Corrected QT interval-polygenic risk score and its contribution to type 1, type 2, and type 3 Long-QT syndrome in probands and genotype-positive family members

Kari L. Turkowski, Steven M. Dotzler, David J. Tester, John R. Giudicessi, J. Martijn Bos, Ashley D. Speziale, Jason M. Vollenweider, Michael J. Ackerman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: Long-QT syndrome (LQTS) is characterized by a prolonged heart rate-corrected QT interval (QTc). Genome-wide association studies identified common genetic variants that collectively explain ≈8% to 10% of QTc variation in the general population. Methods: Overall, 423 patients with LQT1, LQT2, or LQT3 were genotyped for 61 QTc-associated genetic variants used in a prototype QTc-polygenic risk score (QTc-PRS). A weighted QTc-PRS (range, 0-154.8 ms) was calculated for each patient, and the FHS (Framingham Heart Study) population-based reference cohort (n=853). Results: The average QTc-PRS in LQTS was 88.0±7.2 and explained only ≈2.0% of the QTc variability. The QTc-PRS in LQTS probands (n=137; 89.3±6.8) was significantly greater than both FHS controls (87.2±7.4, difference-in-means±SE: 2.1±0.7, P<0.002) and LQTS genotype-positive family members (87.5±7.4, difference-in-mean, 1.8±.7, P<0.009). There was no difference in QTc-PRS between symptomatic (n=156, 88.6±7.3) and asymptomatic patients (n=267; 87.7±7.2, difference-in-mean, 0.9±0.7, P=0.15). LQTS patients with a QTc≥480 ms (n=120) had a significantly higher QTc-PRS (89.3±6.7) than patients with a QTc<480 ms (n=303, 87.6±7.4, difference-in-mean, 1.7±0.8, P<0.05). There was no difference in QTc-PRS or QTc between genotypes. Conclusions: The QTc-PRS explained <2% of the QTc variability in our LQT1, LQT2, and LQT3 cohort, contributing 5× less to their QTc value than in the general population. This prototype QTc-PRS does not distinguish/predict the clinical outcomes of individuals with LQTS.

Original languageEnglish (US)
Pages (from-to)194-201
Number of pages8
JournalCirculation: Genomic and Precision Medicine
DOIs
StatePublished - Aug 1 2020

Keywords

  • genetics
  • genome-wide association study
  • long QT syndrome
  • polymorphism
  • risk

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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