Circulation: Cardiovascular Genetics最新文献

{"title":"Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing.","authors":"Charlotte Burns,&nbsp;Richard D Bagnall,&nbsp;Lien Lam,&nbsp;Christopher Semsarian,&nbsp;Jodie Ingles","doi":"10.1161/CIRCGENETICS.116.001666","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001666","url":null,"abstract":"<p><strong>Background: </strong>Multiple likely pathogenic/pathogenic (LP/P; ≥2) variants in patients with hypertrophic cardiomyopathy were described 10 years ago with a prevalence of 5%. We sought to re-examine the significance of multiple rare variants in patients with hypertrophic cardiomyopathy in the setting of comprehensive and targeted panels.</p><p><strong>Methods and results: </strong>Of 758 hypertrophic cardiomyopathy probands, we included 382 with ≥45 cardiomyopathy genes screened. There were 224 (59%) with ≥1 rare variant (allele frequency ≤0.02%). Variants were analyzed using varying sized gene panels to represent comprehensive or targeted testing. Based on a 45-gene panel, 127 (33%) had a LP/P variant, 139 (36%) had variants of uncertain significance, and 66 (17%) had multiple rare variants. A targeted 8-gene panel yielded 125 (32%) LP/P variants, 52 (14%) variants of uncertain significance, and 14 (4%) had multiple rare variants. No proband had 2 LP/P variants. Including affected family members (total n=412), cluster-adjusted analyses identified a phenotype effect, with younger age (odds ratio, 0.95; 95% confidence interval, 0.92-0.98; <i>P</i>=0.004) and family history of sudden cardiac death (odds ratio, 3.5; 95% confidence interval, 1.3-9.9; <i>P</i>=0.02) significantly more likely in multiple versus single variant patients when considering an 8-gene panel but not larger panels. Those with multiple variants had worse event-free survival from all-cause death, cardiac transplantation, and cardiac arrest (log-rank <i>P</i>=0.008).</p><p><strong>Conclusions: </strong>No proband had multiple LP/P variants in contrast to previous reports. However, multiple rare variants regardless of classification were seen in 4% and contributed to earlier disease onset and cardiac events. Our findings support a cumulative variant hypothesis in hypertrophic cardiomyopathy.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001666","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35393652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>LMNA</i> Mutations Associated With Mild and Late-Onset Phenotype: The Case of the Dutch Founder Mutation p.(Arg331Gln).","authors":"Eloisa Arbustini,&nbsp;Valentina Favalli,&nbsp;Nupoor Narula","doi":"10.1161/CIRCGENETICS.117.001816","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001816","url":null,"abstract":"Cardiolaminopathies are autosomal dominant genetic diseases caused by mutations in the LMNA gene which encodes the nucleus envelope protein Lamin AC.1 There are now 12 phenotypes associated with LMNA mutations, both autosomal dominant and recessive, the majority of which have cardiac involvement (http://omim.org/entry/150330). These include dilated cardiomyopathy (DCM) associated with conduction disease, atrial and ventricular arrhythmias, and phenotypes mimicking arrhythmogenic right ventricular cardiomyopathy.2\u0000\u0000See Article by Hoorntje et al \u0000\u0000Cardiolaminopathies are characterized by high arrhythmogenic risk3 that may manifest in mildly dilated hearts and may be the first clinical presentation of the disease. Fatal arrhythmias may occur even when left ventricular dysfunction does not reach the cutoff value established by guidelines for implantable cardioverter–defibrillator implantation for the primary prevention of sudden death.4 Clinical cardiologists involved in programs dedicated to familial cardiomyopathies are well aware of the arrhythmogenic risk of cardiolaminopathies. The latest ESC Guidelines for primary prevention of sudden cardiac death recommend (Class IIa; Level of Evidence B) implantable cardioverter–defibrillator in patients with DCM, a confirmed disease-causing LMNA mutation, and the following clinical risk factors: nonsustained ventricular tachycardia during ambulatory electrocardiographic monitoring, left ventricular ejection fraction <45% on initial evaluation, male sex, and nonmissense mutations.5\u0000\u0000The genetic diagnosis of laminopathy in DCM patients impacts therapeutic