Monogenic and Polygenic Contributions to QTc Prolongation in the Population

Abstract Background Rare sequence variation in genes underlying the long QT syndrome (LQTS) and common polygenic variation influence QT interval duration. It is unclear how rare and common variation contribute to QT interval duration in the general population. Objectives Investigate monogenic and polygenic contributions to QT interval duration and the role of polygenic variation in modulating phenotypic expression of rare monogenic variation. Methods We performed a genome wide association study (GWAS) of QTc duration in 44,979 United Kingdom Biobank (UKBB) participants and created a polygenic risk score (PRS). The PRS was validated in 39,800 independent UKBB participants. Among 26,976 participants with whole genome sequencing and ECG data in the TransOmics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 LQTS genes. We examined QTc associations with the PRS and with LQTS rare variants in TOPMed. Results Twenty independent loci (4 novel) were identified by GWAS. The PRS comprising 565 common variants was significantly associated with QTc duration in TOPMed (p=1.1×10 −64 ). Carriers of LQTS rare variants had longer QTc intervals than non-carriers (ΔQTc=10.9 ms [7.4-14.4] for all LQTS genes; ΔQTc=26.5 ms [20.7-32.3] for KCNQ1, KCNH2 and SCN5A ). 16.7% of individuals with QTc>480 ms carried either a rare variant in a LQTS gene or had a PRS in the top decile (3.4% monogenic, 13.6% top decile of PRS). We observed a greater effect of rare variants on the QTc among individuals with a higher polygenic risk (lowest PRS tertile:ΔQTc carrier/non-carrier =4.8 ms [-1.2-10.7];highest PRS tertile:ΔQTc carrier/non-carrier =18.9 ms [12.8-25.1];p-interaction=0.001). Conclusions QTc duration is influenced by both rare variants in established LQTS genes and polygenic risk. The phenotypic expression of monogenic variation is modulated by polygenic variation. Nevertheless, over 80% of individuals with prolonged QTc do not carry a rare monogenic variant or polygenic risk equivalent. Condensed Abstract The QT interval duration is a well-established marker of sudden cardiac death. We examined the joint contribution of monogenic and polygenic variation to QT interval duration. Among individuals with pronounced QTc prolongation (>480 ms), 1 in 6 carried either a monogenic rare variant in a LQTS gene or had a PRS in the top decile, and over 80% had no identified genetic risk. Additionally, we found that polygenic risk modulates the phenotypic expression of putative pathogenic rare variants in LQTS genes, with a greater effect of rare variants on the QTc observed among individuals with a greater polygenic risk.