Novel genes for QTc interval. How much heritability is explained, and how much is left to find?

Yalda Jamshidi,Harold Snieder,Ilja M Nolte,Timothy D Spector

doi:10.1186/gm156

Abstract

The corrected QT (QTc) interval is a complex quantitative trait, believed to be influenced by several genetic and environmental factors. It is a strong prognostic indicator of cardiovascular mortality in patients with and without cardiac disease. More than 700 mutations have been described in 12 genes (LQT1-LQT12) involved in congenital long QT syndrome. However, the heritability (genetic contribution) of QTc interval in the general population cannot be adequately explained by these long QT syndrome genes. In order to further investigate the genetic architecture underlying QTc interval in the general population, genome-wide association studies, in which up to one million single nucleotide polymorphisms are assayed in thousands of individuals, are now being employed and have already led to the discovery of variants in seven novel loci and five loci that are known to cause congenital long or short QT syndrome. Here we show that a combined risk score using 11 of these loci explains about 10% of the heritability of QTc. Additional discovery of both common and rare variants will yield further etiological insight and accelerate clinical applications.

Highlights

The corrected QT (QTc) interval is a complex quantitative trait, believed to be in uenced by several genetic and environmental factors
In the TwinsUK study, a UK-based sample of mostly female twins of European ancestry, the proportions of additive genetic influences have been estimated as 55% for resting heart rate, 60% for uncorrected QT interval, and 50% for QTc [15]
Furthermore, variants in nitric oxide synthase 1 adaptor protein (NOS1AP) have since been associated with risk of sudden cardiac death (SCD) in two separate population-based cohorts [33,34] and in subjects with long QT syndrome (LQTS) [35]

Summary

Introduction

The corrected QT (QTc) interval is a complex quantitative trait, believed to be in uenced by several genetic and environmental factors. In the TwinsUK study, a UK-based sample of mostly female twins of European ancestry, the proportions of additive genetic influences have been estimated as 55% for resting heart rate, 60% for uncorrected QT interval, and 50% for QTc [15].

Results

Conclusion