Dataset Information

Monogenic and Polygenic Contributions to QTc Prolongation in the Population.

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.

SUBMITTER: Nauffal V

PROVIDER: S-EPMC9117504 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Monogenic and Polygenic Contributions to QTc Prolongation in the Population.

Nauffal Victor V Morrill Valerie N VN Jurgens Sean J SJ Choi Seung Hoan SH Hall Amelia W AW Weng Lu-Chen LC Halford Jennifer L JL Austin-Tse Christina C Haggerty Christopher M CM Harris Stephanie L SL Wong Eugene K EK Alonso Alvaro A Arking Dan E DE Benjamin Emelia J EJ Boerwinkle Eric E Min Yuan-I YI Correa Adolfo A Fornwalt Brandon K BK Heckbert Susan R SR Kooperberg Charles C Lin Henry J HJ J F Loos Ruth R Rice Kenneth M KM Gupta Namrata N Blackwell Thomas W TW Mitchell Braxton D BD Morrison Alanna C AC Psaty Bruce M BM Post Wendy S WS Redline Susan S Rehm Heidi L HL Rich Stephen S SS Rotter Jerome I JI Soliman Elsayed Z EZ Sotoodehnia Nona N Lunetta Kathryn L KL Ellinor Patrick T PT Lubitz Steven A SA

Circulation 20220407 20

<h4>Background</h4>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.<h4>Methods</h4>We p ...[more]

PMID: 35389749

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Project description:In adults, alcohol intoxication is associated with prolongation of the QT interval corrected for heart rate (QTc). The QTc is influenced by age and sex. Although alcohol intoxication is increasingly common in adolescents, there are no data on the prevalence of QTc prolongation in adolescents with alcohol intoxication. This study aimed to determine the prevalence of QTc prolongation in adolescents with alcohol intoxication and identify at-risk adolescents. In this observational study including adolescents aged 10-18 years, heart rate and QT interval were automatically assessed from an electrocardiogram (ECG) at alcohol intoxication using a validated algorithm. The QTc was calculated using both the Bazett formula (QTcB) and Fridericia formula (QTcF). If present, an ECG recorded within 1 year of the date of admission to the emergency department was obtained as a reference ECG. A total of 317 adolescents were included; 13.3% had a QTcB and 7.9% a QTcF longer than the sex- and age-specific 95th-percentile. None of the adolescents had a QTcB or QTcF > 500 ms, but 11.8% of the adolescents with a reference ECG had a QTcB prolongation of > 60 ms, while no adolescents had a QTcF prolongation of > 60 ms. QTc prolongation was mainly attributable to an increase in heart rate rather than QT prolongation, which underlies the differences between QTcB and QTcF. Male sex and hypokalaemia increased the likelihood of QTc prolongation.Conclusion: QTc prolongation was seen in approximately 10% of the adolescents presenting with alcohol intoxication, and although no ventricular arrhythmias were observed in this cohort, QTc prolongation increases the potential for malignant QT-related arrhythmias. Clinicians must be aware of the possibility of QTc prolongation during alcohol intoxication and make an effort to obtain an ECG at presentation, measure the QT interval, and give an adequate assessment of the findings. We advocate admitting adolescents with alcohol intoxication and QTc prolongation. During hospital admission, we recommend limiting exposure to QTc-prolonging medication, increasing potassium levels to a high-normal range (4.5-5.0 mmol/L) and obtaining a reference ECG at discharge.

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Dataset Information

Monogenic and Polygenic Contributions to QTc Prolongation in the Population.

Background

Methods

Results

Conclusions

Publications

Monogenic and Polygenic Contributions to QTc Prolongation in the Population.

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