gene family members are required for atrioventricular valve formation
Cardiac valves are essential for heart function, and blood flow stimulation is critical for their formation. Here, researchers have identified a set of mechanosensory genes of the pkd and piezo families as key regulators of valve development.
- Thomas Juan
- , Agatha Ribeiro da Silva
- & Didier Y. R. Stainier
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Article
| Open AccessGenetic architecture of heart failure with preserved versus reduced ejection fraction
While the genetic basis of heart failure has been explored by genetic studies, the differences between subtypes are not well understood. Here, the authors performed genetic analyses on the two major subtypes of heart failure in a large biobank with genetic and health record data, finding unique genetic architecture for each subtype.
- Jacob Joseph
- , Chang Liu
- & Yan V. Sun
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Article
| Open AccessA non-coding GWAS variant impacts anthracycline-induced cardiotoxic phenotypes in human iPSC-derived cardiomyocytes
Germline variants may pre-dispose patients to an increased risk of developing anthracycline-induced cardiotoxicity. This report provides insights into the mechanism by which a common genetic variant, rs28714259, may confer an increased risk of cardiac damage.
- Xi Wu
- , Fei Shen
- & Bryan Paul Schneider
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Article
| Open AccessMyocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors
Baroreflex control of cardiac contractility is essential to maintain cardiocirculatory homeostasis. Here, Oda et al show that α1 adrenoceptor-stimulated Zn2+ entry through TRPC6 channels boosts β adrenoceptor-dependent myocardial positive inotropy.
- Sayaka Oda
- , Kazuhiro Nishiyama
- & Motohiro Nishida
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Article
| Open AccessWhole genome sequence analysis of blood lipid levels in >66,000 individuals
Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.
- Margaret Sunitha Selvaraj
- , Xihao Li
- & Pradeep Natarajan
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Article
| Open AccessGenome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities
Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease.
- Catherine M. Francis
- , Matthias E. Futschik
- & Paul M. Matthews
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Article
| Open AccessElucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus
Many individual genetic risk loci associate with multiple diseases, but the molecular basis of these loci often remains unclear. Here, the authors provide a framework to reveal the genetic cross-disease associations at the PROCR vascular disease locus.
- David Stacey
- , Lingyan Chen
- & Dirk S. Paul
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Article
| Open AccessGenetic associations with carotid intima-media thickness link to atherosclerosis with sex-specific effects in sub-Saharan Africans
Genetic studies of disease-relevant traits have mostly been performed on European populations. Here, the authors perform a genome-wide association study for carotid intima-media thickness, in sub-Saharan African samples, finding population-specific and sex-specific loci.
- Palwende Romuald Boua
- , Jean-Tristan Brandenburg
- & Michèle Ramsay
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Article
| Open AccessThe history and geographic distribution of a KCNQ1 atrial fibrillation risk allele
Many rare high-impact variants have been associated with disease, but the origins and functional impact are not always explored. Here, the authors trace the ancestry of a rare high impact atrial fibrillation allele in KCNQ1, and use iPSC-derived cardiomyocytes to characterize the effect of the allele.
- Shannon Hateley
- , Angelica Lopez-Izquierdo
- & Martin Tristani-Firouzi
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Article
| Open AccessGenome sequencing unveils a regulatory landscape of platelet reactivity
Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.
- Ali R. Keramati
- , Ming-Huei Chen
- & Andrew D. Johnson
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Article
| Open AccessCohesin-protein Shugoshin-1 controls cardiac automaticity via HCN4 pacemaker channel
A mutation in Shugoshin-1 causes the Chronic Atrial and Intestinal Dysrhythmia (CAID) Syndrome, but the underlying mechanisms are unknown. Here, the authors show that Shugoshin-1 controls cardiac pacemaker activity by interacting with HCN4 to enhance its cell-surface expression, and that the CAID-Syndrome mutation disrupts cardiac pacemaking by interfering with this important non-canonical interaction.
