Publications by authors named "Helen R Warren"

60 Publications

Adverse Cardiovascular Outcomes and Antihypertensive treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS).

Clin Pharmacol Ther 2021 Jul 7. Epub 2021 Jul 7.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL, USA.

We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-SNP interaction tests for four drug classes (β-blockers, n=9,195; calcium channel blockers [CCB], n=10,511; thiazide/thiazide-like diuretics, n=3,516; ACE-inhibitors/ARBs, n=2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among hypertensive patients of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent CHARGE study (n=21,267), blood pressure (BP) response in independent ICAPS studies (n=1,552), and ethnic validation in African Americans from GenHAT (n=5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P=1.56 x 10 ). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P=6 x 10 , Beta=3.09, diastolic BP response P=5 x 10 , Beta=1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients subgroup (P=2.35 x 10 , OR [95% CI] = 1.57 [1.23-1.99]). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an eQTL for the 50kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted.
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http://dx.doi.org/10.1002/cpt.2355DOI Listing
July 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Genetically Determined Serum Calcium Levels and Markers of Ventricular Repolarization: A Mendelian Randomization Study in the UK Biobank.

Circ Genom Precis Med 2021 Jun 22;14(3):e003231. Epub 2021 Apr 22.

Department of Internal Medicine (D.v.H., R.N.), Leiden University Medical Center, the Netherlands.

Background: ECG markers of ventricular depolarization and repolarization are associated with an increased risk of arrhythmia and sudden cardiac death. Our prior work indicated lower serum calcium concentrations are associated with longer QT and JT intervals in the general population. Here, we investigate whether serum calcium is a causal risk factor for changes in ECG measures using Mendelian randomization (MR).

Methods: Independent lead variants from a newly performed genome-wide association study for serum calcium in >300 000 European-ancestry participants from UK Biobank were used as instrumental variables. Two-sample MR analyses were performed to approximate the causal effect of serum calcium on QT, JT, and QRS intervals using an inverse-weighted method in 76 226 participants not contributing to the serum calcium genome-wide association study. Sensitivity analyses including MR-Egger, weighted-median estimator, and MR pleiotropy residual sum and outlier were performed to test for the presence of horizontal pleiotropy.

Results: Two hundred five independent lead calcium-associated variants were used as instrumental variables for MR. A decrease of 0.1 mmol/L serum calcium was associated with longer QT (3.01 ms [95% CI, 2.03 to 3.99]) and JT (2.89 ms [1.91 to 3.87]) intervals. A weak association was observed for QRS duration (secondary analyses only). Results were concordant in all sensitivity analyses.

Conclusions: These analyses support a causal effect of serum calcium levels on ventricular repolarization, in a middle-aged population of European-ancestry where serum calcium concentrations are likely stable and chronic. Modulation of calcium concentration may, therefore, directly influence cardiovascular disease risk.
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http://dx.doi.org/10.1161/CIRCGEN.120.003231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208093PMC
June 2021

An Academic Clinician's Road Map to Hypertension Genomics: Recent Advances and Future Directions MMXX.

Hypertension 2021 Feb 4;77(2):284-295. Epub 2021 Jan 4.

From the William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.

At the dawn of the new decade, it is judicious to reflect on the boom of knowledge about polygenic risk for essential hypertension supplied by the wealth of genome-wide association studies. Hypertension continues to account for significant cardiovascular morbidity and mortality, with increasing prevalence anticipated. Here, we overview recent advances in the use of big data to understand polygenic hypertension, as well as opportunities for future innovation to translate this windfall of knowledge into clinical benefit.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14535DOI Listing
February 2021

Phospholemman Phosphorylation Regulates Vascular Tone, Blood Pressure, and Hypertension in Mice and Humans.

Circulation 2021 Mar 18;143(11):1123-1138. Epub 2020 Dec 18.

British Heart Foundation Centre of Research Excellence, King's College London, United Kingdom (A.B., S.T., O.P., O.R., D.S.-T., M.J.S.). Clinical Pharmacology, The William Harvey Research Institute (O.P., H.R.W., M.J.C.), National Institute for Health Research, Biomedical Research Centre (H.R.W., M.J.C.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom. Department of Pharmacology, University of Oxford, United Kingdom (H.A.L.L., K.A.D., C.J.G.). Medicines Monitoring Unit, School of Medicine (A.D.), Division of Cardiovascular and Diabetes Medicine (C.N.A.), University of Dundee, United Kingdom. Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (J.V.W., J.H., W.F.).