and prognostic strategies. For example, the percutaneous catheter ablation of sustained monomorphic ventricular tachycardia in LMNA cardiomyopathy could be an important consideration. Poor outcomes, including high rates of recurrence of arrhythmia, progression to end-stage heart failure, and high mortality, have been reported in patients with cardiolaminopathies, wherein 91% of patients experienced ≥1 ventricular tachycardia recurrence, 44% received or were awaiting mechanical circulatory support or transplant for end-stage heart failure, and 26% died during a median 7-month follow-up.6 Use of β-blockers in conduction disease should be postponed until after pacemaker …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001816","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35393654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Genetic Causes of Sudden Unexpected Death in Children Through Targeted Next-Generation Sequencing Analysis.","authors":"Laura J Dewar,&nbsp;Miguel Alcaide,&nbsp;Daniel Fornika,&nbsp;Luisa D'Amato,&nbsp;Sanam Shafaatalab,&nbsp;Charles M Stevens,&nbsp;Thambirajah Balachandra,&nbsp;Susan M Phillips,&nbsp;Shubhayan Sanatani,&nbsp;Ryan D Morin,&nbsp;Glen F Tibbits","doi":"10.1161/CIRCGENETICS.116.001738","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001738","url":null,"abstract":"<p><strong>Background: </strong>Inherited arrhythmia syndromes are responsible for a significant portion of autopsy-negative sudden unexpected death (SUD) cases, but molecular autopsy used to identify potentially causal variants is not routinely included in SUD investigations. We collaborated with a medical examiner's office to assist in finding a diagnosis for their autopsy-negative child SUD cases.</p><p><strong>Methods and results: </strong>191 child SUD cases (<5 years of age) were selected for analyses. Our next generation sequencing panel incorporated 38 inherited arrhythmia syndrome candidate genes and another 33 genes not previously investigated for variants that may underlie SUDY pathophysiology. Overall, we identified 11 potentially causal disease-associated variants in 12 cases, for an overall yield of 6.3%. We also identified 31 variants of uncertain significance in 36 cases and 16 novel variants predicted to be pathogenic in silico in 15 cases. The disease-associated variants were reported to the medical examiner to notify surviving relatives and recommend clinical assessment.</p><p><strong>Conclusions: </strong>We have identified variants that may assist in the diagnosis of at least 6.3% of autopsy-negative child SUD cases and reduce risk of future SUD in surviving relatives. We recommend a cautious approach to variant interpretation. We also suggest inclusion of cardiomyopathy genes as well as other candidate SUD genes in molecular autopsy analyses.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001738","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35318926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissecting the Genetic Basis of the ECG as a Means of Understanding Mechanisms of Arrhythmia.","authors":"Rafik Tadros,&nbsp;Ruben Coronel,&nbsp;Connie R Bezzina","doi":"10.1161/CIRCGENETICS.117.001858","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001858","url":null,"abstract":"The surface ECG records the electrical potential of the heart at the surface of the body as the electrical impulse travels throughout the heart with each heartbeat. The P wave represents depolarization of the atria, which spreads from the sinoatrial node toward the atrioventricular node and from the right to the left atrium. The PR interval reflects the time the electrical impulse takes to travel from the sinus node through the atrioventricular node. The QRS complex represents the rapid depolarization of the ventricles, and the T wave represents the repolarization of the ventricles.