1. Monogenic and Polygenic Contributions to QTc Prolongation in the Population.
- Author
-
Nauffal, Victor, Morrill, Valerie N, Jurgens, Sean J, Choi, Seung Hoan, Hall, Amelia W, Weng, Lu-Chen, Halford, Jennifer L, Austin-Tse, Christina, Haggerty, Christopher M, Harris, Stephanie L, Wong, Eugene K, Alonso, Alvaro, Arking, Dan E, Benjamin, Emelia J, Boerwinkle, Eric, Min, Yuan-I, Correa, Adolfo, Fornwalt, Brandon K, Heckbert, Susan R, National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium, Kooperberg, Charles, Lin, Henry J, J F Loos, Ruth, Rice, Kenneth M, Gupta, Namrata, Blackwell, Thomas W, Mitchell, Braxton D, Morrison, Alanna C, Psaty, Bruce M, Post, Wendy S, Redline, Susan, Rehm, Heidi L, Rich, Stephen S, Rotter, Jerome I, Soliman, Elsayed Z, Sotoodehnia, Nona, Lunetta, Kathryn L, Ellinor, Patrick T, Lubitz, Steven A, and TOPMed Investigators
- Subjects
National Heart ,Lung ,and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium ,TOPMed Investigators ,Humans ,Long QT Syndrome ,Electrocardiography ,Heterozygote ,Multifactorial Inheritance ,Genome-Wide Association Study ,Whole Genome Sequencing ,QT interval ,long QT syndrome ,monogenic ,polygenic ,sudden cardiac death ,Human Genome ,Heart Disease ,Prevention ,Cardiovascular ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Public Health and Health Services ,Cardiovascular System & Hematology - Abstract
BackgroundRare 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.MethodsWe 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.ResultsFifty-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).ConclusionsQTc 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.
- Published
- 2022