Common variation in atrial fibrillation: navigating the path from genetic association to mechanism.

Atrial fibrillation (AF) is the most common cardiac arrhythmia with well-established clinical and genetic risk components. Genome-wide association studies (GWAS) have identified 17 independent susceptibility signals for AF at 14 genomic regions, but the mechanisms through which these loci confer risk to AF remain largely undefined. This problem is not unique to AF, as the field of functional genomics, which attempts to bridge this gap from genotype to phenotype, has only uncovered the mechanisms for a handful of GWAS loci. Recent functional genomic studies have made great strides towards translating genetic discoveries to an underlying mechanism, but the large-scale application of these techniques to AF has remain limited. These advances, as well as the continued unresolved challenges for both common variation in AF and the functional genomics field in general, will be the subject of the following review.

[1]  P. Ellinor,et al.  Korean Atrial Fibrillation (AF) Network: Genetic Variants for AF Do Not Predict Ablation Success , 2015, Journal of the American Heart Association.

[2]  C. Gieger,et al.  A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke , 2009, Nature Genetics.

[3]  Jesper Hastrup Svendsen,et al.  Familial Aggregation of Atrial Fibrillation: A Study in Danish Twins , 2009, Circulation. Arrhythmia and electrophysiology.

[4]  Joseph B Hiatt,et al.  Massively parallel functional dissection of mammalian enhancers in vivo , 2012, Nature Biotechnology.

[5]  W. D. Laat,et al.  A Decade of 3c Technologies: Insights into Nuclear Organization References , 2022 .

[6]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[7]  Toshihiro Tanaka The International HapMap Project , 2003, Nature.

[8]  T. Mikkelsen,et al.  Massively Parallel Reporter Assays in Cultured Mammalian Cells , 2014, Journal of visualized experiments : JoVE.

[9]  Nancy R. Cook,et al.  Novel genetic markers improve measures of atrial fibrillation risk prediction , 2013, European heart journal.

[10]  Matthew C. Canver,et al.  An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level , 2013, Science.

[11]  R. Prather,et al.  Genetically engineered pig models for human diseases. , 2013, Annual review of animal biosciences.

[12]  George M. Church,et al.  Highly Multiplexed Subcellular RNA Sequencing in Situ , 2014, Science.

[13]  Robert W. Mills,et al.  Overexpression of KCNN3 results in sudden cardiac death. , 2014, Cardiovascular research.

[14]  Thomas Meitinger,et al.  Common Variants in KCNN3 are Associated with Lone Atrial Fibrillation , 2010, Nature Genetics.

[15]  Ralph B. D'Agostino,et al.  Parental Atrial Fibrillation as a Risk Factor for Atrial Fibrillation in Offspring , 2004 .

[16]  T. Mikkelsen,et al.  Rapid dissection and model-based optimization of inducible enhancers in human cells using a massively parallel reporter assay , 2012, Nature Biotechnology.

[17]  Christopher R. Ellis,et al.  Common atrial fibrillation risk alleles at 4q25 predict recurrence after catheter-based atrial fibrillation ablation. , 2013, Heart rhythm.

[18]  Wyeth W. Wasserman,et al.  JASPAR: an open-access database for eukaryotic transcription factor binding profiles , 2004, Nucleic Acids Res..

[19]  Eric E. Smith,et al.  Variants conferring risk of atrial fibrillation on chromosome 4q25 , 2007, Nature.

[20]  P. Ellinor,et al.  Emerging Directions in the Genetics of Atrial Fibrillation , 2014, Circulation research.

[21]  T. Mikkelsen,et al.  Systematic dissection of regulatory motifs in 2000 predicted human enhancers using a massively parallel reporter assay. , 2013, Genome research.

[22]  Xavier Messeguer,et al.  PROMO: detection of known transcription regulatory elements using species-tailored searches , 2002, Bioinform..

[23]  S. Verheule,et al.  Cardiac electrophysiology in mice: a matter of size , 2012, Front. Physio..

[24]  S. Nattel,et al.  Animal models for atrial fibrillation: clinical insights and scientific opportunities. , 2010, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[25]  A. Verkerk,et al.  Zebrafish: a novel research tool for cardiac (patho)electrophysiology and ion channel disorders , 2012, Front. Physio..

[26]  D. Roden,et al.  Common genetic polymorphism at 4q25 locus predicts atrial fibrillation recurrence after successful cardioversion. , 2013, Heart rhythm.

[27]  Manolis Kellis,et al.  HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants , 2011, Nucleic Acids Res..