Background: Although it has long been recognized that smooth muscle Na/K ATPase modulates vascular tone and blood pressure (BP), the role of its accessory protein phospholemman has not been characterized. The aim of this study was to test the hypothesis that phospholemman phosphorylation regulates vascular tone in vitro and that this mechanism plays an important role in modulation of vascular function and BP in experimental models in vivo and in humans.

Methods: In mouse studies, phospholemman knock-in mice (PLM; phospholemman [FXYD1] in which the 3 phosphorylation sites on serines 63, 68, and 69 are mutated to alanines), in which phospholemman is rendered unphosphorylatable, were used to assess the role of phospholemman phosphorylation in vitro in aortic and mesenteric vessels using wire myography and membrane potential measurements. In vivo BP and regional blood flow were assessed using Doppler flow and telemetry in young (14-16 weeks) and old (57-60 weeks) wild-type and transgenic mice. In human studies, we searched human genomic databases for mutations in phospholemman in the region of the phosphorylation sites and performed analyses within 2 human data cohorts (UK Biobank and GoDARTS [Genetics of Diabetes Audit and Research in Tayside]) to assess the impact of an identified single nucleotide polymorphism on BP. This single nucleotide polymorphism was expressed in human embryonic kidney cells, and its effect on phospholemman phosphorylation was determined using Western blotting.

Results: Phospholemman phosphorylation at Ser63 and Ser68 limited vascular constriction in response to phenylephrine. This effect was blocked by ouabain. Prevention of phospholemman phosphorylation in the PLM mouse profoundly enhanced vascular responses to phenylephrine both in vitro and in vivo. In aging wild-type mice, phospholemman was hypophosphorylated, and this correlated with the development of aging-induced essential hypertension. In humans, we identified a nonsynonymous coding variant, single nucleotide polymorphism rs61753924, which causes the substitution R70C in phospholemman. In human embryonic kidney cells, the R70C mutation prevented phospholemman phosphorylation at Ser68. This variant's rare allele is significantly associated with increased BP in middle-aged men.

Conclusions: These studies demonstrate the importance of phospholemman phosphorylation in the regulation of vascular tone and BP and suggest a novel mechanism, and therapeutic target, for aging-induced essential hypertension in humans.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.040557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969167PMC
March 2021

Hypertension and the roles of the 9p21.3 risk locus: Classic findings and new association data.

Int J Cardiol Hypertens 2020 Dec 15;7:100050. Epub 2020 Sep 15.

Cellular & Molecular Biology Unit, Corporación para Investigaciones Biológicas, Medellín, Colombia.

Background: The band 9p21.3 contains an established genomic risk zone for cardiovascular disease (CVD). Since the initial 2007 Wellcome Trust Case Control Consortium study (WTCCC), the increased CVD risk associated with 9p21.3 has been confirmed by multiple studies in different continents. However, many years later there was still no confirmed report of a corresponding association of 9p21.3 with hypertension, a major CV risk factor, nor with blood pressure (BP).

Theory: In this contribution, we review the bipartite haplotype structure of the 9p21.3 risk locus: one block is devoid of protein-coding genes but contains the lead CVD risk SNPs, while the other block contains the first exon and regulatory DNA of the gene for the cell cycle inhibitor p15. We consider how findings from molecular biology offer possibilities of an involvement of p15 in hypertension etiology, with expression of the p15 gene modulated by genetic variation from within the 9p21.3 risk locus.

Results: We present original results from a Colombian study revealing moderate but persistent association signals for BP and hypertension within the classic 9p21.3 CVD risk locus. These SNPs are mostly confined to a 'hypertension island' that spans less than 60 kb and coincides with the p15 haplotype block. We find confirmation in data originating from much larger, recent European BP studies, albeit with opposite effect directions.

Conclusion: Although more work will be needed to elucidate possible mechanisms, previous findings and new data prompt reconsidering the question of how variation in 9p21.3 might influence hypertension components of cardiovascular risk.
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http://dx.doi.org/10.1016/j.ijchy.2020.100050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491459PMC
December 2020

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

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

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.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation.

