Monogenic and Polygenic Contributions to QTc Prolongation in the Population.
Author
Nauffal, VictorMorrill, 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
Kooperberg, Charles
Lin, Henry J
Loos, Ruth J F
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
Date
2022-04-07Journal
CirculationPublisher
Lippincott Williams and WilkinsType
Article
Metadata
Show full item recordAbstract
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 variation to the QT interval in the population. Methods: We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) 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 GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 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-value=1.1×10-196). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7% of individuals with QTc>480 ms 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.Identifier to cite or link to this item
http://hdl.handle.net/10713/18543ae974a485f413a2113503eed53cd6c53
10.1161/CIRCULATIONAHA.121.057261
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