[28]  M. Chung,et al.  Atrial Fibrillation Associated Chromosome 4q25 Variants Are Not Associated with PITX2c Expression in Human Adult Left Atrial Appendages , 2014, PloS one.

[29]  K. Lunetta,et al.  Gene expression and genetic variation in human atria. , 2014, Heart rhythm.

[30]  R. Leman Association Between Familial Atrial Fibrillation and Risk of New-Onset Atrial Fibrillation , 2011 .

[31]  J. Ruskin,et al.  Familial aggregation in lone atrial fibrillation , 2005, Human Genetics.

[32]  K. Stefánsson,et al.  Familial aggregation of atrial fibrillation in Iceland. , 2006, European heart journal.

[33]  P. Kirchhof,et al.  An Introduction to Murine Models of Atrial Fibrillation , 2012, Front. Physio..

[34]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[35]  J. Danesh,et al.  A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease , 2016 .

[36]  Alexander E. Kel,et al.  TRANSFAC®: transcriptional regulation, from patterns to profiles , 2003, Nucleic Acids Res..

[37]  K. Lunetta,et al.  Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. , 2014, Journal of the American College of Cardiology.

[38]  K. Lunetta,et al.  Meta-analysis identifies six new susceptibility loci for atrial fibrillation , 2012, Nature Genetics.

[39]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[40]  Nancy F. Hansen,et al.  An enhancer polymorphism at the cardiomyocyte intercalated disc protein NOS1AP locus is a major regulator of the QT interval. , 2014, American journal of human genetics.

[41]  C. Gieger,et al.  Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon , 2014, Genome research.

[42]  Martha L. Bulyk,et al.  UniPROBE: an online database of protein binding microarray data on protein–DNA interactions , 2008, Nucleic Acids Res..

[43]  Douglas L. Jones,et al.  Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. , 2006, The New England journal of medicine.

[44]  Kun Zhang,et al.  Fluorescent in situ sequencing (FISSEQ) of RNA for gene expression profiling in intact cells and tissues , 2015, Nature Protocols.

[45]  T. Doetschman,et al.  Cardiac-specific inducible and conditional gene targeting in mice. , 2012, Circulation research.

[46]  D. Roden,et al.  Symptomatic response to antiarrhythmic drug therapy is modulated by a common single nucleotide polymorphism in atrial fibrillation. , 2010, Journal of the American College of Cardiology.

[47]  J. Seidman,et al.  A common genetic variant within SCN10A modulates cardiac SCN5A expression. , 2014, The Journal of clinical investigation.

[48]  Martin J. Aryee,et al.  Engineered CRISPR-Cas9 nucleases with altered PAM specificities , 2015, Nature.

[49]  Robert W. Mills,et al.  Rapid Cellular Phenotyping of Human Pluripotent Stem Cell-Derived Cardiomyocytes using a Genetically Encoded Fluorescent Voltage Sensor , 2014, Stem cell reports.

[50]  Michael Q. Zhang,et al.  Integrative analysis of 111 reference human epigenomes , 2015, Nature.

[51]  Paul T. Groth,et al.  The ENCODE (ENCyclopedia Of DNA Elements) Project , 2004, Science.

[52]  K. Lunetta,et al.  Integrating Genetic, Transcriptional, and Functional Analyses to Identify 5 Novel Genes for Atrial Fibrillation , 2014, Circulation.

[53]  Calum A Macrae,et al.  Zebrafish genetic models for arrhythmia. , 2008, Progress in biophysics and molecular biology.

[54]  Karl-Ludwig Laugwitz,et al.  Patient-specific induced pluripotent stem-cell models for long-QT syndrome. , 2010, New England Journal of Medicine.

[55]  Stanley Nattel,et al.  Role of the Autonomic Nervous System in Atrial Fibrillation: Pathophysiology and Therapy , 2014, Circulation research.

[56]  Olle Melander,et al.  From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus , 2010, Nature.

[57]  Eric Boerwinkle,et al.  Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry , 2009, Nature Genetics.

[58]  Jay A. Montgomery,et al.  Common Genetic Variants and Response to Atrial Fibrillation Ablation , 2015, Circulation. Arrhythmia and electrophysiology.

[59]  G. Hindricks,et al.  Chromosome 4q25 variants and atrial fibrillation recurrence after catheter ablation. , 2010, Journal of the American College of Cardiology.

[60]  Stanley Nattel,et al.  The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. , 2014, Circulation research.

[61]  Niels Voigt,et al.  Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance, and Progression , 2014, Circulation research.