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 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.

Detection of distant familial relatedness in biobanks for identification of undiagnosed carriers of a Mendelian disease variant: application to Long QT syndrome

“…23 SNPs with low imputation quality (R 2 <0.3) were filtered. We applied the QTc PRS developed by Nauffal et al 24 using the score function in PLINK to calculate the PRS from the imputed genetic data.…”

HiChIPdb: a comprehensive database of HiChIP regulatory interactions

“…HAGS for all genes across different cell types using H3K27ac HiChIP interactions are calculated. Interestingly, two risk genes (NOS1AP and KCNH2) reported in ( 35–37 ) were ranked 1st and 12th in HAEC heart cell line, respectively. In contrast, NOS1AP ranked 3rd while KCNH2 ranked 11 729th in PAEC lung cell line, NOS1AP and KCNH2 all ranked 4179th in HARA lung cell line due to no overlapped HiChIP interactions.…”

“…A QT interval duration study ( 35 ) is taken as an illustrative example. HAGS for all genes across different cell types using H3K27ac HiChIP interactions are calculated.…”

Generation of human induced pluripotent stem cell (hiPSC) lines from patients with extreme high and low polygenic scores for QT interval

“…LQTS is an inherited cardiac arrhythmia with congenital and drug-induced presentations defined by a prolongation of the corrected QT interval on an electrocardiogram. 1, 2 The QT interval, corrected for heart rate (QTc), is 30-40% heritable, 3, 4 with narrow-sense, autosomal common single nucleotide polymorphisms (SNP) contribution estimated around 20%; 5, 6 the SNP contribution to LQTS is similar, around 15%. 7 Until recently, LQTS had been thought of as largely a monogenic disorder with approximately 75% of congenital LQTS probands carrying a variant in one of three cardiac ion channel genes: KCNQ1 , KCNH2 , and SCN5A .…”