Monogenic and Polygenic Contributions to QTc Prolongation in the Population.
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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, TOPMed Investigators
Аннотация
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.