Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis.
Link: https://doi.org/10.1161/CIRCGEN.120.003300
Authors: Choi, Seung Hoan; Jurgens, Sean J; Haggerty, Christopher M; Hall, Amelia W; Halford, Jennifer L; Morrill, Valerie N; Weng, Lu-Chen; Lagerman, Braxton; Mirshahi, Tooraj; Pettinger, Mary; Guo, Xiuqing; Lin, Henry J; Alonso, Alvaro; Soliman, Elsayed Z; Kornej, Jelena; Lin, Honghuang; Moscati, Arden; Nadkarni, Girish N; Brody, Jennifer A; Wiggins, Kerri L; Cade, Brian E; Lee, Jiwon; Austin-Tse, Christina; Blackwell, Tom; Chaffin, Mark D; Lee, Christina J-Y; Rehm, Heidi L; Roselli, Carolina; , ; Redline, Susan; Mitchell, Braxton D; Sotoodehnia, Nona; Psaty, Bruce M; Heckbert, Susan R; Loos, Ruth J F; Vasan, Ramachandran S; Benjamin, Emelia J; Correa, Adolfo; Boerwinkle, Eric; Arking, Dan E; Rotter, Jerome I; Rich, Stephen S; Whitsel, Eric A; Perez, Marco; Kooperberg, Charles; Fornwalt, Brandon K; Lunetta, Kathryn L; Ellinor, Patrick T; Lubitz, Steven A; ,
Abstract: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.