Circ Genom Precis Med 2020 10 21;13(5):387-395. Epub 2020 Aug 21.

DZHK (German Center for Cardiovascular Research), partner site Greifswald, Germany (A.T., U.V., M.D., S.B.F.).

Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.

Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.

Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (, , , , , , , ). The top variants at known sarcomere genes () were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, and ) were associated with longer PWD but lower AF risk.

Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.
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http://dx.doi.org/10.1161/CIRCGEN.119.002874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578098PMC
October 2020

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Nat Commun 2020 05 21;11(1):2542. Epub 2020 May 21.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-020-15706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242331PMC
May 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2020 May 5. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
May 2020

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern.

JCI Insight 2019 12 5;4(23). Epub 2019 Dec 5.

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

BACKGROUNDThe presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown.METHODSTo identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry.RESULTSWe identified a genome-wide significant (P < 5 × 10-8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10-12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery.CONCLUSIONSIn this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.FUNDINGThis project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 - STATS). For detailed funding information per study, see the Supplemental Acknowledgments.
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http://dx.doi.org/10.1172/jci.insight.131156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962032PMC
December 2019

Genome-Wide Analysis of Left Ventricular Image-Derived Phenotypes Identifies Fourteen Loci Associated With Cardiac Morphogenesis and Heart Failure Development.

Circulation 2019 10 25;140(16):1318-1330. Epub 2019 Sep 25.

William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (N.A., H.R.W., K.F., P.B.M., S.E.P.), Queen Mary University of London, United Kingdom.

Background: The genetic basis of left ventricular (LV) image-derived phenotypes, which play a vital role in the diagnosis, management, and risk stratification of cardiovascular diseases, is unclear at present.

Methods: The LV parameters were measured from the cardiovascular magnetic resonance studies of the UK Biobank. Genotyping was done using Affymetrix arrays, augmented by imputation. We performed genome-wide association studies of 6 LV traits-LV end-diastolic volume, LV end-systolic volume, LV stroke volume, LV ejection fraction, LV mass, and LV mass to end-diastolic volume ratio. The replication analysis was performed in the MESA study (Multi-Ethnic Study of Atherosclerosis). We identified the candidate genes at genome-wide significant loci based on the evidence from extensive bioinformatic analyses. Polygenic risk scores were constructed from the summary statistics of LV genome-wide association studies to predict the heart failure events.

Results: The study comprised 16 923 European UK Biobank participants (mean age 62.5 years; 45.8% men) without prevalent myocardial infarction or heart failure. We discovered 14 genome-wide significant loci (3 loci each for LV end-diastolic volume, LV end-systolic volume, and LV mass to end-diastolic volume ratio; 4 loci for LV ejection fraction, and 1 locus for LV mass) at a stringent <1×10. Three loci were replicated at Bonferroni significance and 7 loci at nominal significance (<0.05 with concordant direction of effect) in the MESA study (n=4383). Follow-up bioinformatic analyses identified 28 candidate genes that were enriched in the cardiac developmental pathways and regulation of the LV contractile mechanism. Eight genes (, and ) supported by at least 2 independent lines of in silico evidence were implicated in the cardiac morphogenesis and heart failure development. The polygenic risk scores of LV phenotypes were predictive of heart failure in a holdout UK Biobank sample of 3106 cases and 224 134 controls (odds ratio 1.41, 95% CI 1.26 - 1.58, for the top quintile versus the bottom quintile of the LV end-systolic volume risk score).

Conclusions: We report 14 genetic loci and indicate several candidate genes that not only enhance our understanding of the genetic architecture of prognostically important LV phenotypes but also shed light on potential novel therapeutic targets for LV remodeling.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791514PMC
October 2019

Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.

Am J Hypertens 2019 11;32(12):1146-1153

Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.

Background: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

Methods: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

Results: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

Conclusion: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.
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http://dx.doi.org/10.1093/ajh/hpz150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856621PMC
November 2019

Genome-Wide Meta-Analysis of Blood Pressure Response to β-Blockers: Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies).

J Am Heart Assoc 2019 08 19;8(16):e013115. Epub 2019 Aug 19.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine University of Florida Gainesville FL.

