| Title: | Monogenic and Polygenic Contributions to QTc Prolongation in the Population |
| Journal: | Circulation |
| Published: | 7 Apr 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35389749/ |
| DOI: | https://doi.org/10.1161/circulationaha.121.057261 |
| URL: | https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.121.057261 |
| Citations: | 17 (10 in last 2 years) as of 8 Aug 2024 |
Publication 12423
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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.</p>
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.</p>
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).</p>
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.</p>
7 Keywords
- Electrocardiography
- Genome-Wide Association Study
- Heterozygote
- Humans
- Long QT Syndrome
- Multifactorial Inheritance
- Whole Genome Sequencing
40 Authors
- Victor Nauffal
- Valerie N. Morrill
- Sean J. Jurgens
- Seung Hoan Choi
- Amelia W. Hall
- Lu-Chen Weng
- Jennifer L. Halford
- Christina Austin-Tse
- Christopher M. Haggerty
- Stephanie L. Harris
- Eugene K. Wong
- Alvaro Alonso
- Dan E. Arking
- Emelia J. Benjamin
- Eric Boerwinkle
- Yuan-I Min
- Adolfo Correa
- Brandon K. Fornwalt
- Susan R. Heckbert
- and Blood Institute Trans-Omics for Precision Medicine Consortium National Heart Lung
- Charles Kooperberg
- Henry J. Lin
- Ruth J.F. Loos
- Kenneth M. Rice
- Namrata Gupta
- Thomas W. Blackwell
- Braxton D. Mitchell
- Alanna C. Morrison
- Bruce M. Psaty
- Wendy S. Post
- Susan Redline
- Heidi L. Rehm
- Stephen S. Rich
- Jerome I. Rotter
- Elsayed Z. Soliman
- Nona Sotoodehnia
- Kathryn L. Lunetta
- Patrick T. Ellinor
- Steven A. Lubitz
- for the TOPMed Investigators
1 Application
| Application ID | Title |
|---|---|
| 17488 | Understanding the Genetic Basis of Cardiac Arrhythmias |
Enabling scientific discoveries that improve human health