Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

Abstract

QRS interval on the electrocardiogram reflects ventricular depolarization and conduction time, and is a risk factor for mortality, sudden death, and heart failure. We performed a genome-wide association meta-analysis in 40,407 European-descent individuals from 14 studies, with further genotyping in 7170 additional Europeans, and identified 22 loci associated with QRS duration (P < 5 × 10−8). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors, and calcium-handling proteins, but also point to novel biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a gene at our most significant locus, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

Genome‐Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study)

“…TBX3 deficiency can also lead to insufficient development of AVN,46 which might manifest as prolonged PR interval. Indeed, supporting this connection between QRS and PR interval, the GWAS variant associated with increased QRS interval is also associated with decreased PR interval 42, 43. Importantly, in this locus, several variants were associated with GEH, but not with other ECG variables, suggesting different underlying biology, which should be studied further.…”

“…The fifth locus ( IGF1R ) showed pleiotropy; it has been previously reported as having a genome‐wide significant association with fasting plasma glucose 41. Genetic variants in the first locus (near TBX3 ) have been previously shown to be associated with QRS duration42 and PR43 interval. Locus 2 (near HAND1 ) and locus 3 ( NFIA ) previously have been shown to be associated with QRS duration 42, 44, 45.…”

“…Genetic variants in the first locus (near TBX3 ) have been previously shown to be associated with QRS duration42 and PR43 interval. Locus 2 (near HAND1 ) and locus 3 ( NFIA ) previously have been shown to be associated with QRS duration 42, 44, 45. Adjustment for QRS, PR, QT, and RR′ intervals (Table S2) strengthened association between the first locus (near TBX3 ) and GEH, suggesting that GEH is capturing an independent underlying electrophysiological phenomenon, as opposed to simply being a marker of QRS, PR, QT, or RR′ intervals.…”

Brugada syndrome risk loci seem protective against atrial fibrillation

“…The loci at SCN10A and SCN5A are also associated with both PR interval and QRS duration. 32,33 From an evolutionary perspective, our results may suggest that these common variants known to increase the risk of a rare, but potentially lethal syndrome such as BrS seem to have a dualistic effect, protecting against a much more common disease such as AF.…”

Association Between Genetic Variation in the <i>SCN10A</i> Gene and Cardiac Conduction Abnormalities in Patients With Hypertrophic Cardiomyopathy

“…These data suggest that this polymorphism is not directly associated with the etiology of HCM in Japanese patients. Role of SCN10A polymorphisms in heart block: Various functions have been attributed to the SCN10A as shown in Tables VII, [23][24][25][26]32) VIII, 31,33) and IX. 30) The exact role of the SCN10A polymorphisms is controversial.…”