BackgroundThere exists a wide interindividual variability in blood pressure (BP) response to β-blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome-wide meta-analysis of genetic variants influencing β-blocker BP response.Methods and ResultsGenome-wide association analysis for systolic BP and diastolic BP response to β-blockers from 5 randomized clinical trials consisting of 1254 patients with hypertension of European ancestry were combined in meta-analysis and single nucleotide polymorphisms (SNPs) with P<10 were tested for replication in 2 independent randomized clinical trials of β-blocker-treated patients of European ancestry (n=1552). Regions harboring the replicated SNPs were validated in a β-blocker-treated black cohort from 2 randomized clinical trials (n=315). A missense SNP rs28404156 in BST1 was associated with systolic BP response to β-blockers in the discovery meta-analysis (P=9.33×10, β=-3.21 mm Hg) and replicated at Bonferroni significance (P=1.85×10, β=-4.86 mm Hg) in the replication meta-analysis with combined meta-analysis approaching genome-wide significance (P=2.18×10). This SNP in BST1 is in linkage disequilibrium with several SNPs with putative regulatory functions in nearby genes, including CD38, FBXL5, and FGFBP1, all of which have been implicated in BP regulation. SNPs in this genetic region were also associated with BP response in the black cohort.ConclusionsData from randomized clinical trials of 8 European ancestry and 2 black cohorts support the assumption that BST1 containing locus on chromosome 4 is associated with β-blocker BP response. Given the previous associations of this region with BP, this is a strong candidate region for future functional studies and potential use in precision medicine approaches for BP management and risk prediction.
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http://dx.doi.org/10.1161/JAHA.119.013115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759913PMC
August 2019

Genome-wide association study identifies loci for arterial stiffness index in 127,121 UK Biobank participants.

Sci Rep 2019 06 24;9(1):9143. Epub 2019 Jun 24.

Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, UK.

Arterial stiffness index (ASI) is a non-invasive measure of arterial stiffness using infra-red finger sensors (photoplethysmography). It is a well-suited measure for large populations as it is relatively inexpensive to perform, and data can be acquired within seconds. These features raise interest in using ASI as a tool to estimate cardiovascular disease risk as prior work demonstrates increased arterial stiffness is associated with elevated systolic blood pressure, and ASI is predictive of cardiovascular disease and mortality. We conducted genome-wide association studies (GWASs) for ASI in 127,121 UK Biobank participants of European-ancestry. Our primary analyses identified variants at four loci reaching genome-wide significance (P < 5 × 10): TEX41 (rs1006923; P = 5.3 × 10), FOXO1 (rs7331212; P = 2.2 × 10), C1orf21 (rs1930290, P = 1.1 × 10) and MRVI1 (rs10840457, P = 3.4 × 10). Gene-based testing revealed three significant genes, the most significant gene was COL4A2 (P = 1.41 × 10) encoding type IV collagen. Other candidate genes at associated loci were also involved in smooth muscle tone regulation. Our findings provide new information for understanding the development of arterial stiffness.
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http://dx.doi.org/10.1038/s41598-019-45703-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591384PMC
June 2019

Effects of Calcium, Magnesium, and Potassium Concentrations on Ventricular Repolarization in Unselected Individuals.

J Am Coll Cardiol 2019 06;73(24):3118-3131

Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.

Background: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.

Objectives: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.

Methods: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.

Results: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.

Conclusions: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.
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http://dx.doi.org/10.1016/j.jacc.2019.03.519DOI Listing
June 2019

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.

Hum Mol Genet 2019 08;28(15):2615-2633

Icelandic Heart Association, Kopavogur, Iceland.

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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http://dx.doi.org/10.1093/hmg/ddz070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644157PMC
August 2019

Mendelian randomisation analyses find pulmonary factors mediate the effect of height on coronary artery disease.

Commun Biol 2019 27;2:119. Epub 2019 Mar 27.

1William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ UK.

