Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies (GWAS) followed by transethnic meta-analysis in 1,656 unrelated LQTS patients of European or Japanese ancestry and 9,890 controls to identify susceptibility single nucleotide polymorphisms (SNPs). We estimated the SNP heritability (h2SNP) of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 SNPs previously associated with QTc in the general population using a polygenic risk score (PRSQT). Results: Genome-wide association analysis identified three loci associated with LQTS at genome-wide statistical significance (P<5x10-8) near NOS1AP, KCNQ1 and KLF12, and one missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold (P<10-6). Heritability analyses showed that ~15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error [SE] 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT interval in the general population (rg=0.40, P=3.2x10-3). PRSQT was greater in LQTS cases compared to controls (P<10-13), and notably, among LQTS patients PRSQT was greater in genotype negative compared to genotype positive patients (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.