@article{f56ef38851994ad3a66e7a516516e3d3,
title = "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.",
keywords = "QT interval, long QT syndrome, monogenic, polygenic, sudden cardiac death",
author = "Victor Nauffal and Morrill, {Valerie N.} and Jurgens, {Sean J.} and Choi, {Seung Hoan} and Hall, {Amelia W.} and Lu-Chen Weng and Halford, {Jennifer L.} and Christina Austin-Tse and Haggerty, {Christopher M.} and Harris, {Stephanie L.} and Wong, {Eugene K.} and Alvaro Alonso and Arking, {Dan E.} and Benjamin, {Emelia J.} and Eric Boerwinkle and Yuan-I. Min and Adolfo Correa and Fornwalt, {Brandon K.} and Heckbert, {Susan R.} and Charles Kooperberg and Lin, {Henry J.} and Loos, {Ruth J. F.} and Rice, {Kenneth M.} and Namrata Gupta and Blackwell, {Thomas W.} and Mitchell, {Braxton D.} and Morrison, {Alanna C.} and Psaty, {Bruce M.} and Post, {Wendy S.} and Susan Redline and Rehm, {Heidi L.} and {National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium} and Rich, {Stephen S.} and Rotter, {Jerome I.} and {TOPMed Investigators} and Soliman, {Elsayed Z.} and Nona Sotoodehnia and Lunetta, {Kathryn L.} and Ellinor, {Patrick T.} and Lubitz, {Steven A.}",
note = "Funding Information: This work was supported by National Institutes of Health (NIH) grant 1R01HL139731 and American Heart Association (AHA) grant 18SFRN34250007 to Dr Lubitz. Dr Ellinor is funded by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), and a grant from the AHA Strategically Focused Research Networks (18SFRN34110082). Dr Sotoodehnia is funded by the NIH (R01HL141989). Dr Nauffal is funded by a training grant from the NIH (T32HL007604). Dr Weng is supported by NIH grant 1R01HL139731 and an AHA postdoctoral fellowship 18SFRN34110082. Dr Loos is funded by the NIH (R01DK110113; R01DK075787; R01DK107786; R01HL142302; R01HG010297; R01DK124097; R01HL151152). Molecular data for the TOPMed program were supported by the National Heart, Lung, and Blood Institute. Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity quality control, and general program coordination was provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the NIH; or the US Department of Health and Human Services. Funding Information: This work was supported by National Institutes of Health (NIH) grant 1R01HL139731 and American Heart Association (AHA) grant 18SFRN34250007 to Dr Lubitz. Dr Ellinor is funded by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), and a grant from the AHA Strategically Focused Research Networks (18SFRN34110082). Dr Sotoodehnia is funded by the NIH (R01HL141989). Dr Nauffal is funded by a training grant from the NIH (T32HL007604). Dr Weng is supported by NIH grant 1R01HL139731 and an AHA postdoctoral fellowship 18SFRN34110082. Dr Loos is funded by the NIH (R01DK110113; R01DK075787; R01DK107786; R01HL142302; R01HG010297; R01DK124097; R01HL151152). Molecular data for the TOPMed program were supported by the National Heart, Lung, and Blood Institute. Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity quality control, and general program coordination was provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the NIH; or the US Department of Health and Human Services. Publisher Copyright: {\textcopyright} 2022 American Heart Association, Inc.",
year = "2022",
month = may,
day = "17",
doi = "https://doi.org/10.1161/CIRCULATIONAHA.121.057261",
language = "English",
volume = "145",
pages = "1524--1533",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "20",
}