There is evidence that lower height is associated with a higher risk of coronary artery disease (CAD) and increased risk of type 2 diabetes (T2D). It is not clear though whether these associations are causal, direct or mediated by other factors. Here we show that one standard deviation higher genetically determined height (~6.5 cm) is causally associated with a 16% decrease in CAD risk (OR = 0.84, 95% CI 0.80-0.87). This causal association remains after performing sensitivity analyses relaxing pleiotropy assumptions. The causal effect of height on CAD risk is reduced by 1-3% after adjustment for potential mediators (lipids, blood pressure, glycaemic traits, body mass index, socio-economic status). In contrast, our data suggest that lung function (measured by forced expiratory volume [FEV1] and forced vital capacity [FVC]) is a mediator of the effect of height on CAD. We observe no direct causal effect of height on the risk of T2D.
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http://dx.doi.org/10.1038/s42003-019-0361-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437163PMC
May 2020

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Nat Genet 2019 03 18;51(3):452-469. Epub 2019 Feb 18.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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http://dx.doi.org/10.1038/s41588-018-0334-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560635PMC
March 2019

Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits.

Eur J Hum Genet 2019 06 24;27(6):952-962. Epub 2019 Jan 24.

Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital-The Capital Region, Copenhagen, Denmark.

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.
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http://dx.doi.org/10.1038/s41431-018-0295-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777533PMC
June 2019

Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.

Mol Psychiatry 2020 10 7;25(10):2392-2409. Epub 2019 Jan 7.

Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, Netherlands.

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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http://dx.doi.org/10.1038/s41380-018-0313-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515840PMC
October 2020

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.

Nat Genet 2019 01 21;51(1):51-62. Epub 2018 Dec 21.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
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http://dx.doi.org/10.1038/s41588-018-0303-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365102PMC
January 2019

The narrow-sense and common single nucleotide polymorphism heritability of early repolarization.

Int J Cardiol 2019 Mar 4;279:135-140. Epub 2018 Oct 4.

Molecular and Clinical Sciences Research Institute, St George's University of London, UK. Electronic address:

Background: Early repolarization (ER) is a risk marker for sudden cardiac death. Higher risk is associated with horizontal/descending ST-segment ER in the inferior or inferolateral ECG leads. Studies in family cohorts have demonstrated substantial heritability for the ER pattern, but genome-wide association studies (GWAS) have failed to identify statistically significant and replicable genetic signals.

Methods And Results: We assessed the narrow-sense and common single nucleotide polymorphism (SNP) heritability of ER and ER subtypes using ECG data from 5829 individuals (TwinsUK, BRIGHT and GRAPHIC cohorts). ER prevalence was 8.3%. In 455 monozygous vs 808 dizygous twin pairs, concordances and twin correlations for ER subtypes (except horizontal/descending ST-segment ER) were higher and familial resemblance (except notched ER) was significant. Narrow-sense heritability estimates derived from 1263 female twin pairs using the structural equation program Mx ranged from 0.00-0.47 and common SNP heritability estimates derived from 4009 unrelated individuals of both sexes using Genome-wide Restricted Maximum Likelihood (GREML) ranged from 0.00-0.36, but none were statistically significant.

Conclusion: From our data, ER shows limited genetic predisposition. There appears to be significant environmental influence and these modest narrow-sense and common SNP heritability estimates may explain why previous GWAS have been unsuccessful.
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http://dx.doi.org/10.1016/j.ijcard.2018.09.119DOI Listing
March 2019

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.

Nat Genet 2018 10 17;50(10):1412-1425. Epub 2018 Sep 17.

Laboratory of Genetics and Genomics, NIA/NIH, Baltimore, MD, USA.

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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http://dx.doi.org/10.1038/s41588-018-0205-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284793PMC
October 2018

Hypertension genomics and cardiovascular prevention.

Ann Transl Med 2018 Aug;6(15):291

William Harvey Research Institute, The NIHR Biomedical Research Centre at Barts, Queen Mary University London, London, UK.

Hypertension continues to be a major risk factor for global mortality, and recent genome-wide association studies (GWAS) have expanded in size, leading to the identification of further genetic loci influencing blood pressure. In light of the new knowledge from the largest cardiovascular GWAS to date, we review the potential impact of genomics on discovering potential drug targets, risk stratification with genetic risk scores, drug selection with pharmacogenetics, and exploring insights provided by gene-environment interactions.
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http://dx.doi.org/10.21037/atm.2018.06.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123211PMC
August 2018