scholarly journals Monogenic and Polygenic Contributions to QTc Prolongation in the Population

2021 ◽  
Author(s):  
Victor Nauffal ◽  
Valerie N Morrill ◽  
Sean J Jurgens ◽  
Seung Hoan Choi ◽  
Amelia W Hall ◽  
...  
Keyword(s):  
Qt Interval ◽  
Genome Wide Association Study ◽  
Rare Variants ◽  
Phenotypic Expression ◽  
Polygenic Risk Score ◽  
Interval Duration ◽  
Polygenic Risk ◽  
A Genome ◽  
Qt Interval Duration ◽  
Polygenic Variation

Background: Rare sequence variation in genes underlying the long QT syndrome (LQTS) and common polygenic variation influence QT interval duration. It is unclear how rare and common variation contribute to QT interval duration in the general population. Objectives: Investigate monogenic and polygenic contributions to QT interval duration and the role of polygenic variation in modulating phenotypic expression of rare monogenic variation. Methods: We performed a genome wide association study (GWAS) of QTc duration in 44,979 United Kingdom Biobank (UKBB) participants and created a polygenic risk score (PRS). The PRS was validated in 39,800 independent UKBB participants. Among 26,976 participants with whole genome sequencing and ECG data in the TransOmics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 LQTS genes. We examined QTc associations with the PRS and with LQTS rare variants in TOPMed. Results: Twenty independent loci (4 novel) were identified by GWAS. The PRS comprising 565 common variants was significantly associated with QTc duration in TOPMed (p=1.1x10-64). Carriers of LQTS rare variants had longer QTc intervals than non-carriers (deltaQTc=10.9 ms [7.4-14.4] for all LQTS genes; deltaQTc=26.5 ms [20.7-32.3] for KCNQ1, KCNH2 and SCN5A). 16.7% of individuals with QTc>480 ms carried either a rare variant in a LQTS gene or had a PRS in the top decile (3.4% monogenic, 13.6% top decile of PRS). We observed a greater effect of rare variants on the QTc among individuals with a higher polygenic risk (lowest PRS tertile:deltaQTccarrier/non-carrier=4.8 ms [-1.2-10.7];highest PRS tertile:deltaQTccarrier/non-carrier=18.9 ms [12.8-25.1];p-interaction=0.001). Conclusions: QTc duration is influenced by both rare variants in established LQTS genes and polygenic risk. The phenotypic expression of monogenic variation is modulated by polygenic variation. Nevertheless, over 80% of individuals with prolonged QTc do not carry a rare monogenic variant or polygenic risk equivalent.

scholarly journals A Genome-Wide Association Scan of RR and QT Interval Duration in 3 European Genetically Isolated Populations

2009 ◽  
Vol 2 (4) ◽  
pp. 322-328 ◽  
Author(s):  
Fabio Marroni ◽  
Arne Pfeufer ◽  
Yurii S. Aulchenko ◽  
Christopher S. Franklin ◽  
Aaron Isaacs ◽  
...  
Keyword(s):  
Qt Interval ◽  
Genome Wide Association ◽  
Interval Duration ◽  
Isolated Populations ◽  
Genome Wide ◽  
A Genome ◽  
Qt Interval Duration

scholarly journals Machine Learning to Understand Genetic and Clinical Factors Associated with the Pulse Waveform Dicrotic Notch

2021 ◽  
Author(s):  
Jonathan W. Cunningham ◽  
Paolo Di Achille ◽  
Valerie N. Morrill ◽  
Lu-Chen Weng ◽  
Seung Hoan Choi ◽  
...  
Keyword(s):  
Machine Learning ◽  
Genome Wide Association Study ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Continuous Trait ◽  
Dicrotic Notch ◽  
Digital Phenotyping ◽  
A Genome ◽  
The Uk

AbstractBackgroundAbsence of a dicrotic notch on finger photoplethysmography (PPG) is an easily ascertainable and inexpensive trait that has been associated with age and prevalent cardiovascular disease (CVD). However, the trait exists along a continuum, and little is known about its genetic underpinnings or prognostic value for incident CVD.MethodsIn 169,787 participants in the UK Biobank, we identified absent dicrotic notch on PPG and created a novel continuous trait reflecting notch smoothness using machine learning. Next, we determined the heritability, genetic basis, polygenic risk, and clinical relations for the binary absent notch trait and the newly derived continuous notch smoothness trait.ResultsHeritability of the continuous notch smoothness trait was 7.5%, compared with 5.6% for the binary absent notch trait. A genome wide association study of notch smoothness identified 15 significant loci, implicating genes including NT5C2 (P=1.2×10−26), IGFBP3 (P=4.8×10−18), and PHACTR1 (P=1.4×10−13), compared with 6 loci for the binary absent notch trait. Notch smoothness stratified risk of incident myocardial infarction or coronary artery disease, stroke, heart failure, and aortic stenosis. A polygenic risk score for notch smoothness was associated with incident CVD and all-cause death in UK Biobank participants without available PPG data.ConclusionWe found that a machine learning derived continuous trait reflecting dicrotic notch smoothness on PPG was heritable and associated with genes involved in vascular stiffness. Greater notch smoothness was associated with greater risk of incident CVD. Raw digital phenotyping may identify individuals at risk for disease via specific genetic pathways.