- Donghai Liu
- , Andrew Taehun Song
- & Stanley Nattel
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Article
| Open AccessChromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices
The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.
- Pradeep Natarajan
- , Akhil Pampana
- & Gina M. Peloso
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Article
| Open AccessA fast and efficient colocalization algorithm for identifying shared genetic risk factors across multiple traits
Statistical colocalisation is a method to identify causal genes and shared genetic aetiology across traits. Here, the authors describe HyPrColoc, an efficient Bayesian divisive clustering algorithm which integrates summary statistics from genome-wide association studies to detect clusters of colocalised traits from large numbers of traits.
- Christopher N. Foley
- , James R. Staley
- & Joanna M. M. Howson
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Article
| Open AccessChromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction
Spontaneous coronary artery dissection (SCAD) is a cause of myocardial infarction Here, the authors present a genome-wide association study of SCAD, finding an association at 1q21.2 which potentially affects expression of ADAMTSL4.
- Jacqueline Saw
- , Min-Lee Yang
- & Santhi K. Ganesh
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Article
| Open AccessPolygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions
Genetic variation predisposes to disease via monogenic and polygenic risk variants. Here, the authors assess the interplay between these types of variation on disease penetrance in 80,928 individuals. In carriers of monogenic variants, they show that disease risk is a gradient influenced by polygenic background.
- Akl C. Fahed
- , Minxian Wang
- & Amit V. Khera
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Article
| Open AccessmTADA is a framework for identifying risk genes from de novo mutations in multiple traits
Joint analysis of multiple traits can increase power and provide insights into shared genetic architecture. Here, Nguyen et al. develop multi-trait TADA (mTADA), an extension of TADA (transmission and de novo association test) that jointly analyses de novo mutations of traits for improved risk-gene identification power.
- Tan-Hoang Nguyen
- , Amanda Dobbyn
- & Eli A. Stahl
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Article
| Open AccessMulti-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
- Ioanna Ntalla
- , Lu-Chen Weng
- & Patricia B. Munroe
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Article
| Open AccessAnalysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy
Structural changes to the left ventricle are characteristic of dilated cardiomyopathy (DCM), a disease for which many rare genetic variants are known. Here, Pirruccello et al. report GWAS of seven cardiac MRI measurements in the left ventricle and describe shared loci and polygenic association with DCM.
- James P. Pirruccello
- , Alexander Bick
- & Krishna G. Aragam
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Article
| Open AccessA robust and efficient method for Mendelian randomization with hundreds of genetic variants
Mendelian randomization (MR) is a method for inferring causal relationships between risk factors and outcomes via associated genetic variants. Here, Burgess et al. develop the contamination mixture method which yields robust MR results in the presence of invalid instrumental variables and groups variants by their effect estimates.
- Stephen Burgess
- , Christopher N Foley
- & Joanna M. M. Howson
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Article
| Open AccessGenome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.
- Sonia Shah
- , Albert Henry
- & R. Thomas Lumbers
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Article
| Open AccessSequence variants with large effects on cardiac electrophysiology and disease
Aberrant morphology of the QRS complex in an electrocardiogram can be associated with cardiac morbidity and mortality. Here, the authors perform genome-wide association studies for ten measures of the QRS complex in 81,192 individuals and find 86 previously unreported loci that associate with at least one parameter.
- Kristjan Norland
- , Gardar Sveinbjornsson
- & Kari Stefansson
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Article
| Open AccessA comprehensive study of metabolite genetics reveals strong pleiotropy and heterogeneity across time and context
Genome-wide association studies of metabolites have revealed hundreds of genetic associations using univariate analyses. Here, the authors use a multivariate approach to perform association analyses for 158 serum metabolites, followed by fine mapping and GxE interaction tests with statin use and age.
