Monogenic and Polygenic Contributions to QTc Prolongation in the Population

• Authors: Adolfo Correa, Emory University; Alvaro Alonso, Emory University; V Nauffal, Brigham & Womens Hosp; VN Morrill, Broad Institute; SJ Jurgens, Broad Institute; SH Choi, Broad Institute; AW Hall, Broad Institute; L-C Weng, Broad Institute; JL Halford, Broad Institute; C Austin-Tse, Massachusetts General Hospital; CM Haggerty, Geisinger; SL Harris, Massachusetts General Hospital; EK Wong, Massachusetts General Hospital; DE Arking, Johns Hopkins University; EJ Benjamin, Boston University; E Boerwinkle, Univ Texas Hlth Sci Ctr Houston; Y Min, University of Mississippi; BK Fornwalt, Geisinger; SR Heckbert, University of Washington; C Kooperberg, Fred Hutchinson Canc Ctr; HJ Lin, Harbor UCLA Med Ctr; R J.f. Loos, Icahn Sch Med Mt Sinai; KM Rice, University of Washington; N Gupta, Broad Inst MIT & Harvard; TW Blackwell, University of Michigan; BD Mitchell, Univ Maryland; AC Morrison, Univ Texas Hlth Sci Ctr Houston; BM Psaty, University of Washington; WS Post, Johns Hopkins University; S Redline, Brigham & Womens Hosp; HL Rehm, Massachusetts General Hospital; SS Rich, University of Virginia; JI Rotter, Harbor UCLA Med Ctr; EZ Soliman, Wake Forest Sch Med; N Sotoodehnia, University of Washington; KL Lunetta, Boston University; PT Ellinor, Broad Institute; SA Lubitz, Broad Institute
• Journal Title: CIRCULATION
• Volume: Volume 145, Number 20
• Publisher: LIPPINCOTT WILLIAMS & WILKINS | 2022-05-17, Pages 1524-1533
• Type of Work: Article
• Publisher DOI: http://doi.org/10.1161/CIRCULATIONAHA.121.057261
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cardiac & Cardiovascular Systems; Peripheral Vascular Disease; Cardiovascular System & Cardiology; long QT syndrome; monogenic; polygenic; QT interval; sudden cardiac death; INTERVAL; REGRESSION; HEART; SCORE; RISK

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.