\u0000\u0000See Article by Christophersen et al \u0000\u0000The ECG is one of the most accessible and valuable diagnostic tests. It informs about the presence of cardiac chamber enlargement/hypertrophy, conduction disturbance, arrhythmia, myocardial infarction/ischemia, and even provides indications for electrolyte imbalance or drug intoxication. Since about a decade, researchers have turned to the ECG as a tool to dissect the genetic basis of cardiac electrical function with the idea that the biological processes that underlie or impinge on the different parameters of the ECG are mediators (intermediate phenotypes, endophenotypes) of arrhythmia risk.1 This concept, which in itself is clearly intuitive, is supported by population-based studies that demonstrated that ECG parameters are associated with risk of arrhythmia or sudden cardiac death.2 The approach is furthermore rationalized by the fact that ECG parameters have been shown to have a heritable component (reviewed in reference3). The first ECG parameter that was studied in this way by the genome-wide association study (GWAS) approach was the QT interval1; in fact the QT interval was one of the first traits to be studied at the outset of the GWAS era 10 years ago.4 Facilitated by the availability of large cohorts with ECG recordings and the ability to measure ECG …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001858","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35399914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>CKM</i> Glu83Gly Is Associated With Blunted Creatine Kinase Variation, but Not With Myalgia.","authors":"Moneeza Kalhan Siddiqui, Abirami Veluchamy, Cyrielle Maroteau, Roger Tavendale, Fiona Carr, Ewan Pearson, Helen Colhoun, Andrew D Morris, Jacob George, Alexander Doney, Munir Pirmohamed, Ana Alfirevic, Mia Wadelius, Anke H Maitland van der Zee, Paul M Ridker, Daniel I Chasman, Colin N A Palmer","doi":"10.1161/CIRCGENETICS.117.001737","DOIUrl":"10.1161/CIRCGENETICS.117.001737","url":null,"abstract":"<p><strong>Background: </strong>To test the association of a recently reported variant in the creatine kinase (CK) muscle gene, <i>CKM</i> Glu83Gly (rs11559024) with constitutive creatine phosphokinase (CK) levels, CK variation, and inducibility. Given the diagnostic importance of CK in determining muscle damage, we tested the association of the variant with myalgia.</p><p><strong>Methods and results: </strong>Meta-analysis between longitudinal cohort GoDARTS (Genetics of Diabetes Audit and Research, Tayside Scotland), minor allele frequency (=0.02), and randomized clinical trial (JUPITER [Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin], minor allele frequency=0.018) was used to replicate the association with baseline CK measures. GoDARTS was used to study the relationship with CK variability. Myalgia was studied in JUPITER trial participants. Baseline and SDs of CK were on average 18% (<i>P</i> value=6×10^-⁶³) and 24% (<i>P</i> value=2×10^-5) lower for carriers of the variant, respectively. The variant was not associated with myalgia (odds ratio, 0.84; 95% confidence interval, 0.52-1.38).</p><p><strong>Conclusions: </strong>This study highlights that a genetic factor known to be associated with constitutive CK levels is also associated with CK variability and inducibility. This is discussed in the context of evidence to suggest that the variant has an impact on inducibility of CK by trauma through a previously reported case of a homozygous carrier. However, the lack of association between the variant and myalgia suggests that it cannot reliably be used as a biomarker for muscle symptoms.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35393653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Founder Mutations in Myosin-Binding Protein C: Maybe Not So Benign After All.","authors":"Andrea D Thompson,&nbsp;Sharlene M Day","doi":"10.1161/CIRCGENETICS.117.001872","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001872","url":null,"abstract":"Linkage studies and genetic sequencing in families with hypertrophic cardiomyopathy (HCM) in the 1980s and 1990s established the sarcomere as the genetic basis for HCM.1 In contemporary cohorts, a pathogenic mutation is found in about half of patients with HCM, with ≈50% of these mutations in MYBPC3 (myosin-binding protein C).2,3 Many mutations are unique or seen in a limited number of families. However, in some geographically or culturally isolated populations, founder mutations have arisen from common ancestors many generations ago. The reported frequency of founder mutations for HCM ranges considerably among different countries, with the highest reported prevalence being in Iceland, where almost 90% of all sarcomere gene mutation carriers harbor a single founder mutation in MYBPC3 , comprising 67% of the entire HCM population.4 The vast majority of founder