- Apolline Gallois
- , Joel Mefford
- & Hugues Aschard
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Article
| Open AccessDe novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes
Large whole-exome sequencing studies have suggested that the genetic architecture of syndromic congenital heart disease (CHD) is different from sporadic forms. Here, Watkins et al. estimate the relative contribution of damaging recessive and de novo genotypes to CHD in 2391 trios and find them to be associated with different gene functions.
- W. Scott Watkins
- , E. Javier Hernandez
- & Martin Tristani-Firouzi
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Article
| Open AccessGenetic architecture of human plasma lipidome and its link to cardiovascular disease
Cardiovascular diseases (CVD) are associated with plasma lipid levels. Here, Tabassum et al. perform genome-wide association studies for lipidomic profiles with 141 (non-standard) lipid species which highlights shared genetic loci with CVD and that traditional lipids have low genetic correlation with other lipids.
- Rubina Tabassum
- , Joel T. Rämö
- & Samuli Ripatti
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Article
| Open AccessThe transferability of lipid loci across African, Asian and European cohorts
The majority of published GWAS was performed in European ancestry populations. Here, Kuchenbaecker et al., test to which extent lipid loci are shared and find that the major lipid loci are mostly transferrable between Europeans and Asians while there are notable exceptions for African populations.
- Karoline Kuchenbaecker
- , Nikita Telkar
- & Dieter Wolke
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Article
| Open AccessGWAS for urinary sodium and potassium excretion highlights pathways shared with cardiovascular traits
Levels of sodium and potassium in urine are associated with cardiovascular traits. Here, Pazoki et al. perform genome-wide association studies for urinary sodium and potassium secretion and identify 50 and 13 novel loci, respectively, some of which show a potential causal relationship with blood pressure based on MR analysis.
- Raha Pazoki
- , Evangelos Evangelou
- & Abbas Dehghan
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Article
| Open AccessPathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure
The genetic and pathogenetic basis of heart failure is incompletely understood. Here, the authors present a high-fidelity tissue collection from rapidly preserved failing and non-failing control hearts which are used for eQTL mapping and network analysis, resulting in the prioritization of PPP1R3A as a heart failure gene.
- Pablo Cordero
- , Victoria N. Parikh
- & Euan A. Ashley
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Article
| Open AccessAssessing the causal association of glycine with risk of cardio-metabolic diseases
Epidemiological studies have associated circulating levels of the amino acid glycine with cardiometabolic outcomes. Here, in a genome-wide meta-analysis of 80,003 individuals, Wittemans et al. identify 22 novel genetic loci for glycine and find a causal relationship with coronary heart disease using MR.
- Laura B. L. Wittemans
- , Luca A. Lotta
- & Claudia Langenberg
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Article
| Open AccessMulti-ancestry study of blood lipid levels identifies four loci interacting with physical activity
GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.
- Tuomas O. Kilpeläinen
- , Amy R. Bentley
- & Ruth J. F. Loos
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Article
| Open AccessGWAS identifies 14 loci for device-measured physical activity and sleep duration
Studying the genetic underpinnings of physical activity and sleep duration can be confounded by self-reporting. Here, Doherty et al. use data from 91,105 UK Biobank participants, whose activity had been monitored for a week by a wearable device, for genome-wide association analysis and identify 14 loci.
- Aiden Doherty
- , Karl Smith-Byrne
- & Cecilia M. Lindgren
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Article
| Open AccessGWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
Carotid intima-media thickness (cIMT) and plaque are associated with subclinical atherosclerosis and coronary heart disease (CHD). Here, the authors identify and prioritize genetic loci for cIMT and plaque by GWAS and colocalization approaches and further demonstrate genetic correlation with CHD and stroke.
- Nora Franceschini
- , Claudia Giambartolomei
- & Christopher J. O’Donnell
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Article
| Open AccessInterethnic analyses of blood pressure loci in populations of East Asian and European descent
Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, the authors perform discovery GWAS for BP in East Asians and meta-analysis in East Asians and Europeans and report ancestry-specific BP SNPs and selection signals.
