Monogenic and Polygenic Contributions to the QTc Prolongation
- Twelve novel loci associated with the QTc were identified in a genome-wide association analysis in the UK Biobank and replicated in an independent multi-ancestry cohort, TOPMed (Trans-Omics for Precision Medicine).
- Among individuals with a QTc >480 ms, 3.4% carried a monogenic rare variant, 21% had a top polygenic risk score decile, and 23.7% had either a monogenic rare variant or a polygenic risk equivalent.
- Comprehensive assessment of the genetic determinants of QTc prolongation may require assessment of both monogenic rare variants and common polygenic risk variants.
What is the contribution of rare and common sequence variations in genes underlying cardiac repolarization and resulting in QT prolongation in the general population?
The authors performed a genome-wide association study of 84,630 UK Biobank participants and created a polygenic risk score (PRS) for QT prolongation. They also performed whole-genome sequencing among 26,976 participants in the multi-ancestry TOPMed (Trans-Omics for Precision Medicine) program. The authors examined contribution of monogenic and polygenic variation to QT prolongation.
Fifty-four independent loci were identified by genome-wide association study in the UK Biobank. In TOPMed, they identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. Twenty-one loci among the 54 loci in the UK Biobank 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, 1.3-1.5]; p = 1.1×10-196). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (ΔQTc = 10.9 ms [95% CI, 7.4-14.4]). Of individuals with QTc >480 ms, approximately 24% carried either a monogenic rare variant or had a PRS in the top decile (~3% monogenic, 21% top decile of PRS).
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.
Currently clinically available genetic testing for individuals with QT prolongation is limited to the examination of single gene variants. However, common polygenic variation has been shown to influence a number of medical conditions, including QT interval duration. The authors of the present study show that individuals with QTc prolongation are more likely to have a common polygenic risk equivalent than a rare monogenic variant in a known gene causing QTc prolongation. The authors estimated that assessment of both monogenic rare variants (i.e., known QT-prolonging gene mutations) and common polygenic risk variants may increase the yield of identifying a genetic determinant of QTc prolongation from 1 in 30 to 1 in 4. Still, approximately 3 in 4 individuals with pronounced QTc prolongation (>480 ms) did not have an identified genetic risk factor. Nonetheless, the findings of the present study are likely to have profound implications on the way future clinical evaluation of individuals with prolonged QTc is done.
Clinical Topics: Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Quality Improvement, Acute Heart Failure
Keywords: Arrhythmias, Cardiac, Biological Specimen Banks, Genetic Testing, Genome-Wide Association Study, Heart Defects, Congenital, Heart Failure, Long QT Syndrome, Mutation, Risk Factors, Secondary Prevention
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