mutations in HCM across all reported studies are found in MYBPC3 , with fewer reported in MYH7 (myosin), TNNT2 (troponin T), and TPM1 (tropomyosin).5 Because of the need for founder mutations to withstand negative selection pressure to perpetuate through multiple generations, there is a general perception that founder mutations confer a more benign phenotype and disease course.4,6,7 This view has been supported by a previous study in France, which found that carriers of a founder mutation identified in 8% of their HCM population were diagnosed 15 years later and experienced a delayed onset of disease complications compared with carriers of other sarcomere gene mutations.8 However, other studies have observed relative equivalence between carriers of founder and nonfounder mutations.5,9 All of the previously reported studies are limited by relatively small numbers and some by incomplete genotyping in comparator HCM cohorts, which could confound results. Most studies have also not distinguished between probands and relatives of probands …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001872","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35399916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of Y Chromosome in Blood Is Associated With Major Cardiovascular Events During Follow-Up in Men After Carotid Endarterectomy.","authors":"Saskia Haitjema,&nbsp;Daniel Kofink,&nbsp;Jessica van Setten,&nbsp;Sander W van der Laan,&nbsp;Arjan H Schoneveld,&nbsp;James Eales,&nbsp;Maciej Tomaszewski,&nbsp;Saskia C A de Jager,&nbsp;Gerard Pasterkamp,&nbsp;Folkert W Asselbergs,&nbsp;Hester M den Ruijter","doi":"10.1161/CIRCGENETICS.116.001544","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001544","url":null,"abstract":"<p><strong>Background: </strong>Recent studies found an immune regulatory role for Y chromosome and a relationship between loss of Y chromosome (LOY) in blood cells and a higher risk of cancer and mortality. Given involvement of immune cells in atherosclerosis, we hypothesized that LOY is associated with the severity of atherosclerotic plaque characteristics and outcome in men undergoing carotid endarterectomy.</p><p><strong>Methods and results: </strong>LOY was quantified in blood and plaque from raw intensity genotyping data in men within the Athero-Express biobank study. Plaques were dissected, and the culprit lesions used for histology and the measurement of inflammatory proteins. We tested LOY for association with (inflammatory) atherosclerotic plaque phenotypes and cytokines and assessed the association of LOY with secondary events during 3-year follow-up. Of 366 patients with carotid endarterectomy, 61 exhibited some degree of LOY in blood. LOY was also present in atherosclerotic plaque lesions (n=8/242, 3%). LOY in blood was negatively associated with age (β=-0.03/10 y; <i>r</i>²=0.07; <i>P</i>=1.6×10^-7) but not with cardiovascular disease severity at baseline. LOY in blood was associated with a larger atheroma size (odds ratio, 2.15; 95% confidence interval, 1.06-4.76; <i>P</i>=0.04); however, this association was not significant after correction for multiple testing. LOY was independently associated with secondary major cardiovascular events (hazard ratio=2.28; 95% confidence interval, 1.11-4.67; <i>P</i>=0.02) in blood when corrected for confounders.</p><p><strong>Conclusions: </strong>In this hypothesis-generating study, LOY in blood is independently associated with secondary major cardiovascular events in a severely atherosclerotic population. Our data could indicate that LOY affects secondary outcome via other mechanisms than inflammation in the atherosclerotic plaque.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":"e001544"},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001544","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35284642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiovascular Disease and Long Noncoding RNAs: Tools for Unraveling the Mystery Lnc-ing RNA and Phenotype.","authors":"Elizabeth J Hennessy","doi":"10.1161/CIRCGENETICS.117.001556","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001556","url":null,"abstract":"The last decade has ushered in a surge of genetic information with budget-friendly and more efficient sequencing technologies adding to our understanding of human development and disease. The sequencing of the human genome