- Fumihiko Takeuchi
- , Masato Akiyama
- & Norihiro Kato
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Article
| Open AccessCohort-wide deep whole genome sequencing and the allelic architecture of complex traits
Rare genetic variants can contribute to complex traits but this contribution is not well understood. Here, the authors analyse deep whole genome sequencing data across 1457 individuals from an isolated Greek population and find association of rare variant burdens with cardiometabolic traits.
- Arthur Gilly
- , Daniel Suveges
- & Eleftheria Zeggini
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Article
| Open AccessRare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation
Common genetic variants in structural proteins contribute to risk of atrial fibrillation (AF). Here, using whole-exome sequencing, the authors identify rare truncating variants in TTN that associate with familial and early-onset AF and show defects in cardiac sarcomere assembly in ttn.2-mutant zebrafish.
- Gustav Ahlberg
- , Lena Refsgaard
- & Morten S. Olesen
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Article
| Open AccessConditional and interaction gene-set analysis reveals novel functional pathways for blood pressure
Gene-set analysis (GSA) is widely used to infer functional and biological properties of a gene set. Here, the authors develop a conditional and interaction gene-set analysis approach that can considerably refine results from traditional GSA.
- Christiaan A. de Leeuw
- , Sven Stringer
- & Danielle Posthuma
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Article
| Open AccessDeep-coverage whole genome sequences and blood lipids among 16,324 individuals
Common genetic variants associated with plasma lipids have been extensively studied for a better understanding of common diseases. Here, the authors use whole-genome sequencing of 16,324 individuals to analyze rare variant associations and to determine their monogenic and polygenic contribution to lipid traits.
- Pradeep Natarajan
- , Gina M. Peloso
- & Sebastian Zoellner
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Article
| Open AccessGenome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease
Genetic variation can influence levels of disease-related plasma proteins and, thus, contribute to the pathogenesis of complex diseases. Here, the authors perform genome-wide QTL analysis for 71 plasma proteins to identify causal proteins for coronary heart disease and provide a molecular QTL browser.
- Chen Yao
- , George Chen
- & Daniel Levy
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Article
| Open AccessPR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
Abnormal PR interval duration is associated with risk for atrial fibrillation and heart block. Here, van Setten et al. identify 44 PR interval loci in a genome-wide association study of over 92,000 individuals and find genetic overlap with QRS duration, heart rate and atrial fibrillation.
- Jessica van Setten
- , Jennifer A. Brody
- & Nona Sotoodehnia
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Article
| Open AccessPromoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks
Human embryonic stem cell-derived cardiomyocytes (hESC-CM) are a widely used model to study cardiac genomics. Here, Choy et al. perform promoter capture Hi-C to map long-range chromosomal interactions of hESC-CMs and to study overlap of such regions with genetic loci associated with cardiac phenotypes.
- Mun-Kit Choy
- , Biola M. Javierre
- & Bernard D. Keavney
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Article
| Open AccessThirty loci identified for heart rate response to exercise and recovery implicate autonomic nervous system
Genome-wide association studies have identified multiple loci for resting heart rate (HR) but the genetic factors associated with HR increase during and HR recovery after exercise are less well studied. Here, the authors examine both traits in a two-stage GWAS design in up to 67,257 individuals from UK Biobank.
- Julia Ramírez
- , Stefan van Duijvenboden
- & Patricia B. Munroe
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Article
| Open AccessGenetic study links components of the autonomous nervous system to heart-rate profile during exercise
Response of the heart rate (HR) to exercise is associated with cardiac fitness and risk of cardiac death. Here, in a genome-wide association study, Verweij et al. identify 23 loci for HR increase during exercise or HR recovery, and highlight pleiotropy with blood pressure by polygenic risk score analysis.
- Niek Verweij
- , Yordi J. van de Vegte
- & Pim van der Harst