Monogenic and Polygenic Contributions to QTc Prolongation in the Population
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Key result
Carriers of putative pathogenic rare variants had a 10.9 ms longer QTc than noncarriers, and polygenic risk was also significantly associated with QTc duration (1.4 ms increase per PRS decile).
Why the study?
Clinical genetic testing for unexplained QT prolongation is restricted to monogenic rare variants, leaving the joint contribution of rare and common polygenic variations in the population unexamined.
Does polygenic risk and monogenic rare variation influence QTc interval duration in the general population?
Population
84 630 UK Biobank participants and 26 976 TOPMed participants with whole-genome sequencing and ECG data
Comparison
PRS deciles and carriers vs noncarriers of putative pathogenic rare variants in 10 genes
Design
Genome-wide association study and observational cohort analysis
Authors
Discussion
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Member takes
Implication
Should not yet alter QTc risk assessment; leaves open whether rare variants and PRS improve arrhythmia prediction.
Study Design
Type
Observational (n=111,606)
Multicenter
Yes
Structured PICO
Does polygenic risk and monogenic rare variation influence QTc interval duration in the general population?
P
Population
111,606 adults from the UK Biobank and TOPMed cohorts with paired ECG and genomic data, free of conditions or medications significantly altering the QT interval.
E
Exposure
Presence of a high polygenic risk score (PRS) for QTc and/or putative pathogenic rare monogenic variants in 10 genes associated with the QT interval.
C
Comparator
Noncarriers of rare variants and individuals in lower percentiles of the polygenic risk score.
O
Outcome
QTc interval durationsurrogate
Main Result
Mean Difference: 10.9 (95% CI 7.4–14.4)
p-value: p=1.1x10-9
QTc duration in the general population is significantly influenced by both rare monogenic variants and common polygenic risk, suggesting comprehensive genetic assessment should incorporate both.
Limitations
- Did not specifically ascertain LQTS diagnosis status among TOPMed study participants
- Relied on automated QT measurements rather than manual measurement
- Predominantly European ancestry in the UKB used to derive the PRS
- Relied on ClinVar database's assertions of variant pathogenicity
- Unable to fully account for all nongenetic factors contributing to QTc
- Middle-aged to older adult population limits age-stratified analysis
- UKB population was predominantly of European ancestry, which may not accurately characterize polygenic risk in the TOPMed cohort
Cite This Study
Nauffal et al. (2022) conducted an observational in QTc prolongation (n=111,606). Monogenic rare variants and polygenic risk score vs. Noncarriers and lower polygenic risk was evaluated on QTc interval duration (MD 10.9 ms, 95% CI 7.4-14.4, p=1.1x10-9). Carriers of putative pathogenic rare variants had a 10.9 ms longer QTc than noncarriers, and polygenic risk was also significantly associated with QTc duration (1.4 ms increase per PRS decile).
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