was a remarkable feat, yet using this information to understand human health and disease has proven to be challenging. The mammalian genome is comprised of a complex infrastructure of defined nucleotide sequences and dynamic epigenetic modifications that result in shifts in gene expression patterns and subsequent developmental and phenotypic outcomes. Genome wide association studies (GWAS) have demonstrated the link between alterations in nucleotide sequences created by mutations, such as single nucleotide polymorphisms (SNPs) and disease. However, it remains unclear how SNPs alter gene expression patterns and phenotypes. One hypothesis links SNP containing regions to mutational phenotypes via changes to epigenetic processes that control how genes are regulated, such as DNA methylation and histone acetylation.\u0000\u0000SNPs are changes in nucleotide sequences that occur in at least 1% of the population. It is estimated that there are 10 to 30 million SNPs in humans that occur every 100 to 300 bases, and this variation is the major source of heterogeneity among people. A nonsynonymous SNP changes the amino acid sequence of a protein-coding gene. Less than 10% of SNPs are nonsynonymous, whereas 90% occur in nonprotein coding regions of the genome.1 SNPs can be found in regions of deoxyribonuclease I (DNase I) hypersensitivity or promoters affecting transcription factor–binding sites and chromatin state. SNPs can create or delete microRNA-binding sites in 3′ untranslated regions (UTRs) affecting microRNA target mRNA expression.2 SNPs can also be found in regions expressing noncoding RNAs, such as long noncoding RNAs (lncRNAs) leading to alterations in their expression patterns. SNPs can affect alternative splicing and the secondary structure of an RNA transcript leading to …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":"e001556"},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001556","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35284643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction.","authors":"","doi":"10.1161/HCG.0000000000000038","DOIUrl":"https://doi.org/10.1161/HCG.0000000000000038","url":null,"abstract":"","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":"e000038"},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/HCG.0000000000000038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35313239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fifteen Genetic Loci Associated With the Electrocardiographic P Wave.","authors":"Ingrid E Christophersen,&nbsp;Jared W Magnani,&nbsp;Xiaoyan Yin,&nbsp;John Barnard,&nbsp;Lu-Chen Weng,&nbsp;Dan E Arking,&nbsp;Maartje N Niemeijer,&nbsp;Steven A Lubitz,&nbsp;Christy L Avery,&nbsp;Qing Duan,&nbsp;Stephan B Felix,&nbsp;Joshua C Bis,&nbsp;Kathleen F Kerr,&nbsp;Aaron Isaacs,&nbsp;Martina Müller-Nurasyid,&nbsp;Christian Müller,&nbsp;Kari E North,&nbsp;Alex P Reiner,&nbsp;Lesley F Tinker,&nbsp;Jan A Kors,&nbsp;Alexander Teumer,&nbsp;Astrid Petersmann,&nbsp;Moritz F Sinner,&nbsp;Petra Buzkova,&nbsp;Jonathan D Smith,&nbsp;David R Van Wagoner,&nbsp;Uwe Völker,&nbsp;Melanie Waldenberger,&nbsp;Annette Peters,&nbsp;Thomas Meitinger,&nbsp;Marian C Limacher,&nbsp;Kirk C Wilhelmsen,&nbsp;Bruce M Psaty,&nbsp;Albert Hofman,&nbsp;Andre Uitterlinden,&nbsp;Bouwe P Krijthe,&nbsp;Zhu-Ming Zhang,&nbsp;Renate B Schnabel,&nbsp;Stefan Kääb,&nbsp;Cornelia van Duijn,&nbsp;Jerome I Rotter,&nbsp;Nona Sotoodehnia,&nbsp;Marcus Dörr,&nbsp;Yun Li,&nbsp;Mina K Chung,&nbsp;Elsayed Z Soliman,&nbsp;Alvaro Alonso,&nbsp;Eric A Whitsel,&nbsp;Bruno H Stricker,&nbsp;Emelia J Benjamin,&nbsp;Susan R Heckbert,&nbsp;Patrick T Ellinor","doi":"10.1161/CIRCGENETICS.116.001667","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001667","url":null,"abstract":"<p><strong>Background: </strong>The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.</p><p><strong>Methods and results: </strong>We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (<i>P</i><5×10^-⁸) novel loci and replicated a prior association with S<i>CN10A.</i> We identified 3 loci at <i>SCN5A</i>, <i>TBX5</i>, and <i>CAV1/CAV2</i> that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.</p><p><strong>Conclusions: </strong>We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001667","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35399915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}