|Title||Monogenic and Polygenic Contributions to QTc Prolongation in the Population.|
|Publication Type||Journal Article|
|Year of Publication||2022|
|Authors||Nauffal V, Morrill VN, Jurgens SJ, Choi SHoan, Hall AW, Weng L-C, Halford JL, Austin-Tse C, Haggerty CM, Harris SL, Wong EK, Alonso A, Arking DE, Benjamin EJ, Boerwinkle E, Min Y-I, Correa A, Fornwalt BK, Heckbert SR, Kooperberg C, Lin HJ, Loos RJF, Rice KM, Gupta N, Blackwell TW, Mitchell BD, Morrison AC, Psaty BM, Post WS, Redline S, Rehm HL, Rich SS, Rotter JI, Soliman EZ, Sotoodehnia N, Lunetta KL, Ellinor PT, Lubitz SA|
|Corporate Authors||National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine(TOPMed) Consortium, TOPMed Investigators|
|Date Published||2022 05 17|
|Keywords||Electrocardiography, Genome-Wide Association Study, Heterozygote, Humans, Long QT Syndrome, Multifactorial Inheritance, Whole Genome Sequencing|
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=1.4 ms [95% CI, 1.3 to 1.5]; =1.1×10). 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.
|PubMed Central ID||PMC9117504|
|Grant List||R01 HL120393 / HL / NHLBI NIH HHS / United States |
R01 DK075787 / DK / NIDDK NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HG010297 / HG / NHGRI NIH HHS / United States
K24 HL148521 / HL / NHLBI NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
R01 DK107786 / DK / NIDDK NIH HHS / United States
R01 HL157635 / HL / NHLBI NIH HHS / United States
R01 HL151152 / HL / NHLBI NIH HHS / United States
R01 DK110113 / DK / NIDDK NIH HHS / United States
R01 HL139731 / HL / NHLBI NIH HHS / United States
R01 HL128914 / HL / NHLBI NIH HHS / United States
R01 HL142302 / HL / NHLBI NIH HHS / United States
K24 HL105780 / HL / NHLBI NIH HHS / United States
R01 HL116747 / HL / NHLBI NIH HHS / United States
R01 HL141989 / HL / NHLBI NIH HHS / United States
R01 HL117626 / HL / NHLBI NIH HHS / United States