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Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis.

TitleRare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis.
Publication TypeJournal Article
Year of Publication2021
AuthorsChoi SHoan, Jurgens SJ, Haggerty CM, Hall AW, Halford JL, Morrill VN, Weng L-C, Lagerman B, Mirshahi T, Pettinger M, Guo X, Lin HJ, Alonso A, Soliman EZ, Kornej J, Lin H, Moscati A, Nadkarni GN, Brody JA, Wiggins KL, Cade BE, Lee J, Austin-Tse C, Blackwell T, Chaffin MD, Lee CJ-Y, Rehm HL, Roselli C, Redline S, Mitchell BD, Sotoodehnia N, Psaty BM, Heckbert SR, Loos RJF, Vasan RS, Benjamin EJ, Correa A, Boerwinkle E, Arking DE, Rotter JI, Rich SS, Whitsel EA, Perez M, Kooperberg C, Fornwalt BK, Lunetta KL, Ellinor PT, Lubitz SA
Corporate AuthorsRegeneron Genetics Center, NHLBI Trans-Omics for Precision Medicine(TOPMed) Consortium
JournalCirc Genom Precis Med
Date Published2021 Aug

BACKGROUND: 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.

METHODS: 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).

RESULTS: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (, , and ), a controversial monogenic SCD gene (), and novel genes ( and ) involved in cardiac conduction. Loss-of-function and pathogenic variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (=8.4×10). Similar variants in and (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (=4×10), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals.

CONCLUSIONS: 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.

Alternate JournalCirc Genom Precis Med
PubMed ID34319147
PubMed Central IDPMC8373440
Grant List18SFRN34250007 / AHA / American Heart Association-American Stroke Association / United States
R01 HL139731 / HL / NHLBI NIH HHS / United States