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Author Notes:

Steven A. Lubitz, MD, MPH; Cardiac Arrhythmia Service and Cardiovascular Research Center; Massachusetts General Hospital; 55 Fruit Street; Boston, MA 02114;Telephone: 617-724-4500. Email: slubitz@mgh.harvard.edu

We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed and the study participants of the UKB.

Dr. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Drs. Haggerty and Fornwalt receive sponsored research support from Tempus Labs. Dr. Lubitz receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM, and has consulted for Bristol Myers Squibb / Pfizer, Bayer AG, and Blackstone Life Sciences. Dr. Ellinor receives sponsored research support from Bayer AG, Novartis, Myokardia and Quest. Remaining authors have nothing to disclose. Dr. Weng receives sponsored research support from IBM to the Broad Institute.

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Research Funding:

This work was supported by National Institutes of Heatlh (NIH) grant 1R01HL139731 and American Heart Association (AHA) grant 18SFRN34250007 to Dr. Lubitz. Dr. Ellinor is funded by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577,R01HL128914,K24HL105780), and by a grant from the AHA Strategically Focused Research Networks (18SFRN34110082). Dr. Sotoodehnia is funded by the NIH (R01HL141989).

Research Networks (18SFRN34110082). Dr. Sotoodehnia is funded by the NIH (R01HL141989). Dr. Nauffal is funded by a training grant from the NIH (T32HL007604). Dr. Weng is supported by National Institutes of Heatlh (NIH) grant 1R01HL139731 and American Heart Association (AHA) postdoctoral fellowship 18SFRN34110082. Dr. Loos is funded by the NIH (R01DK110113; R01DK075787; R01DK107786; R01HL142302; R01HG010297; R01DK124097; R01HL151152). Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626–02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cardiac & Cardiovascular Systems
  • Peripheral Vascular Disease
  • Cardiovascular System & Cardiology
  • long QT syndrome
  • monogenic
  • polygenic
  • QT interval
  • sudden cardiac death
  • INTERVAL
  • REGRESSION
  • HEART
  • SCORE
  • RISK

Monogenic and Polygenic Contributions to QTc Prolongation in the Population

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Journal Title:

CIRCULATION

Volume:

Volume 145, Number 20

Publisher:

, Pages 1524-1533

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Background: Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variations to the QT interval in the population. Methods: We performed a genome-wide association study of the QTc in 84 630 UK Biobank participants and created a polygenic risk score (PRS). Among 26 976 participants with whole-genome sequencing and ECG data in the TOPMed (Trans-Omics for Precision Medicine) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Results: Fifty-four independent loci were identified by genome-wide association study in the UK Biobank. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS composed of 1 110 494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/decile of PRS=1.4 ms [95% CI, 1.3 to 1.5]; P=1.1×10-196). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (ΔQTc=10.9 ms [95% CI, 7.4 to 14.4]). Of individuals with QTc>480 ms, 23.7% carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). Conclusions: QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.
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