scholarly journals Coffee, Alcohol, Smoking, Physical Activity and QT Interval Duration: Results from the Third National Health and Nutrition Examination Survey

PLoS ONE ◽  
2011 ◽  
Vol 6 (2) ◽  
pp. e17584 ◽  
Author(s):  
Yiyi Zhang ◽  
Wendy S. Post ◽  
Darshan Dalal ◽  
Elena Blasco-Colmenares ◽  
Gordon F. Tomaselli ◽  
...  
Keyword(s):  
Physical Activity ◽  
National Health ◽  
Qt Interval ◽  
Nutrition Examination Survey ◽  
Interval Duration ◽  
The Third ◽  
Health And Nutrition ◽  
Qt Interval Duration

scholarly journals Complex Influence of Gonadotropins and Sex Steroid Hormones on QT Interval Duration

2016 ◽  
Vol 101 (7) ◽  
pp. 2776-2784 ◽  
Author(s):  
Guillaume Abehsira ◽  
Anne Bachelot ◽  
Fabio Badilini ◽  
Laurence Koehl ◽  
Martine Lebot ◽  
...  
Keyword(s):  
Steroid Hormones ◽  
Qt Interval ◽  
Sex Steroid Hormones ◽  
Sex Steroid ◽  
Interval Duration ◽  
Qt Interval Duration ◽  
Complex Influence

Abstract 2924: Association of NOS1AP Genetic Variants with QT Interval Duration in Families from the Diabetes Heart Study

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Allison B Lehtinen ◽  
Christopher Newton-Cheh ◽  
Julie T Ziegler ◽  
Carl D Langefeld ◽  
Barry I Freedman ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Qt Interval ◽  
Genetic Model ◽  
Additive Model ◽  
Adaptor Protein ◽  
European Ancestry ◽  
Nucleotide Polymorphisms ◽  
Interval Duration ◽  
Common Genetic Variants ◽  
Qt Interval Duration

Background: Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD) in unselected samples as well as in post-myocardial infarction patients or those with diabetes. Common genetic variants in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene have been reported to be associated with QT interval duration in individuals of European ancestry. We sought to replicate the association of NOS1AP variants with QT interval duration in pedigrees enriched for type 2 diabetes mellitus (T2DM). Methods and Results: Two single nucleotide polymorphisms (SNPs) in the NOS1AP gene, rs10494366 and rs10918594, were genotyped in a collection of 937 European Americans (EAs) and 177 African Americans (AAs) in 450 pedigrees containing at least two siblings with T2DM. An additive genetic model was tested for each SNP in ancestry-specific analyses using SOLAR in the total sample and in the diabetic subset (EA n=778, AA n=159), with and without exclusion of QT-altering medications. In the EA individuals, rs10494366 minor allele homozygotes had an 8.9 msec longer mean QT interval compared to major homozygotes (additive model p=4.4x10 -3 ); rs10918594 minor homozygotes had a 12.9 msec longer mean QT interval compared to major homozygotes (p=9.9x10 -5 ). Excluding users of QT-altering medications in the diabetic-only EA sample (n=514) strengthened the association despite the reduction in sample size (20.6 msec difference, p=2.0x10 -5 ; 23.4 msec difference, p=8.9x10 -7 , respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of AA individuals examined. Conclusions: Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic EA sample. Stronger effects of NOS1AP variants in diabetic individuals compared to previously reported unselected samples suggest that this patient subset may be particularly susceptible to genetic variants that influence myocardial depolarization and repolarization as manifest in the QT interval.

scholarly journals Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

2019 ◽  
Author(s):  
Richard J Allen ◽  
Beatriz Guillen-Guio ◽  
Justin M Oldham ◽  
Shwu-Fan Ma ◽  
Amy Dressen ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Telomere Maintenance ◽  
Genome Wide Association ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genome Wide

AbstractRationaleIdiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.ObjectivesTo improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations.Methods and measurementsWe performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Main resultsWe identified and replicated three new genome-wide significant (P<5×10-8) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility.ConclusionsNovel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases

2021 ◽  
pp. ASN.2020111599
Author(s):  
Zhi Yu ◽  
Jin Jin ◽  
Adrienne Tin ◽  
Anna Köttgen ◽  
Bing Yu ◽  
...  
Keyword(s):  
Kidney Function ◽  
Kidney Diseases ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Plasma Proteome ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome

Background: Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. Methods: We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (N=765,348) and UK Biobank GWAS (90% of the cohort; N=451,508), followed by best parameter selection using the remaining 10% of UK Biobank (N=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (N=8,866) with incident chronic kidney disease, kidney failure, and acute kidney injury. We also examined associations between the PRS and 4,877 plasma proteins measured at at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. Results: The developed PRS showed significant associations with all outcomes with hazard ratios (95% CI) per 1 SD lower PRS ranged from 1.06 (1.01, 1.11) to 1.33 (1.28, 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin-C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for 5 proteins including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. Conclusions: A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.

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