scholarly journals Genome-wide association studies of atrial fibrillation: Finding meaning in the life of risk loci

2019 ◽  
Vol 24 ◽  
pp. 100397
Author(s):  
Henry Sutanto ◽  
Dobromir Dobrev ◽  
Jordi Heijman
Keyword(s):  
Atrial Fibrillation ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Finding Meaning ◽  
Genome Wide

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

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sonia Shah ◽  
◽  
Albert Henry ◽  
Carolina Roselli ◽  
Honghuang Lin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Cardiac Development ◽  
Association Studies ◽  
Meta Analysis ◽  
Left Ventricular ◽  
Genome Wide Association ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Genome Wide

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

scholarly journals Genome-wide association study provides new insights into the genetic architecture and pathogenesis of heart failure

2019 ◽  
Author(s):  
Sonia Shah ◽  
Albert Henry ◽  
Carolina Roselli ◽  
Honghuang Lin ◽  
Garðar Sveinbjörnsson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Meta Analysis ◽  
Left Ventricular ◽  
Genome Wide Association ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractHeart failure (HF) is a leading cause of morbidity and mortality worldwide1. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained2–4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.

scholarly journals Genome-wide association studies of atrial fibrillation: past, present, and future

2011 ◽  
Vol 89 (4) ◽  
pp. 701-709 ◽  
Author(s):  
M. F. Sinner ◽  
P. T. Ellinor ◽  
T. Meitinger ◽  
E. J. Benjamin ◽  
S. Kaab
Keyword(s):  
Atrial Fibrillation ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

Common variants for atrial fibrillation: results from genome-wide association studies

2011 ◽  
Vol 131 (1) ◽  
pp. 33-39 ◽  
Author(s):  
Xinyuan Liu ◽  
Fei Wang ◽  
Ashley C. Knight ◽  
Jiangmin Zhao ◽  
Junjie Xiao
Keyword(s):  
Atrial Fibrillation ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Genome Wide

scholarly journals Genetics of Height and Risk of Atrial Fibrillation: A Mendelian Randomization Study

2019 ◽  
Author(s):  
Michael G. Levin ◽  
Renae Judy ◽  
Dipender Gill ◽  
Marijana Vujkovic ◽  
Matthew C. Hyman ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Odds Ratio ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Standard Deviation Increase ◽  
Genome Wide ◽  
Predicted Height

ABSTRACTObjectiveTo determine whether height has a causal effect on risk of atrial fibrillationDesignMendelian randomization studySettingGenome-wide association studies of height and atrial fibrillation; Penn Medicine BiobankParticipantsMultiethnic (predominantly European ancestry) participants in genome-wide association studies of height (693,529 individuals) and atrial fibrillation (65,446 cases and 522,744 controls); 7,023 Penn Medicine Biobank participants of European ancestryExposuresHeight, cardiometabolic risk factors for atrial fibrillation, and randomly allocated genetic variants strongly associated with these traitsMain outcome measureRisk of atrial fibrillation (measured in odds ratio)ResultsAt the population level, a 1 standard deviation increase in genetically-predicted height was associated with increased odds of AF (Odds ratio [OR] 1.34; 95% Confidence Interval [CI] 1.29 to 1.40; p = 5×10−42). These findings remained consistent in sensitivity analyses that were robust to the presence of pleiotropic variants. Results from analyses considering individual-participant data were similar, even after adjustment for clinical covariates, including left atrial size.ConclusionGenetically predicted height is a positive causal risk factor for AF. This finding raises the possibility of investigating height/growth-related pathways as a means for gaining novel mechanistic insights to atrial fibrillation, as well as incorporating height into population screening strategies for atrial fibrillation.

scholarly journals Genome-wide association study of atrial fibrillation in 114,539 Finnish individuals reveals novel locus associated with cardiac remodelling

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
C Paludan-Muller ◽  
O B Vad ◽  
J H Svendsen ◽  
M S Olesen
Keyword(s):  
Myocardial Infarction ◽  
Atrial Fibrillation ◽  
Endoplasmic Reticulum ◽  
Association Studies ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Endoplasmic Reticulum Membrane ◽  
Genome Wide Association Studies ◽  
Finnish Population ◽  
Genome Wide

Abstract Background/Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia and it is associated with serious complications, such as stroke, heart failure, and premature death. Previous genome-wide association studies (GWAS) have associated more than 140 genomic loci with AF; however, these studies predominantly include subjects of European ancestry. Although, the Finnish population is European, it is genetically considered different from other European populations as it has been isolated and developed through multiple bottlenecks followed by population growth. Therefore, pathogenic variants are more easily discovered and heritably diseases are more prevalent. Methods We accessed summary statistics on atrial fibrillation and flutter (I48) from the Finngen project. Loci were defined as 1 megabase regions around lead SNPs, and loci were considered novel when the SNPs had P-values <5x10–8 after conditional analysis, and no previously reported SNPs were within the loci. FINEMAP was done with a Finnish LD reference panel, and colocalization of GWAS and eQTL signals were analysed with MetaXcan. Results A GWAS on 17,325 Finnish AF cases and 97,214 controls confirms 16 previous identified loci and reveals one novel locus on chromosome 19. The novel lead SNP, rs190065070 (odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.29–1.61, P-value = 5.96x10–11), is close to the gene EMC10, which encodes the endoplasmic reticulum membrane protein complex subunit 10. While the locus harbours other genes, our MetaXcan analysis could not provide conclusive evidence for other plausible genes. The EMC complex consists of 10 subunits and is a chaperone in endoplasmic reticulum-resident membrane proteins. Previous mouse studies have shown EMC10 to be important in angiogenesis after myocardial infarction, and it has recently been associated with a novel neurodevelopment syndrome. The EMC1 subunit has been associated with congenital heart disease. Conclusion We present a novel susceptibility locus associated with AF in the Finnish population. The locus is in proximity to the gene EMC10, which is involved in structural remodelling of the heart after myocardial infarction. These results propose a potentially novel pathophysiological pathway in AF. FUNDunding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): The Research Foundation RigshospitaletThe John and Birthe Meyer Foundation

scholarly journals Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation

2020 ◽  
Vol 127 (1) ◽  
pp. 34-50 ◽  
Author(s):  
Antoinette F. van Ouwerkerk ◽  
Amelia W. Hall ◽  
Zachary A. Kadow ◽  
Sonja Lazarevic ◽  
Jasmeet S. Reyat ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Transcription Factors ◽  
Target Genes ◽  
Transcriptional Regulatory Network ◽  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association ◽  
Transcriptional Networks ◽  
Genome Wide Association Studies ◽  
Genome Wide

Genome-wide association studies have uncovered over a 100 genetic loci associated with atrial fibrillation (AF), the most common arrhythmia. Many of the top AF-associated loci harbor key cardiac transcription factors, including PITX2, TBX5, PRRX1, and ZFHX3. Moreover, the vast majority of the AF-associated variants lie within noncoding regions of the genome where causal variants affect gene expression by altering the activity of transcription factors and the epigenetic state of chromatin. In this review, we discuss a transcriptional regulatory network model for AF defined by effector genes in Genome-wide association studies loci. We describe the current state of the field regarding the identification and function of AF-relevant gene regulatory networks, including variant regulatory elements, dose-sensitive transcription factor functionality, target genes, and epigenetic states. We illustrate how altered transcriptional networks may impact cardiomyocyte function and ionic currents that impact AF risk. Last, we identify the need for improved tools to identify and functionally test transcriptional components to define the links between genetic variation, epigenetic gene regulation, and atrial function.

Sign in / Sign up

Export Citation Format

Share Document